Special Issue

www.gastrojournal.org Volume 150 Number 6 May 2016

Rome IV
Functional Gastrointestinal Disorders:
Disorders of Gut-Brain Interaction
 CONTENTS
TABLE OF
www.gastrojournal.org Vol. 150, No. 6 May 2016

Contents
ON THE COVER
Recognition of the intricate rela-
tionship in FGIDs between the
brain and the gut has emerged as
a prominent underlying theme
from the work of Rome IV
1305 The Intestinal Microenvironment and
WWW
Functional Gastrointestinal Disorders
G. Barbara, C. Feinle–Bisset, U. C. Ghoshal, J. Santos,
S. J. Vanner, N. Vergnolle, E. G. Zoetendal, and
E. M. Quigley
1319 Pharmacologic, Pharmacokinetic, and
WWW
Pharmacogenomic Aspects of Functional
Gastrointestinal Disorders
M. Camilleri, L. Buéno, V. Andresen, F. De Ponti,
M.–G. Choi, and A. Lembo

INTRODUCTION 1332 Age, Gender, and Women’s Health and

1257 Rome IV—Functional GI Disorders: WWW
the Patient
Disorders of Gut-Brain Interaction L. A. Houghton, M. Heitkemper, M. D. Crowell,
D. A. Drossman and W. L. Hasler A. Emmanuel, A. Halpert, J. A. McRoberts, and
B. Toner
SECTION I: FGIDs: BACKGROUND
INFORMATION 1344 Multicultural Aspects in Functional
WWW
1262 Functional Gastrointestinal Disorders: Gastrointestinal Disorders (FGIDs)
WWW
History, Pathophysiology, Clinical C. F. Francisconi, A. D. Sperber, X. Fang, S. Fukudo,
Features, and Rome IV M.–J. Gerson, J.–Y. Kang, and M. Schmulson
D. A. Drossman
1355 Biopsychosocial Aspects of Functional
WWW
Gastrointestinal Disorders: How Central
1280 Fundamentals of Neurogastroenterology: and Environmental Processes Contribute
Basic Science to the Development and Expression of
S. J. Vanner, B. Greenwood–Van Meerveld,
Functional Gastrointestinal Disorders
G. M. Mawe, T. Shea–Donohue, E. F. Verdu,
L. Van Oudenhove, R. L. Levy, M. D. Crowell,
J. Wood, and D. Grundy
D. A. Drossman, A. D. Halpert, L. Keefer,
J. M. Lackner, T. B. Murphy, and B. D. Naliboff
1292 Fundamentals of Neurogastroenterology:
WWW
Physiology/Motility – Sensation SECTION II: FGIDS: DIAGNOSTIC GROUPS
G. Boeckxstaens, M. Camilleri, D. Sifrim, 1368 Esophageal Disorders
L. A. Houghton, S. Elsenbruch, G. Lindberg, Q. Aziz, R. Fass, C. P. Gyawali, H. Miwa,
F. Azpiroz, and H. P. Parkman J. E. Pandolfino, and F. Zerbib

V Video CGH Related article in CGH

CME CME quiz E Editorial accompanies this article WWW Additional online content available COV Cover

Publisher: Gastroenterology (ISSN 0016-5085) is published monthly (semi monthly in May and June) in two indexed volumes by Elsevier Inc, 360 Park
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 1380 Gastroduodenal Disorders
V. Stanghellini, F. K. L. Chan, W. L. Hasler,
CONTENTS
TABLE OF
J. R. Malagelada, H. Suzuki, J. Tack, and N. J. Talley
1393 Bowel Disorders
WWW
B. E. Lacy, F. Mearin, L. Chang, W. D. Chey,
A. J. Lembo, M. Simren, and R. Spiller
1408 Centrally Mediated Disorders of
Gastrointestinal Pain
L. Keefer, D. A. Drossman, E. Guthrie, M. Simrén,
K. Tillisch, K. Olden, and P. J. Whorwell
1420 Gallbladder and Sphincter of Oddi
WWW
Disorders
P. B. Cotton, G. H. Elta, C. R. Carter, P. J. Pasricha,
and E. S. Corazziari
1430 Anorectal Disorders
WWW
S. S. C. Rao, A. E. Bharucha, G. Chiarioni,
R. Felt–Bersma, C. Knowles, A. Malcolm, and
A. Wald
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1443 Childhood Functional Gastrointestinal
WWW
Disorders: Neonate/Toddler
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1456 Childhood Functional Gastrointestinal
WWW
Disorders: Child/Adolescent
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1469 Design of Treatment Trials for Functional
WWW
Gastrointestinal Disorders
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1481 Development and Validation of the Rome
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INTRODUCTION
Rome IV—Functional GI Disorders: Disorders of
Gut-Brain Interaction
Douglas A. Drossman William L. Hasler
Special Issue Editors
E very May, Gastroenterology publishes a supplemen-
tary issue devoted to a topic of particular interest to
the science and practice of gastroenterology. Through a
collaboration between Gastroenterology and the Rome
Foundation, we are delighted to present to you the
launching of Rome IV with this series of reviews on func-
tional gastrointestinal disorders. Rome IV occurs fully 10
years after publication of Rome III in this same journal.1
Functional GI Disorders, better defined as Disorders of
Gut-Brain Interaction, though ever present in human society,
have only in the last several decades been studied scientif-
ically, categorized and treated based on well-designed
clinical investigative studies. Without a structural basis to
explain its clinical features, our understanding of these
disorders adhere to a biopsychosocial model2 which is best
represented for these disorders in the growing field of
neurogastroenterology.3 Symptoms are generated based on
a complex interaction among factors such as microbial
dysbiosis within the gut, altered mucosal immune function,
altered gut signaling (visceral hypersensitivity) and central
nervous system dysregulation of the modulation of gut
signaling and motor function. Since publication of Rome III
there has been a marked and exciting expansion in our
scientific understanding of these disorders, as detailed in
this issue, and this has led to improved treatments.
The process for developing the database of information
ultimately leading to this special issue is complex. Each article is
produced by a series of 5 to 8 expert international investigators
and clinicians who were selected for a multi-year project based
on their scientific record as well as diversity criteria to cover the
broad range of knowledge needed. We covered a wide range of
scientific disciplines; from basic science to physiology, mental
health, social science and clinical gastroenterology, and
geographic localization spanning six continents. The first stage
of this effort began over 6 years ago by selecting working teams
to acquire and publish reviews and recommendations of new
information in areas needed to help the future Rome IV com-
mittees produce their articles and chapters. Working team re-
ports included cross-cultural aspects of research, the concept of
severity of functional GI disorders (FGIDs), end points and
Gastroenterology 2016;150:1257–1261
outcomes in clinical trials, the microbiome, and food and diet.
4–12
Then in 2011 the work began to form the 17 committees
charged to review and synthesize information and produce
manuscripts with communication over conference call, email
and in 2014, a meeting in Rome. There were 5 iterations of the
manuscripts, most of which were reviewed and modified based
on feedback from the 6 members of the Rome IV editorial board
and over 50 outside reviewers. In the end, each committee
produced a chapter for the Rome IV book that includes a more
detailed online version with graphical illustrations, while the
reviews in this special issue of Gastroenterology provide
condensed articles that cover the essentials of each topic.
This special issue covers the full range of the field of
FGIDs. It starts with an overview by Douglas Drossman13
who provides an operational definition and classification
system for FGIDs (Table 1), discusses the process with
which the committees created the scientific content through
evidence-based review and when needed consensus (Delphi
method)14, the changes that occurred between Rome III and
Rome IV, the history, conceptual and scientific under-
standing of FGIDs as a group via the biopsychosocial model,
and it ends with a general approach to the care of patients
with disorders ranging from mild to severe.
The overview is followed by a series of reviews by the
committees that drill down on the bases for understanding
these disorders, and set the stage for the clinical information
to follow. Stephen J. Vanner, et al15 (Fundamentals of
Neurogastroenterolgy: Basic Science; pages 1280–1291)
provide basic information on the enteric nervous system,
sensory physiology underlying pain and neuroimmune
signaling, intestinal barrier function and the role of the
microbiome. Guy Boeckxstaens, et al16 (Fundamentals of
Neurogastroenterology: Physiology/Motility –Sensation; pages
1292–1304) carries this information further into the
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.03.035
1258 Drossman and Hasler Gastroenterology Vol. 150, No. 6

Table 1.Functional Gastrointestinal Disorders

A. Esophageal Disorders

A1. Functional chest pain A4. Globus

A2. Functional heartburn A5. Functional dysphagia
A3. Reflux hypersensitivity

B. Gastroduodenal Disorders

B1. Functional dyspepsia B3. Nausea and vomiting disorders

B1a. Postprandial distress syndrome (PDS)
B1b. Epigastric pain syndrome (EPS)
B2. Belching disorders
B2a. Excessive supragastric belching
B2b. Excessive gastric belching
B3a. Chronic nausea vomiting syndrome (CNVS)
B3b. Cyclic vomiting syndrome (CVS)
B3c. Cannabinoid hyperemesis syndrome (CHS)
B4. Rumination syndrome

C. Bowel Disorders

C1. Irritable bowel syndrome (IBS) C2. Functional constipation

IBS with predominant constipation (IBS-C) C3. Functional diarrhea
IBS with predominant diarrhea (IBS-D) C4. Functional abdominal bloating/distension
IBS with mixed bowel habits (IBS-M) C5. Unspecified functional bowel disorder
IBS unclassified (IBS-U) C6. Opioid-induced constipation

D. Centrally Mediated Disorders of Gastrointestinal Pain

D1. Centrally mediated abdominal pain syndrome (CAPS)

D2. Narcotic bowel syndrome (NBS)/
Opioid-induced GI hyperalgesia

E. Gallbladder and Sphincter of Oddi (SO) Disorders

E1. Biliary pain

E1a. Functional gallbladder disorder
E1b. Functional biliary SO disorder
E2. Functional pancreatic SO disorder

F. Anorectal Disorders

F1. Fecal incontinence F2c. Proctalgia fugax

F2. Functional anorectal pain F3. Functional defecation disorders
F2a. Levator ani syndrome F3a. Inadequate defecatory propulsion
F2b. Unspecified functional anorectal pain F3b. Dyssynergic defecation

G. Childhood Functional GI Disorders: Neonate/Toddler

G1. Infant regurgitation G5. Functional diarrhea

G2. Rumination syndrome G6. Infant dyschezia
G3. Cyclic vomiting syndrome (CVS) G7. Functional constipation
G4. Infant colic

H. Childhood Functional GI Disorders: Child/Adolescent

H1. Functional nausea and vomiting disorders H2a1. Postprandial distress syndrome
H1a. Cyclic vomiting syndrome (CVS) H2a2. Epigastric pain syndrome
H1b. Functional nausea and functional vomiting H2b. Irritable bowel syndrome (IBS)
H2c. Abdominal migraine
H1b1. Functional nausea H2d. Functional abdominal pain ‒ NOS
H1b2. Functional vomiting H3. Functional defecation disorders
H1c. Rumination syndrome H3a. Functional constipation
H1d. Aerophagia H3b. Nonretentive fecal incontinence
H2. Functional abdominal pain disorders
H2a. Functional dyspepsia
May 2016
physiological realm discussing the function of anatomic
regions of the digestive tract, the abnormalities in physiolog-
ical processes that lead to symptom generation, and
the pathophysiology of enhanced visceral perception, and
motor dysfunction. Giovanni Barbara, et al17 (The Intestinal
Microenvironment and Functional Gastrointestinal Disorders;
pages 1305–1318) discuss the role of luminal factors (diet,
the microbial environment, and the epithelial barrier) on
regulation and dysregulation of gut function leading to func-
tional GI symptoms. Michael Camilleri, et al18 (Pharmacolog-
ical, Pharmacokinetic and Pharmacogenomic Aspects of
Functional Gastrointestinal Disorders; pages 1319–1331) re-
view preclinical pharmacology, pharmacokinetics and toxi-
cology and the application of pharmacogenomics in
understanding medicinal treatments for patients with FGIDs.
Lesley A. Houghton, et al19 (Age, Gender, and Women’s Health
and the Patient; pages 1332–1343) cover the range of societal
and sociological factors relevant to the clinical expression of
FGIDs (gender, age, culture, and society) and in addition
discuss the patient’s perspective of illness. Carlos F. Francis-
coni and Ami D. Sperber, et al20 (Multicultural Aspects in
Functional Gastrointestinal Disorders (FGIDs); pages
1344–1354) offer a global perspective on the FGIDs to help us
understand how geographical diversities in culture, race, and
ethnicity impact the patient’s explanatory model of their
illness, symptom reporting and behavior, and treatments.
Lukas Van Oudenhove, et al21 (Biopsychosocial Aspects of
Functional Gastrointestinal Disorders: How Central and Envi-
ronmental Processes Contribute to the Development and
Expression of Functional Gastrointestinal Disorders; pages
1355–1367) offer a comprehensive review on the complex
interaction of environmental, psychological and biological
factors leading to the genesis, clinical expression and perpet-
uation of functional GI disorders. They also include a detailed
flowchart to help the clinician navigate the evaluation and
treatment of psychosocial aspects of the illness.
With this comprehensive introduction to the basic aspects
of the field, the subsequent articles cover epidemiology, path-
ophysiology, psychosocial and clinical features and diagnostic
evaluation (including the Rome IV diagnostic criteria) and
treatment recommendations for the 33 adult and 17 pediatric
FGIDs. As is traditional for the Rome Foundation, the disorders
are categorized by anatomic regions in adults and by age in
pediatric FGIDs Qasim Aziz, et al22 (Esophageal Disorders;
pages 1368–1379) introduce more information on the rela-
tionship of visceral hypersensitivity, central hypervigilance and
motor disturbance in explaining the variety of esophageal
conditions from globus to chest pain, to functional dysphagia
and describe the new entity of reflux hypersensitivity, where
there is physiologically normal acid reflux but symptoms
related to visceral hypersensitivity. Vincenzo Stanghellini,
et al23 (Gastroduodenal Disorders; pages 1380–1392) provide
additional information and evidence to support the subcate-
gorization of functional dyspepsia into overlapping post-
prandial distress and epigastric pain syndrome,24 introduce
the cannabinoid hyperemesis syndrome25 and discuss further
our understanding and management of chronic nausea vom-
iting syndrome and supragastric belching. Brian E. Lacy and
Fermín Mearin, et al26 (Bowel Disorders; pages 1393–1407)
Introduction 1259
provide revised definitions for the subcategorization of IBS
based on recent normative population data, and introduce
opioid induced constipation (OIC).27 Laurie Keefer, et al28
(Centrally Mediated Disorders of Gastrointestinal Pain; pages
1408–1419) update our knowledge of centrally mediated
abdominal pain syndrome (CAPS, formerly known as func-
tional abdominal pain syndrome - FAPS) and introduce the new
entity, Narcotic bowel syndrome (Opioid induced GI hyper-
algesia).29 Peter B. Cotton, et al30 (Gallbladder and Sphincter of
Oddi disorders; pages 1420–1429) provide compelling evidence
and make recommendations to reconsider the Milwaukee
classification of the sphincter of oddi (SOD) disorders. Now
removed from FGIDs is the previous SOD type I which is due to
structural stenosis and SOD type III which falls into the general
functional GI pain realm, since there is no benefit for sphinc-
terotomy.31 Finally, Satish Rao, et al32 (Anorectal Disorders;
pages 1430–1442) provide an in depth discussion of the rectal
pain and dyssynergic syndromes and the use of physiological
testing for diagnostic assessment and treatment application.33
There are two pediatric articles that cover the FGIDs in
neonate-toddlers and children. Marc A. Benninga and Samuel
Nurko, et al34 (Childhood Functional Gastrointestinal Disorders:
Neonate/Toddler; pages 1443–1455) offer more neurobiolog-
ical evidence to support our understanding of GI pain experi-
enced in infants and toddlers and provides the classification
system for 7 FGIDs. Finally, Jeffrey Hyams and Carlo Di
Lorenzo, et al35 (Childhood Functional Gastrointestinal Disor-
ders: Child/Adolescent; pages 1456–1468) present revised
diagnostic criteria to more closely approximate the adult dis-
orders including the postprandial distress syndrome (PDS)
and epigastric pain syndrome (EPS) subsets of functional
dyspepsia. Finally, E. Jan Irvine and Jan Tack, et al36 provide an
update on methodological issues relating to the design of
treatment trials in FGIDs (Design of Treatment Trials for
Functional Gastrointestinal Disorders; pages 1469–1480).
Functional GI disorders are separated from everyday GI
symptoms based on frequency data that determines ab-
normality. By determining abnormal frequencies one can
create a diagnostic questionnaire that can be used to iden-
tify patients with FGIDs for clinical research. To this end
Olafur Palsson, et al37 (Development and Validation of the
Rome IV Diagnostic Questionnaire for Adults; pages
1481–1491) report the results of the multicenter validation
of the Rome IV questionnaire based on a US population
sample of over 1000 subjects.
We do hope that this special issue has something for
everyone engaged in the research and care of patients with
functional GI Disorders. We have come a long way in the last
10 years and special thanks to the efforts of the 120 in-
vestigators involved in Rome IV, we can now provide this
information to you. Enjoy!
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May 2016 Introduction 1261

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Acknowledgments
We wish to extend our thanks and gratitude to the Rome IV authors for their
expertise, dedicated pursuit of the literature, and to synthesize their
outstanding efforts into a clear and concise set of knowledge and
recommendations. Special thanks also go to our Rome IV Managing Editor
(Ceciel Rooker) and her staff for coordinating this effort in a short period of
time, to Laura Flecha who served as the managing editor of this special
issue, and to Jerry Schoendorf for creating the cover of this issue.

Senior Editor of Rome IV: Douglas A. Drossman, MD, Professor Emeritus of Medicine and Psychiatry, University of
North Carolina, Center for Education and Practice of Biopsychosocial Care and Drossman Gastroenterology, Chapel Hill,
North Carolina. Associate Editors of Rome IV: Lin Chang, MD, Professor of Medicine, Oppenheimer Center for
Neurobiology of Stress, Division of Digestive Diseases, David Geffen School of Medicine at University of California, Los
Angeles, Los Angeles, California; William D. Chey, MD, Timothy T. Nostrant Professor of Gastroenterology & Nutrition
Sciences, Director, GI Nutrition & Behavioral Wellness Program, Co-Director, Michigan Bowel Control Program, Division
of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan; JOHN KELLOW, MD, Associate Pro-
fessor and Head of the Discipline of Medicine, Northern Clinical School, University of Sydney, Sydney, NSW, Australia;
JAN TACK, MD, PhD, Professor of Medicine, Head, Department of Clinical and Experimental Medicine, Head of Clinic,
Department of Gastroenterology, University Hospital KU Leuven, Translational Research Center for Gastrointestinal
Disorders (TARGID), Leuven, Belgium; WILLIAM E. WHITEHEAD, PhD, Professor of Medicine and OBGYN, Director,
UNC Center for Functional GI and Motility Disorders, Division of Gastroenterology and Hepatology, UNC School of
Medicine, Chapel Hill, North Carolina.

FUNCTIONAL GI OVERVIEW
SECTION I: FGIDs: BACKGROUND INFORMATION
Functional Gastrointestinal Disorders: History, Pathophysiology,
Clinical Features, and Rome IV
Douglas A. Drossman
Center for Education and Practice of Biopsychosocial Care, Drossman Gastroenterology; Center of Functional GI and Motility
Disorders, University of North Carolina; and Rome Foundation, Chapel Hill, North Carolina
Functional gastrointestinal disorders (FGIDs), the most
common diagnoses in gastroenterology, are recognized by
morphologic and physiological abnormalities that often
occur in combination including motility disturbance,
visceral hypersensitivity, altered mucosal and immune
function, altered gut microbiota, and altered central ner-
vous system processing. Research on these gut–brain
interaction disorders is based on using specific diagnostic
criteria. The Rome Foundation has played a pivotal role in
creating diagnostic criteria, thus operationalizing the
dissemination of new knowledge in the field of FGIDs.
Rome IV is a compendium of the knowledge accumulated
since Rome III was published 10 years ago. It improves
upon Rome III by: (1) updating the basic and clinical
literature; (2) offering new information on gut microenvi-
ronment, gut–brain interactions, pharmacogenomics, bio-
psychosocial, gender and cross-cultural understandings of
FGIDs; (3) reduces the use of imprecise and occasionally
stigmatizing terms when possible; (4) uses updated diag-
nostic algorithms; and (5) incorporates information on the
patient illness experience, and physiological subgroups or
biomarkers that might lead to more targeted treatment.
This introductory article sets the stage for the remaining
17 articles that follow and offers a historical overview of
the FGID field, differentiates FGIDs from motility and
structural disorders, discusses the changes from Rome III,
reviews the Rome committee process, provides a bio-
psychosocial pathophysiological conceptualization of
FGIDs, and offers an approach to patient care.
Keywords: Functional GI Disorders; Rome Foundation; Rome
Criteria; History; Biopsychosocial Model; Neuro-
gastroenterology; Patient Provider Relationship; Rome IV;
Classification; Diagnosis; Treatment Approach.
A
lthough descriptions of functional gastrointestinal
symptoms have been noted for centuries, the func-
tional gastrointestinal disorders (FGIDs) emerged only over
the past several decades. Our conceptual understanding of
their origins and clinical features evolved from a dualistic
and reductive perspective to a more comprehensive bio-
psychosocial model,1,2 and the scientific bases for symptom
generation changed from being disorders of motility to the
more inclusive disturbances of neurogastroenterology and
brain–gut interactions.3 This evolution has legitimized
FGIDs to patients and health care providers and nurtured
the science to better characterize these disorders and pro-
duce new drug discoveries and treatments.
Gastroenterology 2016;150:1262–1279
The Rome Foundation has its origins in the late 1980s, at a
time when there was little understanding of the pathophysi-
ology of FGIDs, no established classification system, and no
guidelines for standardized research of the patients. Subse-
quently, the Foundation has played a pivotal role in oper-
ationalizing the research and disseminating the knowledge
surrounding these disorders. Also, by gathering experts from
around the world who use more positive parameters for
diagnosis and perform fewer studies to exclude other disease,
the Rome Foundation identifies experts who are in the best
position to provide guidelines for diagnosis and treatment.
History of the Functional
Gastrointestinal Symptoms and
Disorders and the Role
of Psychosocial Factors
Throughout recorded history, the bowels and intestinal
activity have had meanings that go beyond their actual
function. They usually are considered private and shrouded
in mystery. Their dysfunction is linked to embarrassment,
emotion, and shame, and proper bowel functioning is
thought to be required for general well-being. We also
recognize bowel function and dysfunction as being related
closely to stress and emotion: “I find this hard to swallow,”
“I cannot stomach that any longer,” and “I feel butterflies in
my stomach.” Conversely, and likely as evolving for health
benefit, intestinal contents and feces are noxious to the
senses; the sight, smell, and touch of these can lead to
avoidant emotional responses, nausea, and vomiting. Thus,
brain and gut more than any other organ systems are
hardwired; each has a nervous system that is linked and
derived from the same anlage, the embryonic neural crest.
This brain–gut connection also explains why stress and
psychological factors are linked so closely to gut function and
dysfunction, gastrointestinal symptoms, illness, and disease.
Understanding how these factors relate to one another has
evolved from the changing mores, belief systems, or
explanatory (folk) models of the time. Explanatory models of
Abbreviations used in this paper: CNS, central nervous system; FGID,
functional gastrointestinal disorder; GI, gastrointestinal; IBS, irritable
bowel syndrome; SOD, sphincter of Oddi.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.032
May 2016
illness and disease arise and change in response to new
technologies and the need for clinical solutions; however,
new models require acceptance by society based on theories
that may have existed for centuries and across cultures.
Thus, the perception of symptoms may be considered
problems in one population, but ignored in another. This
perception can occur simply based on prevalence, in that
symptoms that are more common would be considered
normal. For example, among lower socioeconomic Mexican
Americans in the Southwest, diarrhea is common and is not
usually perceived as an illness requiring health care seeking,4
whereas in other sectors of society, diarrhea is considered an
illness to be investigated or treated.
Another important influencing factor for a symptom to
be perceived as an illness relates to its congruence with
dominant or major value orientations: that is, how it is
recognized by the society. In some nonliterate societies, the
description of hallucinations is accepted with interest,
possibly indicating specialness, having magical powers, or
connecting with spiritual beings. However, in Western so-
ciety, the admission of a hallucination would be considered
a potentially serious medical problem possibly caused by
psychosis or drug toxicity.5 Societal and cultural values also
can affect even the development or nondevelopment of
symptoms. Margaret Mead noted that nausea, which is a
common and acceptable part of pregnancy in the West, does
not occur among the Arapesh of New Guinea, because there
is denial that a child exists until shortly before birth.6 The
following section traces cultural influences on research and
knowledge of gastrointestinal symptoms and illness,
consequently leading to the identification and categorization
of functional gastrointestinal (GI) disorders.
Antiquity Through the Late 19th Century:
Holism and Cartesian Dualism
The possibility that passions or emotions could lead to
the development of medical disease was first proposed by
the Greek physician Claudius Galen and has been upheld by
medical writers into the 21st century. This supposition is
not surprising because we observe the effects of intense
emotion on autonomic arousal, leading to diarrhea, the
production of chest or abdominal pain, or even sudden
death.7 Even today, when the pathophysiology of a disease is
not clearly related to a particular, usually structural, etiol-
ogy, it is common to attribute the disease to a psychogenic
cause, and this has its roots in the historical tension
between holism and dualism.
The concept of holism, from the Greek holos, or whole,
was first proposed by Plato, Aristotle, and Hippocrates in
ancient Greece.8 Holism postulates that the mind and body
are integrated and inseparable, and the study of medical
disease must take into account the whole person rather than
merely the diseased part. This approach accepts medical
symptoms and behavioral disturbances as legitimate fea-
tures of the individual and traditionally has existed in
Eastern cultures.
However, by the 17th century in Western Europe,
the concept of holism was eclipsed by the influence of the
Functional GI and Rome IV 1263
FUNCTIONAL GI OVERVIEW
philosopher René Descartes, who in 1637 proposed the
separation of the thinking mind (res cogitans) from
the machine-like body (res extensa).2 Descartes’s concept of
mind–body separation rapidly took hold on the backdrop of
evolving sociocultural influences, at the time relating to the
separation of church and state. Mind–body dualism had
profound effects on how medical disease became concep-
tualized. Until that time, the body could not be dissected
because the spirit was thought to reside there. Medical
investigation based on the writings of Galen related to
observation of the body and its humors. When the mind–
body dualism construct lifted the mind and soul from the
realm of the body, human dissection then would be
permitted, and this led to emerging knowledge of disease
pathology. Over the next few centuries, the morphologic
study of disease through pathology, then histopathology,
radiology, and nuclear imaging, led to many new diagnoses
and treatments for diseases.
However, with a morphologic construct, there was no
understanding of symptoms or behaviors in the absence of
pathology. In the 17th century, patients showing these fea-
tures were believed to be under demonic possession and, in
later centuries, were considered insane. They were rele-
gated to asylums and were excluded from scientific study.
Consequently, another result of Cartesian mind–body
dualism is that the study of behavioral abnormalities and
mental illness was marginalized; the mind as the seat of the
soul was not to be tampered with. Thus, it evolved in
Western society that behavioral abnormalities were not
available for study, and, in addition, mental illness or
physical symptoms in the absence of pathology were
considered second class: less legitimate than structural
disease and even stigmatized.9
In the United States, Benjamin Rush, a prominent
physician in the 18th century, sought to integrate psycho-
logical and medical knowledge in the diagnosis and treat-
ment of medical illness. However, after his death in 1813,
psychiatry was separated from medical practice and mental
illness remained unstudied in the asylums. Later in the
1800s, Louis Pasteur’s discovery of microorganisms and
Robert Koch’s development of the germ theory of disease
further moved medicine in the direction of biologic reduc-
tionism, in which diagnosis was related to specific etiologic
agents. However, in recent years (eg, with tuberculosis and
acquired immune deficiency syndrome) we now know that
infectious agents are conditional factors in disease etiology;
host resistance and the social environment also contribute
to the clinical expression of the disease.
Because of limited technology, explanatory models of
illness and disease through the 19th century developed from
natural observations, which then were interpreted in terms of
etiology. However, an important advance occurred in 1833
with William Beaumont’s studies of Alexis St. Martin, a voya-
geur who developed a traumatic gastric fistula from a gunshot
injury, thus allowing direct observation of gastric mucosal
color and secretion. Beaumont’s studies systematically re-
ported the association of emotions such as anger and fear with
gastric mucosal morphology and function, and was an early
psychophysiological investigation of the human GI tract.
 1264 Douglas A. Drossman
FUNCTIONAL GI OVERVIEW
Early to Mid-20th Century: Observations of
Gut and Brain Behavior (1900–1959)
Beaumont set the stage for further investigations of the
effects of emotion on gastrointestinal function. William
Cannon noted a cessation in bowel activity among cats
reacting to a growling dog. Ivan Pavlov studied surgically
produced fistulas in dogs, which led to an understanding of
the role of the vagus nerve in mediating the cephalic phase
of acid secretion. Later, studies of Tom and Monica, 2 people
with gastric fistulas studied by Steward Wolf and George
Engel, respectively, showed that different emotional con-
figurations are associated with distinct changes in gastric
function.2 Gastric hyperemia and increased motility and
secretion occurred with feelings of anger, intense pleasure,
or aggressive behavior patterns related to the subject’s
active engagement with the environment. Conversely,
mucosal pallor and decreased secretion and motor activity
occurred with fear or depression: states of withdrawal
(giving-up behavior) or disengagement from others. A series
of experiments by Tom Almy indicated that physical and
psychological stimuli led to increased sigmoid motility and
vascular engorgement in healthy subjects and in subjects
with irritable colon (irritable bowel syndrome [IBS]).2
Almy’s later studies with healthy subjects and IBS patients
using an emotive (stress) interview attempted to correlate
mood with motility. In healthy medical students, he noted
increased rectal contractility when falsely diagnosed with
cancer. He also reported increased motility concurrent with
states of aggression (particularly in those individuals with
constipation) and decreased motility associated with feel-
ings of helplessness (and diarrhea). Another important
observation during this period was by Alvarez,10 who
observed “nongaseous abdominal bloating” in women. He
noted that “the pronounced bloating is due not to any excess
gas in the digestive tract, but apparently to a contraction of
the muscles lining the back and the upper end of the
abdominal cavity..In addition there may be a relaxation of
the muscles of the anterior abdominal wall.”10 He also re-
ported that the swelling often occurred after a meal. These
findings preceded by decades the recent work using more
sophisticated assessment methods.11
These data provided scientific evidence that the gut is
physiologically responsive to emotion and environmental
(stressful) stimuli. However, the studies were limited
because the measurement techniques were rudimentary,
and unidirectional, and did not evaluate the reciprocal ef-
fects of changes in gut physiology on mental functioning.
Finally, the relation of these observations to actual gastro-
intestinal symptoms were rudimentary at best.
The Biomedical Era: Looking for Disease
Specificity: 1960–1979
With the impressive growth of medical technology after
1960, social and political forces moved scientists into an era
of biomedical research. The search for the etiology and
pathophysiology of disease took precedence over direct
observations of the patient. Psychosocial processes were
considered important but only as secondary phenomena,
Gastroenterology Vol. 150, No. 6
because “if the cause of a disease could be found and
treated, then certainly any psychosocial difficulties would
disappear.”9
Physiological investigation of the GI tract. More
scientific investigation of gut functioning began in the 1960s
with studies of secretory activity using gastrointestinal
tubes. By the early 1970s, technological improvements led
to new modalities to assess electromechanical function. GI
physiologists were developing and testing systems to assess
motor and electrical activity of the gut in most areas of the
GI tract and were able to delineate mechanisms for many of
the esophageal motor disorders (eg, achalasia, scleroderma)
and to determine the somewhat paradoxic mechanisms of
constipation (increased sigmoid pressures) and diarrhea
(decreased pressures).
A logical extension of this research effort was to explore
the pathophysiology of the functional GI disorders. These
disorders, represented primarily by IBS having both pain and
altered gut function, heretofore were unexplained, but the
symptoms were presumed to arise from intestinal dysmotility.
The studies showed that patients with IBS, when compared
with normal subjects, had an enhanced motor response to
various environmental stimuli such as psychological stress,
peptide hormone sand fatty meals, and increased motility was
associated, to a degree, with symptoms of pain.
Later in the 1970s, some investigators sought to find
biomarkers and one group reported a unique myoelectric
pattern, a basic electrical rhythm of 3 cycles/min in patients
with IBS, occurring at a frequency up to 40% of the time
that was thought to be specific for IBS. However, later work
did not reproduce these findings. Investigators also noted
that the correlation between altered motility and painful
symptoms was poor: experimentally induced motility in IBS
did not usually produce pain, and many patients with IBS
did not have abnormal motility when having pain.
Psychosocial and behavioral investigation of
functional GI disorders. For the most part, psychosocial
investigation during this period remained out of the main-
stream of biomedical research, and was limited to mental
health scientists and a few medical investigators whose
research was undertaken separately from physiological in-
vestigations. Psychological reports showed that patients
with IBS had a very high frequency of psychological distress
or disturbance. Some investigators then argued that IBS was
a psychiatric disorder akin to somatization. The ongoing
argument as to whether IBS was medical or psychiatric later
was clarified by epidemiologic and biopsychosocial studies
in the 1980s that evaluated gastrointestinal function and
symptoms along with psychological state simultaneously. It
was found that psychosocial distress enabled symptom
severity and illness behaviors, which led to health care
seeking. Thus, the prevalence of psychological disturbance
was greater in IBS patients rather than in those surveyed
who have IBS but are not patients.12,13
Given the variety of these somewhat dissimilar obser-
vations, it was difficult at the time to identify a unifying
concept for IBS. In subsequent years, Christensen14 even
questioned the existence of IBS as a distinct entity. Never-
theless his belief that “heterogeneity of pathological
May 2016
processes must exist in such a diagnostic category”15
opened the door to research that later identified meaning-
ful biological subsets of IBS or, alternatively, disorders
considered distinctly separate from IBS. It also led in-
vestigators to consider alternative conceptualizations for
the symptoms of IBS relating to a more integrative multi-
component model as discussed later.
Introduction of the Biopsychosocial Model and
Neurogastroenterology: 1980 to the Present
The 1980s began a period of major changes in the psy-
chosocial understanding of GI disease and illness. In the
1960s and 1970s, it was believed that technologic advances
would lead to finding a biological cause (and cure) of FGIDs.
However, by the end of this period, clinicians and scientists
were confronted with the inefficiencies of this model: (1)
diagnostic imaging and physiologic assessment did not fully
explain the symptoms of many patients presenting with
functional complaints, and, conversely, active disease was
not necessarily associated with symptoms; (2) the promi-
nence of psychosocial disturbances and illness behaviors
with chronic illness, particularly among those seen at
referral centers, was not seen among patients with the same
diagnoses in the community, and did not correlate well with
the observed physiological disturbance or disease pathol-
ogy; (3) social and political forces along with newer psy-
chosocial assessment methods such as health-related
quality of life led to interests away from disease and toward
the patients’ illness experiences; and (4) advances in
brain–gut physiology yielded findings that could not fit with
a dualistic biomedical concept.
Biopsychosocial (systems) model. The pivotal event
that brought together a unified understanding of health and
disease began in 1977 with the publications by George
Engel.1,16 These articles influenced many investigators and
Figure 1. A biopsycho-
social conceptualization of
the pathogenesis, clinical
experience, and effects of
functional GI disorders.
There is a relationship be-
tween early life factors that
can influence the psycho-
social milieu of the individ-
ual, their physiological
functioning, as well as their
mutual interaction (brain–
gut axis). These factors
influence the clinical pre-
sentation of the disorder
and the clinical outcome.
Modified from Rome III.42
Functional GI and Rome IV 1265
FUNCTIONAL GI OVERVIEW
clinicians away from seeking specific underlying biological
etiologies to a more integrated, biopsychosocial model of
illness and disease.1,2,16 Engel, an internist and psychoana-
lyst, offered a modern exposition of holistic (now called
systems) theory by proposing that illness is the product of
biological, psychological, and social subsystems interacting
at multiple levels; it is the combination of these interacting
subsystems that determines the illness (Figure 1).
The biopsychosocial or systems model offers certain
advantages: (1) an understanding of human illness that
reconciles the discrepancies between biomedical thought
and clinical observation; (2) a clinical framework for the
physician to integrate the broad range of biomedical and
psychosocial factors that explain the illness experience; and
(3) a unifying structure for multidisciplinary research
methodology and the inclusion of biopsychosocial assess-
ment in GI illness that emerged over the next few decades.
See the article “Biopsychosocial Aspects of FGIDs” for more
detail.
The research that evolved led to the following: (1) the
development of new questionnaires to assess broader psy-
chosocial domains such as health-related quality of life and
coping; (2) a shift in research articles focusing away from
solely physiological measurement to those that integrate
physiology with patient perceptions and behaviors; (3) in-
clusion of both psychosocial and physiological assessments
in treatment protocols; (4) evaluation of softer outcomes
(eg, health care use, daily function, symptom severity, gen-
eral well-being) than death or disease complications; and
(5) use of multivariate statistical methods to simultaneously
control for interacting biopsychosocial variables.
Neurogastroenterology. By the end of the 1990s,
newer clinical and translational techniques relating to gut
afferent signaling, neural stimulation and recording, pain
perception assessment, evaluation of the association be-
tween neural cells and immune functioning, and brain
 1266 Douglas A. Drossman
FUNCTIONAL GI OVERVIEW
imaging improved our understanding of the interactions
between the brain and gut, and this led to the concept of the
brain–gut axis. The term neurogastroenterology was
mentioned in Rome II in 1999 with the basic science and
physiology chapters17,18 as a means to reflect this emerging
field of research. In effect, neurogastroenterology reflects
the structural and physiological components of the bio-
psychosocial model, and the latter represents the clinical
research and application. The use of neurogastroenterology
as a research domain provides a level of legitimacy to
gut–brain research as never seen before.3 Over the past 2
decades, the term has been used by numerous research
societies, as well as journals and book publications.
Gastrointestinal Symptoms, Syndromes,
and Diagnostic Criteria
The preceding history sets the stage for understanding
the place of functional gastrointestinal symptoms and syn-
dromes within gastroenterology, and it provides the basis
for the development of diagnostic criteria and the work of
the Rome Foundation.
Concepts of Gastrointestinal Disease, Motility, and
Functional GI Disorders. Table 1 identifies the major
clinical domains seen in gastroenterology.
1. The organic (structural) disorders (eg, esophagitis,
inflammatory bowel disease) are classified in terms of
organ morphology and the criterion for a disease is
pathology at a macro- or microlevel.
2. A motility disorder (eg, gastroparesis, intestinal
pseudo-obstruction), is classified in terms of organ
function and specifically altered motility. Although
dysmotility relates to abnormal visceral muscle ac-
tivity (ie, slow bowel transit, delayed gastric
emptying), a motility disorder is presumed to be
persistent or recurrent dysmotility recognized as a
clinical entity, and variably associated with symp-
toms. We also recognize that dysmotility may come
and go with repeated physiological testing.
3. A functional GI disorder (eg, IBS, functional dyspepsia)
relates to the patient’s interpretation and reporting of
Table 1.Major Clinical Domains in Gastroenterology
Organic
GI disorder
Primary domain Organ morphology
Criterion Pathology (disease)
Measurement Histology
Pathology
Endoscopy
Radiology
Examples Esophagitis
Peptic ulcer
IBD
Colon cancer
IBD, inflammatory bowel disease.
Gastroenterology Vol. 150, No. 6
an illness experience, and it is classified primarily in
terms of symptoms. A symptom is a noticeable expe-
riential change in the body or its parts that is reported
by the patient as being different from normal and may
or may not be interpreted as meaningful. However, a
syndrome relates to the association of several clini-
cally recognizable symptoms or signs that occur
together to define a clinical entity. A functional GI
disorder is a syndrome based on symptoms that
cluster together and are diagnosed by Rome criteria.
Notably, there is overlap across these 3 domains. An
organic disorder such as ulcerative colitis, identified by gut
pathology, may be associated with a motility disturbance
and usually is associated with symptoms of pain and diar-
rhea, but neither the motility disturbance nor the symptoms
are necessary for the diagnosis. A motility disorder such as
gastroparesis is identified by a persistent motility distur-
bance (eg, delayed gastric emptying). It may occur from
altered gut neuronal morphology and often has symptoms
of nausea and vomiting, but patients do not necessarily have
symptoms that correlate with the disturbed motility.19
However, it is the motility finding that characterizes the
disorder. Similarly, a functional GI disorder such as IBS or
functional dyspepsia may have pathologic findings of in-
flammatory cells in the lamina propria of the gut or eosin-
ophils in the duodenum, respectively, as well as disturbed
motility, but histopathology is not necessary for defining a
functional GI disorder. The caveat is that although FGID
criteria primarily are symptom-based, there are exceptions,
such as with the anorectal disorders, in which physiological
findings are part of the criteria. Furthermore, identification
of biological substrates may help in terms of subclassifi-
cation and treatment.
History of Rome Criteria for Diagnosis of
FGIDs and of the Rome Foundation
Pre-Rome: working team publications leading to
classification of FGIDs. This history began in Rome 30
years ago when Aldo Torsoli, Professor of Gastroenterology at
the University of Rome, was engaged in developing Working
Teams for the International Gastroenterology meetings (held
Motility Functional
disorder GI disorder
Organ function Illness experience
Altered motility Symptoms
Motility Motility
Visceral sensitivity Visceral sensitivity
Symptom criteria (Rome)
Psychosocial
Diffuse esophageal spasm Esophageal chest pain
Gastroparesis Functional dyspepsia
Pseudo-obstruction IBS
Colonic inertia Functional constipation
May 2016
in Rome in 1988). By using the Delphi approach, he selected
experts from around the world to work through consensus to
answer difficult clinical questions that could not be answered
through scientific evidence at the time, and present their re-
sults at this meeting.20,21 Torsoli collaborated with W. Grant
Thompson, MD, from Ottawa, a respected gastroenterologist
studying in the nascent field of FGIDs to form a working team
to develop consensus criteria for the diagnosis of IBS.
Thompson et al22 were some of the few experts working on
epidemiologic, clinical, and psychosocial investigation of IBS
at the time. They then published the first diagnostic criteria
for IBS based on consensus.22
This IBS working team was generative of the later Rome
process, by generating diagnostic criteria by consensus
among experts globally. However, IBS was not the only
FGID. By the 1980s publications on other nonstructural,
symptom-based disorders were being studied: noncardiac
functional chest pain23; nonulcer dyspepsia24; post-
cholecystectomy pain25; bowel disorders related to bloating,
diarrhea, and constipation; and anorectal disorders
including fecal incontinence, difficult defecation, and rectal
pain.26,27 However, there was no overarching operational
definition or classification for them.
In 1989, Torsoli and Corazziari, a collaborator from the
University of Rome GI group, approached me to continue the
working team process. I proposed that we develop a clas-
sification system for all the FGIDs and that we create diag-
nostic criteria for them. With the support of the journal
Gastroenterology International we began the process of
creating a classification system with diagnostic criteria for
all of the FGIDs.
The first committee consisted of experts in the various
anatomic regions under consideration. They established 5
anatomic regions (esophagus, gastroduodenal, bowel,
biliary, and anorectal), and within each region identified
several disorders and for each categorized their clinical
features, diagnosis (using symptom-based criteria), and
treatment. They worked by e-mail over 2 years and met
once in the Gastroenterology International office in Rome to
consolidate the work and subsequently published it.28
Rome I: 1994. Over the next few years a series of
publications relating to each anatomic domain was elabo-
rated upon and published in Gastroenterology International.
Each member of the original committee created his own
working team of experts and elaborated on the epidemi-
ology, pathophysiology, psychosocial features, diagnostic
criteria, and treatment aspects of the diagnoses.29–33 Also,
given the poor standardization of clinical trials in the
functional GI disorders,34 we also created a working team to
provide guidelines for proper trials.35 Finally, with new
criteria for 21 functional GI disorders, we created a ques-
tionnaire to use in epidemiologic surveys and clinical
studies. This questionnaire was applied in the US House-
holder study, the first national epidemiologic database on
the prevalence, demographic factors, and health care–
seeking features of people with FGIDs.36
In 1994, the articles were compiled into a book: “The
Functional Gastrointestinal Disorders: Diagnosis, Patho-
physiology, and Treatment”37 and in retrospect is
Functional GI and Rome IV 1267
FUNCTIONAL GI OVERVIEW
considered Rome I. Although the book sales were quite
limited, with fewer than 1000 copies sold, the 5 editors and
the 32 other internationally recognized committee members
creating these chapters began publishing studies using these
criteria. From this initiative, the concept of the FGID clas-
sification system and diagnostic criteria began to grow in
use.
Rome II: 1999–2000. By the mid-1990s, 2 factors
helped to promote the FGID classification and use of diag-
nostic criteria: the US Food and Drug Administration rec-
ommended the IBS criteria be used to select patients for
pharmaceutical studies, and the pharmaceutical industry
took interest in supporting the efforts of the Rome Foun-
dation. The Rome Foundation was incorporated in 1996,
and with the support of 8 pharmaceutical sponsors an in-
dustry council was created as a forum for the exchange of
ideas between the Rome Foundation and the sponsors.
However, to avoid any perception of influence, this council
was separate from the work of the Rome Board of Directors
or committees. Then, by the late 1990s, as a result of the
increased growth of publications in FGIDs, the Foundation
recruited 52 authors representing 13 countries to update
the literature and produce the Rome II book by 2000.38 In
addition, to gain Medline access, the committees produced
condensed versions of the chapters that were published in a
special issue of Gut in 1999.39
Rome III: 2006. After publication of Rome II, the
number of studies published using the Rome criteria in
clinical trials grew 8-fold over the next 12–14 years. The
Industry Advisory Council also expanded to include 12
pharmaceutical companies and at various times represen-
tatives from the Food and Drug Administration, Japanese
Regulatory Authority, the European Medicines Agency, and
the International Foundation of Functional GI Disorders. By
2002, the process began to produce Rome III, with the
addition of several new chapters and the recruitment of 87
authors representing 18 countries. Rome III differed from
Rome I and Rome II by the use of more evidence-based
rather than consensus-based data because research
studies were being published using the Rome criteria, which
allowed for more precise patient selection and with data
more representative of these disorders. The book was
published in May 2006,40 just after the publication of a
special Rome III issue of Gastroenterology, which contained
condensed versions of the book chapters.41
Rome IV: 2016. After 2006, the Rome Foundation
became increasingly recognized as an authoritative body
developing diagnostic criteria for research and also for
providing education about the FGIDs to clinicians, trainees,
and investigators worldwide. However, to meet their goal to
advance the field of FGIDs, the Foundation had to address
the following limitations: (1) the term functional GI disor-
ders, although entrenched in the literature, was imprecise
and to some degree stigmatizing; (2) the diagnostic criteria
were cumbersome to use in clinical practice; (3) the criteria
did not specify the investigative pathway to use before
applying the criteria; (4) the criteria oversimplified the
full dimension of the patients’ illness experience and were
not precise enough to identify meaningful physiological
 1268 Douglas A. Drossman
FUNCTIONAL GI OVERVIEW
subgroups or biomarkers that might lead to more targeted
treatment; and (5) the Foundation traditionally approached
knowledge acquisition from a Western base of knowledge,
and this was a limitation to other countries and cultures.
Thus, the Rome Foundation made efforts to address these
limitations with Rome IV, as discussed later and further
delineated in the articles that follow. Although perhaps not
all of these limitations are addressed fully, Rome IV pro-
vides a foundation for future changes that will be made in
our understanding of these disorders.
Definition
The definition of FGIDs has varied based on societal
perspectives of illness and disease over time, on the scien-
tific evidence, and on the clinician’s training and personal
biases. Even today, FGIDs are considered by many as less
legitimate than pathologically based diagnoses, and patients
with FGIDs may be stigmatized for having symptoms that
they consider to be very real. This originated as discussed
earlier from the influence of dualistic principles that sepa-
rate organic disorders, which are attributed by some to be
legitimate, and functional disorders, which often are
considered psychiatric or undefined.9 However, over time
and with each book publication, the definition has changed
from the absence of organic disease to a stress-related or
psychiatric disorder to a motility disorder, and with Rome
III, to a disorder of GI functioning.42
However, there is still a need for a meaningful working
definition to approach these disorders scientifically and
without bias. To achieve that for Rome IV, the Foundation
again relied on the Delphi method20,21 to create a definition
for FGIDs that is positive (rather than by the exclusion of
other disease), reflective of current scientific knowledge,
and nonstigmatizing. The new definition created by the
Board of Directors was shared among the chairs and
co-chairs of the Rome IV committees to obtain feedback for
modification and, ultimately, approval. The agreed-upon
definition is as follows: functional GI disorders are disor-
ders of gut–brain interaction. It is a group of disorders
classified by GI symptoms related to any combination of the
following: motility disturbance, visceral hypersensitivity,
altered mucosal and immune function, altered gut micro-
biota, and altered central nervous system (CNS) processing.
This definition is most consistent with our evolving un-
derstanding of multiple pathophysiological processes that in
part or together determine the symptom features that
characterize the Rome classification of disorders. We believe
it to be readily understood and acceptable to clinicians,
academicians, regulatory agencies, and the pharmaceutical
industry, as well as to patients.
Although the FGIDs share these physiological features in
common, their relative contribution may differ by bodily
location, the duration of symptoms, and across individuals
or within the same individual over time. For example, fecal
incontinence is primarily a disorder of motor function, while
centrally mediated abdominal pain syndrome (formerly
functional abdominal pain syndrome) primarily is amplified
central perception of normal visceral input. However, IBS
Gastroenterology Vol. 150, No. 6
appears to be more complex and may result from a com-
bination of factors relating to motility, visceral hypersensi-
tivity, mucosal immune dysregulation, alterations of
bacterial flora, and CNS–enteric nervous system dysregula-
tion. In addition, an individual who develops postinfection
IBS may have more influence from mucosal immune
dysfunction with altered microflora than another individual
with the same diagnosis with a lifelong history of chronic
symptoms and psychiatric comorbidities relating to altered
CNS regulation of GI function. Thus, the classification system
is an important component for categorizing these disorders,
but effective management requires a biopsychosocial
approach that addresses the variability and complexity of
patients who have these disorders.
Rome IV Classification and
Criteria for FGIDs
The Rome Foundation classification of FGIDs is based
primarily on symptoms rather than physiological criteria.28
This has been favored because of its utility in clinical care,
limited evidence that physiological disturbance (ie, motility)
fully explained patient symptoms, and the fact that symp-
toms are what bring patients to health care providers.
However, physiological criteria still are permitted, as for the
anorectal disorders, if they increase diagnostic precision. We
believe that in the future biomarkers will be included in the
criteria if they can enhance their positive predictive value.
The classification of the disorders into anatomic regions
(ie, esophageal, gastroduodenal, bowel, biliary, and ano-
rectal) presumes unifying features underlying diagnosis and
management that relate to these organ locations. Thus,
functional heartburn relates to the esophagus, fecal incon-
tinence to the anorectum, and sphincter of Oddi (SOD)
disorder to the biliary system. However, symptom localiza-
tion is not enough, particularly painful FGIDs (eg, irritable
bowel syndrome, functional dyspepsia, and centrally medi-
ated abdominal pain syndrome) are not as easy to localize
and are influenced more by overarching effects resulting
from CNS–enteric nervous system dysregulation of symp-
tom control pathways.
Table 2 lists the 33 adult and 20 pediatric FGIDs for
Rome IV. In this issue, the articles covering the respective
anatomic domains listed will discuss the pathophysiology,
diagnostic features (including Rome IV criteria), and treat-
ment aspects.
The Rome Committee Process
In addition to this special issue of Gastroenterology,
there are other educational materials created to address
the limitations stated earlier and that are part of Rome IV:
(1) a 2-volume textbook that more comprehensively covers
the information provided in this issue; (2) a book on
diagnostic clinical algorithms based on common symptom
presentations; (3) the Multidimensional Clinical Profile, a
case-based method to teach patient care by integrating the
multiple (diagnosis, psychosocial, physiological, severity)
components contributing to the illness; (4) a book of the
May 2016 Functional GI and Rome IV 1269

FUNCTIONAL GI OVERVIEW
Table 2.Functional Gastrointestinal Disorders: Disorders of Gut–Brain Interaction

A. Esophageal Disorders

A1. Functional chest pain A4. Globus

A2. Functional heartburn A5. Functional dysphagia
A3. Reflux hypersensitivity

B. Gastroduodenal Disorders

B1. Functional dyspepsia B3. Nausea and vomiting disorders

B1a. Postprandial distress syndrome (PDS)
B1b. Epigastric pain syndrome (EPS)
B2. Belching disorders
B2a. Excessive supragastric belching
B2b. Excessive gastric belching
B3a. Chronic nausea vomiting syndrome (CNVS)
B3b. Cyclic vomiting syndrome (CVS)
B3c. Cannabinoid hyperemesis syndrome (CHS)
B4. Rumination syndrome

C. Bowel Disorders

C1. Irritable bowel syndrome (IBS) C2. Functional constipation

IBS with predominant constipation (IBS-C) C3. Functional diarrhea
IBS with predominant diarrhea (IBS-D) C4. Functional abdominal bloating/distension
IBS with mixed bowel habits (IBS-M) C5. Unspecified functional bowel disorder
IBS unclassified (IBS-U) C6. Opioid-induced constipation

D. Centrally Mediated Disorders of Gastrointestinal Pain

D1. Centrally mediated abdominal pain syndrome (CAPS)

D2. Narcotic bowel syndrome (NBS)/
Opioid-induced GI hyperalgesia

E. Gallbladder and Sphincter of Oddi (SO) Disorders

E1. Biliary pain

E1a. Functional gallbladder disorder
E1b. Functional biliary SO disorder
E2. Functional pancreatic SO disorder

F. Anorectal Disorders

F1. Fecal incontinence F2c. Proctalgia fugax

F2. Functional anorectal pain F3. Functional defecation disorders
F2a. Levator ani syndrome F3a. Inadequate defecatory propulsion
F2b. Unspecified functional anorectal pain F3b. Dyssynergic defecation

G. Childhood Functional GI Disorders: Neonate/Toddler

G1. Infant regurgitation G5. Functional diarrhea

G2. Rumination syndrome G6. Infant dyschezia
G3. Cyclic vomiting syndrome (CVS) G7. Functional constipation
G4. Infant colic

H. Childhood Functional GI Disorders: Child/Adolescent

H1. Functional nausea and vomiting disorders H2a1. Postprandial distress syndrome
H1a. Cyclic vomiting syndrome (CVS) H2a2. Epigastric pain syndrome
H1b. Functional nausea and functional vomiting H2b. Irritable bowel syndrome (IBS)
H2c. Abdominal migraine
H1b1. Functional nausea H2d. Functional abdominal pain ‒ NOS
H1b2. Functional vomiting H3. Functional defecation disorders
H1c. Rumination syndrome H3a. Functional constipation
H1d. Aerophagia H3b. Nonretentive fecal incontinence
H2. Functional abdominal pain disorders
H2a. Functional dyspepsia
 1270 Douglas A. Drossman
FUNCTIONAL GI OVERVIEW
Rome IV criteria and validated questionnaires to make a
diagnosis in adults and children for research and clinical
care; (5) a primary care book; (6) a pediatric book; (7)
more than 800 graphic images to be used as slides and in
the online book; and (8) translations of the criteria to be
used for a global epidemiology survey to understand cross-
cultural differences in symptom experience and
presentation.
To accomplish this, Rome IV used a rigorous process of
prospective and retrospective data gathering, data syn-
thesis, data presentation, group decision making, and
extensive peer-review as indicated by the following
process.
1. In 2008 the Rome Foundation Board of Directors
identified key areas to acquire preliminary knowledge
for the Rome IV chapter committees to use. Commit-
tees were created to evaluate, compile, and publish
reviews in these areas of interest: brain imaging,43
severity in IBS44 intestinal microbiota,45 food/diet
and FGIDs,46–51 cross-cultural research (2014),52,53
development of an Asian questionnaire to address
cross-cultural differences in symptom interpreta-
tion,54 and primary care.55
2. Between 2010 and 2012 the Rome IV Editorial
Board was created, and they identified the chairs
and co-chairs of the 18 committees who in turn
selected their committee members to produce the
Rome IV chapters
3. Support committees were created to provide ancil-
lary service to the chapter committees: (1) a Ques-
tionnaire Committee to develop and validate the
Rome IV diagnostic criteria and create research
questionnaires, (2) a Systematic Review Committee
to perform systematic reviews and meta-analyses
for the chapter committees, (3) a Multidimensional
Clinical Profile committee to develop a case-based
book designed to improve patient care by using a
multicomponent assessment to target better treat-
ments,56 and (4) a Primary Care Committee to assess
and publish perspectives of primary care physicians
relating to IBS and FGIDs, and to create a primary
care book on Rome IV.
4. During Digestive Diseases Week 2013, the chapter
committees participated in an orientation in which
the support committees presented their work and
the new chapter committees were tasked to develop
online and printed book manuscripts and a journal
article for Gastroenterology. They also were reques-
ted to develop graphs and images for the online
book version, a revision of the Rome III diagnostic
algorithms,57 and a revision with additional cases for
the Multidimensional Clinical Profile book.56
5. From 2013 through the end of 2015 the committee
members critically synthesized the literature and
created the requested documents through several
revisions.
Gastroenterology Vol. 150, No. 6
6. In December 2014 the chapter committees met in
Rome (Rome IV Conference 2014) to revise the
documents and establish a consensus on the diag-
nostic criteria and scientific content.
7. At the end of the Rome meeting, the editorial board
and the chairs and co-chairs held a full-day harmo-
nization meeting to summarize and present their
committees’ recommendations to the group. This led
to feedback and discussion relating to gaps or re-
dundancies in content that were reconciled by
consensus.
8. The documents then were sent to up to 5 outside
international experts for peer-review and the docu-
ments were modified further as needed.
9. By autumn 2015, the manuscripts for the 13th issue
of Gastroenterology were created and reviewed by
the editorial board of Rome IV.
10. Finally, the committee members signed off on all
documents before it was sent to the copy editor for a
final check on content and style before publication.
Limitations in Using Rome Criteria
for Diagnosis and Management in
Clinical Practice
The Rome symptom-based categoric criteria are of
particular value for clinical research and pharmaceutical
trials. They provide a clear strategy for selecting study
subjects, they are endorsed by regulatory agencies, and are
used by clinical investigators and industry for clinical trials
around the world. Nevertheless, there are limitations for use
in clinical practice. A categoric diagnosis may exclude
patients who do not fully meet these criteria but who could
be treated similarly. A patient with abdominal pain and
bowel dysfunction for fewer than 6 months or fewer than 1
episode a week, or who does not meet 2 of the 3 criteria
associating pain with bowel habit, or who has pain not
associated with altered bowel habit, would not be diagnosed
by criteria as having IBS, yet the clinician could still judge a
need for treatment. Furthermore, patients can have 2 or
more FGID diagnoses (eg, IBS and functional dyspepsia),
although for the purpose of clinical trials the Rome IV
criteria exclude this co-occurrence. Thus, for clinical prac-
tice, meeting criteria may not be necessary in the daily care
of patients but still can serve as a useful guide to help
characterize these disorders.
Also, a diagnosis per se does not capture all dimensions
of the patient’s clinical condition to optimize treatment. For
example, a patient meeting criteria for functional dyspepsia
may have only occasional symptoms with no lifestyle
impairment and not require treatment. In contrast, another
patient with the same diagnosis with severe and disabling
pain, major depression, and weight loss from eating re-
strictions needs to be managed quite differently. In addition,
the criteria for cyclic vomiting syndrome does not require
the presence of pain, yet patients who meet criteria for this
diagnosis but who also have pain are more disabled, with
May 2016
more health care visits, and a greater likelihood of being
prescribed opioids leading to other complications. To
address these limitations in classification, the Multidimen-
sional Clinical Profile method teaches individualized treat-
ment based on identifying and integrating the multiple
components (psychosocial, clinical, physiological, quality of
life, and impact aspects) of the symptom experience.56
Changes for Rome IV
Rome IV changes are as follows.
1. The addition of new diagnoses with known etiol-
ogies. Narcotic bowel syndrome (opioid-induced
gastrointestinal hyperalgesia) has been added to the
Centrally Mediated Disorders of Gastrointestinal
Pain article, opioid-induced constipation has been
added to the Bowel article, and cannabinoid hyper-
emesis syndrome has been added to the Gastrodu-
odenal article. These diagnoses differ from other
FGIDs by having substances (opioids and cannabi-
noids) that produce the symptoms, and their
avoidance may lead to recovery. Because these di-
agnoses result from known etiologies, they are not
truly functional, but we include them in Rome IV
because they fit the new definition: disorders of
gut–brain interaction being characterized by altered
function of the CNS or enteric nervous system; their
clinical presentations are similar to FGIDs and thus
need to be distinguished from them; and they have
not yet been well characterized or reached a level of
acceptance in the field to be considered separate
disorders (such as lactose intolerance, microscopic
colitis).
2. Removal of functional terminology when possible.
The debate to retain or change the term functional
has existed for decades, however, the word “func-
tional” has become so embedded in our health care
nosology that it cannot easily be substituted at this
time. However, the word “functional” has limitations
by being nonspecific and potentially stigmatizing.
Therefore, we provide an improved definition of
FGIDs (ie, disorders of gut–brain interaction) to help
clarify its meaning. In addition, we have removed the
word functional from article titles (eg, Esophageal
Disorders rather than Functional Esophageal Disor-
ders) and from certain diagnoses (eg, fecal inconti-
nence instead of functional fecal incontinence) as
occurred in Rome III. In addition, functional
abdominal pain syndrome has been changed to
centrally mediated abdominal pain syndrome to
more appropriately address the disorder’s patho-
genesis, minimize the stigma of the term functional,
and reverberate with the new brain–gut information
that is emerging. However, some clinical disorders
(eg, functional diarrhea, functional heartburn) have
retained the term to distinguish them from disor-
ders having similar symptoms but with clear struc-
tural etiologies.
Functional GI and Rome IV 1271
FUNCTIONAL GI OVERVIEW
3. Article additions and modifications. A new article
entitled Intestinal Microenvironment and the Func-
tional Gastrointestinal Disorders combines knowl-
edge of the microbiome, food, and nutrition to
improve understanding of the luminal aspects of GI
function. Pharmacological and Pharmacokinetic As-
pects of Functional GI Disorders has been changed to
Pharmacological, Pharmacokinetic, and Pharmaco-
genomic Aspects of Functional Gastrointestinal Dis-
orders to include the role of genetics in the clinical
response to pharmaceutical treatments. Gender, Age,
Society, Culture and the Patient’s Perspective from
Rome III has been split into 2 articles to reflect the
rapid growth of knowledge in these areas of Age,
Gender, Women’s Health, and the Patient and
Multicultural Aspects of Functional Gastrointestinal
Disorders. Psychosocial Aspects of Functional
Gastrointestinal Disorders has been changed to
Biopsychosocial Aspects of Functional Gastrointes-
tinal Disorders to reflect the multidetermined nature
of biopsychosocial processes. The Rome III article
Functional Abdominal Pain Syndrome is changed to
Centrally Mediated Disorders of Gastrointestinal
Pain to reflect the predominant CNS contribution to
the symptoms.
4. Threshold changes for diagnostic criteria. With
limited information on normal bowel symptom
frequencies and inadequate data from the literature
on the frequency of GI symptoms using Rome
criteria, the Foundation conducted a Normative
Symptom Study so the chapter committees can
include evidence-based thresholds for judging
symptoms as out of the range of normal. The Rome
Foundation Questionnaire Committee conducted a
survey of physical symptoms including FGID
symptoms on a nonclinical nationwide sample in
the United States. Using this information, frequency
thresholds were created for the diagnostic criteria
that were different from general sample
frequencies.
5. Addition of reflux hypersensitivity diagnosis. In
Rome III, Functional Heartburn defined heartburn
symptoms in the absence of evidence that the
heartburn is associated with gastroesophageal
reflux. However, there also are patients who have
normal acid reflux levels, but they are sensitive to
the physiological reflux and so develop heartburn.
For Rome IV, A3 Reflux Hypersensitivity character-
izes this situation and is to be differentiated from A2
Functional Heartburn or even nonerosive reflux
disease by their greater association of symptoms
with reflux, albeit physiological.
6. Revision of SOD disorder criteria. Recommenda-
tions58 to perform biliary sphincterotomy based on
clinical criteria (biliary dilatation and increased liver
chemistries or increased pancreatic enzyme levels)
for presumed sphincter of Oddi pain has not had
 1272 Douglas A. Drossman
FUNCTIONAL GI OVERVIEW
convincing supportive evidence. Thus, balancing the
benefits of symptomatic relief with the potential
risks of pancreatitis, bleeding, and perforation has
been challenging, and the Rome III criteria for these
disorders were not particularly helpful in providing
proper guidelines. Now, driven by evidence that
debunks the value of sphincterotomy for type III
SOD,59 the Gallbladder and Sphincter of Oddi Dis-
orders chapter committee has reclassified these
disorders, and they provide a more rational algo-
rithm for treatment. The previous type III SOD
categorization of the Milwaukee classification has
been removed, so patients without evidence of bile
duct obstruction should not be referred for endo-
scopic retrograde cholangiopancreatography with
manometry for possible sphincterotomy. Instead,
they should be treated symptomatically. In addition,
treatment of functional biliary sphincter of Oddi
disorder in patients with only moderate objective
evidence of biliary obstruction should consider
other investigative options before a decision for
sphincterotomy is entertained.
7. Functional bowel disorders now exist on a spectrum
of symptom presentations. The predominant bowel
diagnoses of IBS with subtypes of constipation,
diarrhea, mixed, and unclassified, are no longer
considered distinct disorders. Instead, they exist on a
spectrum with linked pathophysiological features
that are variably expressed clinically by patient-
specific differences in the quantity, intensity, and
severity of symptoms. This overlap of clinical fea-
tures is well observed for IBS with predominant
constipation and chronic constipation in which cate-
gories may switch depending on the degree of pain
and across the subcategories of IBS related to
changes in stool habit over time.60–63 This also can
occur for IBS with functional dyspepsia or functional
constipation with pelvic floor dyssynergia. For clin-
ical trials, specific diagnostic criteria are necessary to
assess the targeted effects of the drugs, however, in
clinical care, patients may transition from one diag-
nosis to another or have combinations of diagnoses
that may require overarching management (eg, anti-
depressants for pain across multiple diagnoses).
8. Change in identification of IBS subtypes. The Rome
III classification for IBS subtypes required that the
proportion of total stools using the Bristol Stool
Form Scale be used to classify IBS with predominant
diarrhea (>25% loose/watery, <25% hard/lumpy),
IBS with predominant constipation (>25% hard/
lumpy, <25% loose/watery), mixed-type IBS
(>25% loose/watery, >25% hard/lumpy), and IBS
unclassified (<25% loose/watery, <25% hard/
lumpy). However, because patients can have large
periods of time with normal stool consistency, there
is a large number of patients with unclassified IBS
subtype relative to the other groups.64,65 Based on
Gastroenterology Vol. 150, No. 6
this observation and the results of a Rome Founda-
tion Normative Symptom Study, the criteria for
subtypes of IBS have been changed and relate to the
proportion of symptomatic stools (ie, loose/watery
and hard/lumpy) rather than all stools (including
normal ones). As a result, the unclassified group is
reduced markedly.
9. Removal of the term discomfort from IBS criteria.
The Rome III criteria for IBS required abdominal
pain or discomfort, presuming that these terms exist
on a continuum from more severe (pain) to less
severe (discomfort). However, more recent data66
have indicated that patients consider the two
terms as qualitatively different, and discomfort can
incorporate a variety of symptoms. In addition, the
term discomfort has different meanings and is re-
ported with different frequencies across cultures.67
Therefore, to avoid symptom-related and cultural
heterogeneity, only the term pain is used as the key
diagnostic criterion for IBS.
10. Combined nausea and vomiting disorder. For Rome
IV the new diagnosis B3a. Chronic Nausea Vomiting
Syndrome combines the previous Rome III entities
Chronic Idiopathic Nausea and Functional Vomiting.
This is owing to a lack of evidence delineating
different diagnostic approaches and management of
nausea compared with vomiting, and the clinical
observation that these 2 symptoms commonly are
associated. Although we recognize that patients may
present only with nausea, the clinical approach to
diagnosis and management is still the same.
Biopsychosocial Model of Functional
GI Disorders
Figure 1 shows an updated Biopsychosocial Conceptual
Model for functional gastrointestinal disorders68 (see the
article Biopsychosocial Aspects of Functional Gastrointes-
tinal Disorders). Early in life, genetics, sociocultural in-
fluences, and environmental factors may affect one’s
psychosocial development in terms of personality traits,
susceptibility to life stresses, psychological state, and
cognitive and coping skills. These factors also influence the
susceptibility to gut dysfunction: abnormal motility or
sensitivity, altered mucosal immune dysfunction or
inflammation, and the microbial environment, as well as
the effect of food and nutritional substances. Furthermore,
these brain–gut variables reciprocally influence CNS
expression.
An FGID is the product of these interactions of psycho-
social factors and altered gut physiology via the brain–gut
axis.68,69 Thus, an individual with bacterial gastroenteritis
who has a reduced inoculation of bacteria, no concurrent
psychosocial difficulties, and good coping skills may not
develop a clinical syndrome and, if it does develop, may
have mild symptoms and not perceive the need to seek
medical care. Another individual with a larger inoculation of
May 2016
bacteria or a longer period of gastroenteritis, co-existent
psychosocial comorbidities, high life stress, abuse history,
or maladaptive coping may develop a severe syndrome of
postinfection IBS or dyspepsia, go to the physician
frequently, and have a generally poorer outcome.70–73
Furthermore, the clinical outcome will, in turn, affect the
severity of the disorder (Figure 1, double-sided arrow). For
example, a family that addresses the illness behavior
adaptively and attends to the individual and his or her
psychosocial concerns may reduce the impact of the illness
experience and resultant behaviors. Conversely, a family
that is overly solicitous to the person’s illness74 or a societal
group that interprets certain symptoms with threat may
amplify the symptoms and illness behaviors. With regard to
management, when the physician acknowledges the reality
of the patient’s complaints, provides empathy, and engages
in an effective physician–patient interaction, symptom
severity and health care seeking are reduced.75 In contrast,
the physician who does not engage in these skills and who
repeatedly performs unnecessary diagnostic studies to rule
out pathologic disease, dismisses the patient’s concerns, or
does not collaborate effectively in the patient’s care, is likely
to promote a vicious cycle of symptom anxiety and health
care seeking.76
Biopsychosocial Overview of Functional
GI Disorders
Using Figure 1 as a template, the concepts and associa-
tions of this model are discussed briefly and covered in
more detail in the article Biopsychosocial Aspects of Func-
tional Gastrointestinal Disorders.
Early life. A person’s genetic composition and in-
teractions with the environment affect later susceptibility to
disease, their phenotypic expression, as well as patient at-
titudes and behaviors (including health care seeking)
relating to it. Family and twin studies have indicated a ge-
netic component to IBS and likely other FGIDs, with several
polymorphisms and candidate genes that can affect physi-
ological functioning including motor function, membrane
permeability, and visceral sensitivity.77 However, Mendelian
single-gene susceptibility is unlikely; rather, multiple genes
likely interact with environmental risk factors to produce
the clinical heterogeneity among individuals with FGIDs,78
and psychophysiological factors such as stress may affect
the epigenetic expression of these genes, leading to visceral
hypersensitivity and other functions associated with these
disorders.79
Sociocultural factors and family interactions shape later
reporting of symptoms, the development of FGIDs, and
health care seeking. The expression of pain varies across
cultures from denial to stoicism to dramatic expression.
Symptoms such as bloating are reported commonly in
China, however, there is no word for bloating in Latin cul-
tures. With regard to health care use, diarrhea is highly
prevalent in Mexico and may not be considered an illness
leading to health care visits,5 and, in general, rural Latin
Americans are more likely to go to a local health care pro-
vider, a curandero, for common illnesses, and reserve seeing
Functional GI and Rome IV 1273
FUNCTIONAL GI OVERVIEW
a traditional medical provider for more serious or life-
threatening diseases.4
Environmental exposures such as childhood Salmonella
infection can be a risk factor for IBS in adulthood.70 Early
learning difficulties or emotionally challenging interactions
in childhood may predispose to FGIDs. For example, diffi-
culties surrounding bowel habit80 or early abuse81 may
result in encopresis and even painful dyssynergic defecation
later in life, which can be reconditioned through anorectal
biofeedback.82 Early family attention toward GI symptoms
and other illnesses can influence later symptom reporting,
health behaviors, and health care costs.74
Psychosocial factors. Although psychosocial factors
are not required for diagnosis, they influence physiological
functioning of the GI tract via the brain–gut axis (motility,
sensitivity, barrier function), are modulators of the patient’s
pain experience and symptom behavior, and, ultimately,
affect treatment selection and the clinical outcome (see
article Biopsychosocial Aspects of FGIDs). When evaluating
for psychosocial factors, the clinician should consider four
general observations:
1. Psychological stress or one’s emotional response to
stress exacerbates gastrointestinal symptoms and
may contribute to FGID development. This occurs
among healthy subjects and patients with structural
diagnoses, and is well demonstrated in patients who
develop functional gastrointestinal disorders, a com-
mon example being postinfection IBS or dyspepsia.71
We also see a high association of psychosocial
comorbidities, life stress, and abuse among patients
with FGIDs, which lead to poorer outcomes.
2. Psychosocial factors modify the experience of illness
and illness behaviors such as health care seeking.
Although patients with FGIDs show greater psycho-
logical disturbance than otherwise healthy subjects
and patients with medical disease, the data are drawn
from patients seen at referral centers. This explains
why psychosocial trauma (eg, sexual or physical
abuse history) is more common in referral centers
than in primary care, may decrease the pain threshold
and symptom reporting, and is associated with a
poorer clinical outcome.72 These factors can be
reduced or buffered by adaptive coping skills and
social support. Thus, it follows that the psychosocial
response of family, society, and culture also can have
a palliative effect on the illness experience.
3. A functional GI disorder may have psychosocial con-
sequences. Any chronic illness has psychosocial con-
sequences on one’s general well-being, daily function
status, and sense of control over the symptoms, as
well as implications of the illness in terms of future
functioning at work and at home. This is understood
in terms of one’s health-related quality of life.
4. Psychosocial effects of illness, namely emotional
distress and maladaptive cognitions, may feed back to
perpetuate and amplify symptoms. Patients with
 1274 Douglas A. Drossman
FUNCTIONAL GI OVERVIEW
severe symptoms may develop a morbid pessimism
and helplessness (ie, catastrophize) and selectively
attend to and be hypervigilant to their symptoms,
leading to visceral anxiety, all of which decreases
sensation thresholds and produces feelings of poor
self-efficacy and self-esteem. In these cases, a behav-
ioral intervention is needed to help re-establish a
psychological substrate of improved health.
Physiology. A variety of physiological processes may
lead to GI symptoms and, when more prevalent, to func-
tional GI disorders.
Abnormal motility. Disturbed gastrointestinal motility
can generate symptoms of nausea, vomiting, diarrhea, acute
abdominal pain, incontinence, and others. Furthermore, in
healthy subjects, and more so in patients with FGIDs, strong
emotion or environmental stress via the brain–gut axis can
lead to dysmotility throughout the GI tract. FGIDs have an
even greater motility response to stressors when compared
with normal subjects.83 However, these motor responses
only partially are correlated with symptoms, and are not
sufficient to explain reports of chronic or recurrent
abdominal pain.
Visceral hypersensitivity. The poor association of pain
with GI motility with many functional GI disorders (eg,
functional chest pain, functional dyspepsia–epigastric pain
syndrome, IBS, and so forth) is explained by the concept of
visceral hypersensitivity.84 These patients have a lower
pain threshold with balloon distension of the bowel
(visceral hyperalgesia), or they have increased sensitivity
even to normal intestinal function (eg, allodynia). Visceral
hypersensitivity may be amplified in patients with FGIDs:
repetitive balloon inflations in the colon lead to a pro-
gressive although transient increase in pain intensity in
healthy subjects and for a longer period in patients with
FGIDs. Hypersensitivity and sensitization may be amplified
at all levels of the brain–gut axis such as by factors listed
later.
Immune dysregulation, inflammation, and barrier
dysfunction. The work on postinfection IBS and dyspepsia
have been associated with increased interest in mucosal
membrane permeability via alteration of tight junctions,85
the intestinal flora, and altered mucosal immune func-
tion.86 These associations increase the access of intra-
luminal antigens into the submucosa associated with
low-grade activation of mast cells and increased inflam-
matory cytokine release.87 These actions alter receptor
sensitivity at the gut mucosa and myenteric plexus, pro-
ducing visceral hypersensitivity. Factors contributing to
this occurrence include genetics, psychological stress via
mast cell activation, and altered receptor sensitivity at the
gut mucosa and myenteric plexus. This is enhanced by
alteration of the bacterial environment or outright
infection.
Microbiome. The microbiome represents the collection
of microorganisms, which is shaped by host factors such as
genetics and nutrients, but in turn is able to influence host
biology in health and disease. It has become a major area for
research in gut functioning in the FGIDs, and there is also
an emerging concept of the microbiome–gut–brain axis.69,88
Gastroenterology Vol. 150, No. 6
Differences among IBS patients in the bacterial composition
of the gut (eg, increased firmicutes and reduced bacter-
oidetes and bifidobacter), and also reduced fecal microbial
diversity relative to healthy individuals, have implied a
causative role in the onset and maintenance of IBS. This is
supported by the modest effect of probiotics and more
substantive benefit of periodic antibiotic treatment in
improving IBS symptoms.45 However, further research is
needed to fully understand the place of the bacterial flora in
the pathogenesis of FGIDs.
Food, diet, and intraluminal factors. A recent addition
to understanding FGIDs relates to food and diet46 and also
their relationship to intestinal microbiota.89 Certain specific
alterations in diet such as low fermentable oligo-, di-, and
monosaccharides and polyols, or gluten restriction in some
patients, may provide benefit as a result of reduced osmotic
effects or alterations in gut mucosa. However, no one diet is
of specific value and treatment must be individualized. In
addition, the diet provides substrates for microbial
fermentation, and because the composition of the intestinal
microbiota is altered in IBS, the link between food and diet,
microbiota composition, and fermentation products may
play an important role in IBS pathogenesis. This is note-
worthy because there has been a discrepancy between
patients’ and physicians’ attributions to the effect of food
on FGID symptoms, with patients believing the effect was
more relevant.90 Further study is needed to define the
subsets of patients who are more likely to respond to al-
terations in diet.
Another recent area of interest relates to the effect of
intraluminal factors in addition to maldigested nutrients on
gut function. This includes microflora alterations in short-
chain fatty acids; the products of enteroendocrine cells
including granins and their effect on nervous, endocrine,
and immune cells; and the proportion of secondary to
primary bile acids, possibly affecting gut-transit rates.83
For example, the prevalence and role of cholerheic enter-
opathy likely has been underestimated previously in con-
ditions such as diarrhea-predominant IBS, and when
recognized can lead to a more specific treatment using bile
acid binders.
Brain–gut axis. The brain-gut axis is the neuroana-
tomic substrate in which the psychosocial factors just
described influence the GI tract and vice versa. The hard-
wiring between the brain and gut is a complex integrated
circuitry that communicates information from emotional
and cognitive centers (subserving thoughts, feelings, mem-
ories, and pain regulation) of the brain via neurotransmit-
ters (software) to the peripheral functioning of the GI tract
and vice versa.91 Structurally, there are direct connections
between the CNS and myenteric plexus to the visceral
muscles and other end-organ structures that affect sensory,
motor, endocrine, autonomic, immune, and inflammatory
function.92 Thus, emotions such as fear, anger, anxiety,
painful stimuli, and physical stress can delay gastric
emptying and intestinal transit. They also can stimulate
colonic motor function, reflected by decreased colonic
transit time, increased contractile activity, the induction of
defecation, and symptoms of diarrhea. Also, psychological
May 2016
stress can disrupt the gut-pain threshold and impair
mucosal secretory and barrier functions, and this is asso-
ciated with transmigration of bacterial cell products leading
to GI pain and diarrhea, as with IBS. Conversely, enhanced
motility, visceral inflammation, and injury can amplify
ascending visceral pathways and affect brain areas, leading
to greater pain and contributing to altered mental func-
tioning including anxiety and depression. In effect, the
reciprocal relationships that we call the brain–gut axis is
the neuroanatomic and neurophysiologic substrate for the
clinical application of the systems or biopsychosocial
model.93
With regard to pain regulation, the relationships
between psychosocial distress and painful symptoms ap-
pears mediated through impairment in the ability of various
brain networks such as the cingulate cortex to process
bodily pain. In effect, the brain’s pain control system can act
as a filter to enhance or block pain by up-regulating or
down-regulating the incoming neural signals affecting
symptom perception through this gate control mechanism.
Down-regulation, which increases the pain threshold, seems
not to occur as well in patients with functional GI pain. The
anterior cingulate cortex, involved in the motivational and
affective components of the emotional arousal and salience
network, is dysfunctional with IBS and other functional
GI pain, fibromyalgia, and other functional somatic symp-
toms. When this system is influenced by psychosocial
distress, the gate is open and the pain threshold is
decreased. Conversely, improvement in pain control can be
enabled by cognitive or emotional factors such as focused
attention, hypnosis, psychological treatment, and certain
antidepressants. These effects may be more than physio-
logical based on growing evidence for their role in
enhancing neurogenesis as well, thus possibly contributing
to more lasting effects for these treatments.94 A more recent
understanding expands upon the complexity of multiple
brain network operating systems including emotional
arousal, salience and executive functions, sensorimotor and
autonomic functions related to FGIDs.93 In sum, the clinical
phenotype that we understand as FGIDs emerges from the
interactions of multiple systems in the periphery (micro-
biome, altered mucosal inflammation, visceral hypersensi-
tivity) and in the brain (brain network systems of emotional
arousal, sensorimotor function, central autonomic function)
interacting with each other in bidirectional ways that lead to
the FGID phenotype.93
FGID symptom experience severity and behav-
ior. The product of the interacting effects of the brain and
GI tract in any individual with an FGID relates to the clinical
expression of illness; namely, the symptom experience, its
severity, and subsequent illness-related behaviors. This in-
cludes the meaning of illness, the fears of continued symp-
toms, the perceived concerns relating to alterations in body
image, social acceptability (eg, feeling stigmatized), the de-
gree of functional impairment with its implications at work
and at home, the sense of helplessness to effect symptom
relief, and the difficulty of coping with disability must all be
dealt with by the patient. How well the patient adapts based
Functional GI and Rome IV 1275
FUNCTIONAL GI OVERVIEW
on personal and family resources, in addition to the quality
of the physician’s involvement, is crucial to the patient’s
psychological well-being and clinical course. Given the
proper biopsychosocial milieu, many patients can adapt to
their illness with some support from family, friends, and
health care providers. Other patients, possibly shaped by
genetics and early experiences, respond by feeling helpless
and unable to feel in control of their symptoms and the
effects on their life; they regress and become dependent.
Their continued symptoms, restricted activity, and health
care needs may tax family, friends, and their physician, all of
whom may feel helpless to provide enough emotional or
medical assistance. If the patient has a limited capacity to
cope psychologically with the illness, the disorder is
particularly incapacitating, or if the interpersonal family
relationships are dysfunctional, additional efforts by the
physician and ancillary personnel (eg, psychological coun-
selors, social workers, peer support groups) will be
required.
Outcome. The outcome of the biopsychosocial model
as discussed is what we see in the patient’s health and
personal care behaviors, and in the impact on family, the
physician, and society. Psychosocial factors are strong de-
terminants of medication use, health care visits, functional
ability, loss of work time, and health care costs. All of these
factors can be addressed and potentially modified by the
physician’s ability to listen, engage, and effect good
communication skills, as discussed later, regardless of the
diagnostic condition.75
An Approach to the Care of Patients
With Functional GI Disorders
Twelve Steps to Enhance the
Therapeutic Relationship
An effective physician–patient relationship can improve
patient satisfaction, adherence to treatment, symptom
reduction, and other health outcomes. This section provides
general care guidelines that can help to optimize this rela-
tionship for patients with FGIDs.75
1. Improve patient satisfaction and engage with the
patient. Patient satisfaction relates to the patient’s
perception of the doctor’s humaneness, technical
competence, interest in psychosocial factors, and
provision of relevant medical information, and too
much focus on biomedical issues can have a negative
effect. Engagement relies on nonverbal communica-
tion: good eye contact, affirmative nods, gentle tone
of voice, close interpersonal distance, and creation of
a partner-like interaction.
2. Obtain the history through a nondirective, nonjudg-
mental, patient-centered interview. This involves
active listening and using questions based on the
patient’s thoughts, feelings, and experiences rather
than on using a personal or preset agenda of
questions.
 1276 Douglas A. Drossman
FUNCTIONAL GI OVERVIEW
Table 3.Proposed Clinical Profile for Patient-Rated Severity in IBS44
Clinical feature Mild
estimated prevalence 40%
Psychometric correlate FBDSI, <36
IBS-SSS, 75–175
Physiological factors Primarily bowel dysfunction
Psychosocial difficulties None or mild psychosocial
distress
Sex Men ¼ women
Age Older > younger
Abdominal pain Mild/intermittent
Number of other symptoms Low (1–3)
Health-related quality of life Good
Health care use 0–1/y
Activity restriction Occasional (0–15 days)
Work disability <5%
NOTE. Based on Drossman et al.44
FBDSI, Functional Bowel Disorder Severity Index; IBS-SSI, IBS Symptom Severity Index.
3. Determine the immediate reason for the patient’s
visit (eg, What led you to see me at this time?) and
evaluate the patient’s verbal and nonverbal
communication. Some possible reasons include the
following: (a) new or exacerbating factors (dietary
change, concurrent medical disorder, side effects of
new medication), (b) personal concern about a
serious disease (eg, recent family death), (c) per-
sonal or family stressors (eg, recent or anniversary
of death or other major loss, abuse event, or history),
(d) worsening or development of psychiatric co-
morbidity (depression, anxiety), (e) impairment in
daily function (recent inability to work or socialize),
or (f) a hidden agenda such as narcotic or laxative
abuse or pending litigation or disability claims.
4. Conduct a careful physical examination and cost-
efficient investigation. A well-conducted physical
examination has therapeutic value.95
5. Determine what the patient understands of the
illness and his or her concerns (eg, What do you
think is causing your symptoms? or What concerns
or worries do you have about your condition?).
6. Elicit the patient’s understanding of the symptoms
(illness schema) and provide a thorough explanation
of the disorder that takes into consideration the pa-
tient’s beliefs. For example: “I understand you believe
you have an infection that has been missed; as we
understand it, the infection is gone but your nerves
have been affected by the infection to make you feel
like it is still there, similar to a phantom limb.”
7. Identify and respond realistically to the patient’s
expectations for improvement (eg, How do you feel I
can be helpful to you?).
8. When possible, provide a link between stressors
and symptoms that are consistent with the patient’s
Gastroenterology Vol. 150, No. 6
Moderate Severe
35% 25%
FBDSI, 36–109 FBDSI, >110
IBS-SSS, 175–300 IBS-SSS, >300
Bowel dysfunction and CNS Primarily CNS pain dysregulation
pain dysregulation
Moderate psychosocial distress Severe–high psychosocial distress,
catastrophizing, abuse history
Women > men Women >>> men
Older ¼ younger Younger > older
Moderate, frequent Severe/very frequent or constant
Medium (4–6) High (7)
Fair Poor
2–4/y 5/y
More often (15–50 days) Frequent/constant (>50 days)
6%–10% 11%
beliefs. Many patients are unable or unwilling to
associate stressors with illness but most patients
will understand the stress of the illness on their
emotional state: “I understand you do not see
stress as causing your pain, but you have
mentioned how severe and disabling your pain is.
How much do you think that is causing you
emotional distress?”
9. Set consistent limits (eg, I appreciate how bad the
pain must be, but narcotic medication is not indi-
cated because it can be harmful).
10. Involve the patient in the treatment (eg, Let me
suggest some treatments for you to consider).
11. Make recommendations consistent with patient in-
terests (eg, Antidepressants can be used for
depression, but they also are used to “turn down”
the pain, and pain benefit occurs in doses lower than
that used for depression).
12. Help establish an ongoing relationship with you or in
association with a primary care provider (eg,
Whatever the result of this treatment, I am prepared
to consider other options, and I will continue to
work with you through this).
Symptom Severity as a Guide to Treatment
Although illness severity exists on a continuum, there is
heuristic value in separating FGIDs into mild, moderate, and
severe categories in planning treatment. Table 3 applies
primarily to IBS patients, the group that has been most
studied. Although this information may not fully represent
non–health care seekers or patients with other FGIDs, it is
presented to help the clinician understand the variability in
symptom reports, illness behaviors, and treatment recom-
mendations all based on severity factors. In general, the
greater the severity the more intervening psychosocial and
May 2016
other comorbidities will influence the clinical presentation
and will require different treatments.
Mild symptoms. Patients with mild or infrequent
symptoms comprise approximately 40% of patients, are
seen more in primary care than in gastroenterology prac-
tices, and do not have major impairment in function or
psychological distress. Symptoms often are based on
gastrointestinal dysfunction (ie, vomiting, diarrhea, con-
stipation), and pain is minimal or mild and without other
comorbid physical symptoms. Patients with mild symptoms
do not usually have dominant psychiatric diagnoses and
their quality of life is good, but they may report concerns
about the implications of their symptoms on their life. These
patients do not make frequent medical visits and usually
maintain normal activity levels without restriction. Here,
treatment is directed toward the following
1. Education. Indicate that FGIDs are very real disorders in
which the gastrointestinal system is overly responsive
to a variety of stimuli such as food, hormonal changes,
medication, and stress. Pain resulting from spasm or
stretching of the gut, from a sensitive gut, or from both
can be experienced anywhere in the abdomen and can
be associated with other effects on gastrointestinal
function leading to symptoms (eg, pain, nausea, vomit-
ing, diarrhea). Both physiological and psychological
factors interact to produce symptoms.
2. Reassurance. First elicit the patient’s concerns and
then respond to them. This is usually done after
appropriate evaluation.
3. Diet and medication. Offending dietary substances
(eg, lactose, fermentable oligo-, di-, and mono-
saccharides and polyols, caffeine, fatty foods, alcohol)
and medications that adversely cause symptoms
should be identified and reduced or eliminated.
Sometimes a food diary is helpful.
Moderate symptoms. A smaller proportion of
patients, approximately 30%–35%, seen in primary or sec-
ondary care report moderate symptoms and have inter-
mittent disruptions in activity, for example, missing social
functions, work, or school. They may identify a close rela-
tionship between symptoms and inciting events such as
dietary indiscretion, travel, or distressing experiences. They
may have more moderate abdominal pain and be more
psychologically distressed than patients with mild symp-
toms. There may be several other medical or psychological
comorbidities, and these patients may lose time from work
or need to curtail usual functioning. For this group, addi-
tional treatment options are recommended.
1. Symptom monitoring. Keeping a symptom diary for
1–2 weeks encourages the patient’s participation in
treatment and sense of control over the illness. It may
help to identify inciting factors such as dietary in-
discretions, lifestyle factors, or specific stressors not
considered previously.
2. Pharmacotherapy directed at specific symptoms.
Medication can be considered for symptom episodes
Functional GI and Rome IV 1277
FUNCTIONAL GI OVERVIEW
that are distressing or that impair daily function. The
choice of medication depends on the predominant
symptoms. In general, prescription medications
should be considered as ancillary to dietary or life-
style modifications for mild chronic symptoms and
used during periods of acute symptom exacerbation,
or they may be required on a regular basis for
symptoms of moderate or frequent severity.
3. Psychological treatments. Psychological treatments
may be considered for motivated patients with
moderate-to-severe GI symptoms and for patients with
pain. It is more helpful if the patient can associate
symptoms with stressors. These treatments, which
include cognitive-behavioral therapy, relaxation, hyp-
nosis, mindfulness, and combination treatments, help
to reduce anxiety levels, encourage health-promoting
behaviors, and provide the patient with greater re-
sponsibility and control in the treatment and in
potentially improving pain tolerance. See the article
Biopsychosocial Aspects of FGIDs, for more details.
Severe symptoms. Approximately 20%–25% of pa-
tients with FGIDs often seen in referral practices have se-
vere symptoms and a smaller proportion have very severe
and refractory symptoms. They often have a high frequency
of associated psychosocial difficulties including anxiety,
depression or somatization, personality disturbance, and
chronically impaired daily functioning, and approximately
10% or more will have work disability. There may be a
history of major loss or abuse, poor social networks or
coping skills, and catastrophizing behaviors. These patients
may see gastroenterology consultants frequently and may
hold unrealistic expectations to be cured. Perhaps from
earlier experiences in the health care system, they may feel
stigmatized with their condition and deny or not consider a
role for psychosocial factors in the illness. As a result, they
may be unwilling to engage in psychological or psycho-
pharmacologic treatment but more often will seek further
diagnostic studies to legitimize their complaints and choose
pharmacologic treatments directed at the gut. For this
group, the following treatment options are recommended.
1. The physician’s approach. In addition to the general
12-step approach previously described, the clinician
also should: (a) perform diagnostic and therapeutic
measures based on objective findings rather than in
response to patient demands; (b) set realistic treat-
ment goals, such as improved quality of life rather
than complete pain relief or cure; (c) shift the re-
sponsibility for treatment to the patient by giving
therapeutic options; and (d) change the focus of care
from treatment of disease to adjustment to and
management of chronic illness.
2. Antidepressant treatment. If pain is a dominant
feature, tricyclic antidepressants (eg, desipramine,
amitriptyline) or the serotonin-norepinephrine reup-
take inhibitors (eg, duloxetine, milnacipran) help
control pain via central analgesia as well as provide
 1278 Douglas A. Drossman
FUNCTIONAL GI OVERVIEW
relief of associated depressive symptoms. The selec-
tive serotonin reuptake inhibitors (eg, citalopram,
fluoxetine, paroxetine) are less effective for pain but
can help reduce anxiety and associated depression.
Antidepressants should be considered for patients
with chronic pain and impaired daily functioning, co-
existent symptoms of major depression, symptom
anxiety, or panic attacks. Even without depressive
symptoms, these agents may help when the pain is
dominant and consuming. For more information, see
the articles entitled, “Biopsychosocial Aspects of
FGIDs” and “Centrally Mediated Disorders of GI Pain.”
3. Functional GI or pain treatment center referral. There are
several GI programs and possibly pain treatment centers
that provide a multidisciplinary approach to FGID man-
agement. Here, the team approach is directed toward pain
management, improved coping skills, and overall reha-
bilitation of patients who have become disabled.
Concluding Comments
In providing an overview of the functional GI disorders
and the Rome Foundation process, we set the stage for the
information to follow. A great deal has happened in the 10
years since the publication of Rome III. We believe that this
new information will help the reader gain a better under-
standing of these disorders and improve the diagnosis and
care of his or her patients. Rome IV is the culmination of a
6-year effort of 117 internationally recognized in-
vestigators and clinicians representing 23 countries along
with 10 administrative staff and consultants. As we look
back on the process, the information obtained is compre-
hensive, although there is still more to learn. When more
advances in our understanding and treatment of these
disorders occur in future years, we will revise the infor-
mation again as we advance to Rome V. The Rome process
is a dynamic one, and we look forward to future activities
designed to help improve the science of FGIDs and care of
the patients.
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. Visit the online version of
Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.032.
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Reprint requests
Address requests for reprints to: Douglas A. Drossman, MD, 901 Kings Mill
Road, Chapel Hill, NC 27517. e-mail: drossman@med.unc.edu.
Conflicts of interest
The author discloses no conflicts.
1279.e1 Douglas A. Drossman
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 Gastroenterology 2016;150:1280–1291

Fundamentals of Neurogastroenterology: Basic Science

Stephen J. Vanner,1 Beverley Greenwood-Van Meerveld,2 Gary M. Mawe,3
BASIC SCIENCE

Terez Shea-Donohue,4 Elena F. Verdu,5 Jackie Wood,6 and David Grundy7

1
Gastrointestinal Diseases Research Unit, Kingston General Hospital, Kingston, Ontario, Canada; 2Oklahoma Center for
Neuroscience, Department of Physiology, VA Medical Center, University of Oklahoma, Health Sciences Center, Oklahoma City,
Oklahoma; 3Department of Neurological Sciences, Pharmacology and Medicine Division, Gastroenterology and Hepatology,
University of Vermont, Burlington, Vermont; 4Department of Medicine and Physiology, University of Maryland School of
Medicine, Baltimore, Maryland; 5Farncombe Family Digestive Health Research Institute, McMaster University, Health Sciences
Center, Hamilton, Ontario, Canada; 6Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio;
7
Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom

This review examines the fundamentals of neuro-
gastroenterology that may underlie the pathophysiology of
functional GI disorders (FGIDs). It was prepared by an
invited committee of international experts and represents
an abbreviated version of their consensus document that
will be published in its entirety in the forthcoming book
and online version entitled Rome IV. It emphasizes recent
advances in our understanding of the enteric nervous
system, sensory physiology underlying pain, and stress
signaling pathways. There is also a focus on neuro-
immmune signaling and intestinal barrier function, given
the recent evidence implicating the microbiome, diet, and
mucosal immune activation in FGIDs. Together, these ad-
vances provide a host of exciting new targets to identify
and treat FGIDs, and new areas for future research into
their pathophysiology.
Keywords: Sensory Physiology; Enteric Nervous System; Neu-
roimmune Signaling; Mucosal Barrier Function.
to these ostensibly conflicting functions is the ability to
monitor events in the gut wall and within the gut lumen to
orchestrate reflexes that bring about appropriate patterns of
motility, secretion, and blood flow to digest and absorb or to
dilute and expel. GI sensory mechanisms play a pivotal role
in triggering these reflexes by conveying sensory informa-
tion to the enteric reflex circuits that provide local control
and through afferent pathways to the CNS.
Pathways From Gut to Brain
Sensory information is conveyed from the GI tract to the
brainstem and spinal cord via vagal and spinal (splanchnic
and pelvic) afferents, respectively. Most dorsal root ganglion
neurons innervate somatic structures. It is estimated that
the proportion of dorsal root ganglion neurons innervating
the GI tract range between 3% and -7%. The dominance of
somatic afferent input to the spinal cord and the conver-
gence of visceral and somatic afferents on ascending spinal
pathways accounts for the phenomenon of referred pain. In
addition, afferent fibers from the colon and rectum may
converge with fibers from other pelvic organs, contributing

I
n the 8 years since the publication of Rome III there
has been rapid expansion in our understanding of the
fundamentals of neurogastroenterology. What has fueled
this advance is the desire to integrate basic science research
with clinical gastroenterology to better diagnose and treat
functional gastrointestinal disorders (FGIDs). This research
continues to shed light on the complex hierarchy of neural,
molecular, and cellular interactions that control gut func-
tion. However, what recent research also has shown is the
complex interaction between the host gut wall and the
luminal microbial environment that is responsible for
balancing immune tolerance with protection against path-
ogenic and antigenic material. Neuroimmune function and
the mechanisms that regulate mucosal barrier function,
immune surveillance, innate and adaptive immunity, sen-
sory signaling, and central nervous system (CNS) adaptation
consequently are the major themes for this review.
The Basis of Brain–Gut Interactions
The GI tract has important barrier and immune functions
that interface with the luminal microbiota and protect
against potential pathogenic and antigenic material. Integral
to cross-organ sensitization between gut, bladder, and
reproductive organs that often complicates the clinical
diagnosis of pelvic pain.1 The low density of innervation,
convergence with somatic inputs, and viscerovisceral
convergence in the spinal cord can explain why gut pain
generally is localized poorly.
Subtypes of Visceral Afferents
GI afferent fibers terminate within the gut wall mainly as
bare nerve endings and are classified according to their
Abbreviations used in this paper: CNS, central nervous system; CRF,
corticotrophin-releasing factor; DC, dendritic cell; EC, enterochromaffin;
ELA, early life adversity; ENS, enteric nervous system; FGID, functional
gastrointestinal disorder; HPA, hypothalamic-pituitary-adrenal; 5-HT,
5-hydroxytryptamine; IBS, irritable bowel syndrome; ICC, interstitial cells
of Cajal; IEC, intestinal epithelial cells; IEL, intraepithelial lymphocytes; IL,
interleukin; ILC, innate lymphoid cells; PAG, periaqueductal gray; PFC,
prefrontal cortex; PRR, pattern recognition receptor; SERT, serotonin-
selective reuptake transporter; TLR, Toll-like receptor; TRP, transient
receptor potential; VIP, vasoactive intestinal polypeptide.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.018
May 2016
terminal distribution as mesenteric, serosal, muscular,
ganglionic (intraganglionic laminar endings), or mucosal
endings.2 The location of these endings plays an important
role in determining the functional properties of the afferent.
Mucosal afferents respond to distortion of the mucosal
epithelium and to luminal chemicals. Stretch or distension is
effective for stimulating endings in the muscle layers,
ganglia, and serosa. These endings express an array of
membrane receptors and ion channels that determine
neuronal excitability, mechanosensitivity, and modulation
by a host of chemical mediators within the GI milieu.
Different populations of afferents respond over a range of
distension volumes from innocuous (physiological) to
noxious levels that cause pain. Powerful contractions,
especially against an obstruction, cause traction on the
mesentery and is especially painful.
There is a continuous barrage of information projecting
from the gut to the CNS. Many afferent endings respond to
levels of distension that occur as part of normal digestion
and these usually go unperceived. Instead, this information
is used in reflexes that control motility, secretion, blood
flow, and other aspects of GI function. In contrast, there are
other afferents that respond only at high levels of stimulus
intensity and function as nociceptors that mediate pain.
Some afferents (so-called silent or “sleeping” nociceptors)
are mechanically insensitive under normal circumstances
but can be awakened in response to inflammation or
injury. In patients this process of sensitization can give rise
to altered pain perception. In some cases, stimuli that
normally are innocuous can cause pain (allodynia),
whereas responses that are painful can become exagger-
ated (hyperalgesia).
Mechanotransduction
Mechanotransduction refers to the process by which
stimulus energy is interpreted by sensory nerve endings,
leading to the generation of action potentials. There are
specific molecular mechanisms that underlie mechano-
transduction. Moreover, the excitability of the afferent
ending is determined by various voltage-gated and calcium-
dependent ion channels3 that set gain in the system, and
that can change according to external influences leading to
hypersensitivity.
Sensory endings contain a variety of mechanosensitive
ion channels that can convert the stimulus energy into ac-
tion potentials. They respond to membrane deformation,
causing channels to open or close, carrying ionic currents
into or out of the nerve terminal to cause depolarization.
Three main ion channel families have been identified as
mechanosensitive: (1) the DEG/ENaC family that includes
the acid-sensing ion channels 1, 2, and 3; (2) the transient-
receptor potential (TRP) channel family; and (3) the 2-pore
potassium channel family that includes TREK-1 and TRAAK.
Different combinations of these channels exist in different
populations of vagal, pelvic, and splanchnic afferents, sug-
gesting a complex heterogeneity in sensory signaling.4
Another mechanism of mechanotransduction occurs
when a secondary sense cell releases mediators that act on
Neurogastroenterology Basic Science 1281
ionotropic or metabotropic receptors to stimulate sensory
endings. This indirect mechanism relies on close association
between afferent endings in the gut wall and various other
cell types that are a source of these chemical ligands. These
include mast cells, epithelial cells, enteroendocrine cells,
macrophages, interstitial cells of Cajal (ICC), and enteric
BASIC SCIENCE
neurons. Considerable attention has been paid to the role of
5-hydroxytryptamine (5-HT) and adenosine triphosphate in
sensory signaling, especially in the context of post-
inflammatory hypersensitivity.5
Luminal Sensing
Some vagal and pelvic afferent endings come into close
proximity to the mucosal epithelium, but never penetrate
through to the lumen. However, their proximity to the mu-
cosa exposes them to chemicals absorbed across the
mucosal epithelium or released from enteroendocrine cells
whose apical membrane is exposed to luminal content. This
is similar to the relationship seen between taste buds in the
mouth and gustatory afferents and as such provides a
mechanism by which mucosal afferents can taste luminal
contents. This is important for controlling digestive function
via reflex effects on motility and secretion. However,
nutrient detection also influences metabolic activity and
energy intake. The molecular basis for each modality of
gustatory taste has been identified. Strikingly, many of these
same G-protein–coupled receptors and ion channels are
expressed within the GI tract. The cells expressing taste-
receptor molecules in the GI mucosa have a characteristic
morphology, which is typified by the enterochromaffin (EC)
cell.6 However, EC cells are just one of a diverse family of
enteroendocrine cells that are scattered diffusely in the GI
mucosa and whose mediators can act in a paracrine fashion
on afferent fibers or diffuse into the blood stream for more
distant endocrine actions. Each type of enteroendocrine cell
has a characteristic distribution along the GI tract. Among
the mediators released, cholecystokinin and glucagon-like
peptide-1 play important roles in reflex control of GI func-
tion and in regulating food intake.
Peripheral Sensitization
Sensory neurons express a large array of receptors that
are activated by mediators released from various cellular
sources within the gut wall. Neurotrophins, for example,
play a role in axon guidance and remodeling of the sensory
innervation after inflammation and injury. Their receptors
are expressed on different populations of GI sensory neu-
rons. Both nerve growth factor and glial-derived neuro-
trophic factor are important in the adaptive response to
nerve injury and inflammation. Both also are possible me-
diators underlying chronic pain. Increasing neurotrophin
signaling causes increased TRP channel expression (eg,
TRPV1 and TRPA1), an increase in sodium channel
expression (NaV1.87), and a decrease in potassium channels.
Any, or all of these, could contribute to the development of
hypersensitivity.8
Many other mediators are released during inflammation,
injury, and ischemia, from platelets, leukocytes, lymphocytes,
 1282 Vanner et al
BASIC SCIENCE
macrophages, mast cells, glia, fibroblasts, blood vessels,
muscle, and neurons. Some mediators act directly on sensory
nerve terminals and others act indirectly, causing release of
yet other agents from nearby cells. This “inflammatory soup”
(Figure 1) contains amines, purines, prostanoids, proteases,
cytokines, and so forth, which act on sensory nerve terminals
to increase sensitivity to both mechanical and chemical
stimuli (referred to as “plasticity”). Recent data have sug-
gested that bacterial products also may drive afferent
signaling.9 Hypersensitivity is a feature of chronic pain states
and is considered to be a hallmark of FGIDs including irri-
table bowel syndrome (IBS). Moreover, because these
afferents also trigger reflexes that coordinate gut function,
sensitization also can cause hyper-reflexia or dysreflexia,
leading to altered transit, resulting in diarrhea and
constipation.
Peripheral sensitization normally develops rapidly and is
relatively short-lived. However, in the presence of main-
tained injury or inflammation, the sensitization can be pro-
longed by changes in gene expression. These genes may alter
the expression of channels, receptors, or mediators in the
sensory neuron.8 They also may modify the amount and
pattern of neurotransmitters released by central nerve ter-
minals in the brain and spinal cord. This alters the way that
sensory signals are processed within the CNS and contrib-
utes to “central sensitization,”10 and may prolong hyper-
sensitivity beyond the acute period of injury or inflammation.
Central Sensitization
These mechanisms can undergo plasticity in response to
injury and inflammation, leading to hypersensitivity and
chronic pain states. These neurons transmit visceral signals
to ascending spinal pathways via glutamate and neuropep-
tides. These transmitter mechanisms are up-regulated in
response to inflammation and injury and contribute to
hypersensitivity.
Gastroenterology Vol. 150, No. 6
Figure 1. Mechanisms
underlying sensitization.
Luminal factors and medi-
ators released in response
to ischemia, injury, and
inflammation act on the
sensory endings to drive
sensitization. These pe-
ripheral mechanisms are
reinforced by central
mechanisms in the spinal
cord and CNS. ATP,
adenosine triphosphate;
LIF, leukemia inhibitory
factor; NGF, nerve growth
factor; PGE, prostaglandin
E; TNF, tumor necrosis
factor. Modified from
Grundy and Brookes2 with
permission from Morgan
and Claypool.
In the brain and spinal cord there are central neuro-
plastic changes, termed central sensitization, that contribute
to chronic pain. Within the dorsal horn of the spinal cord,
there are 2 mechanisms that increase pain signals reaching
the brain: (1) increased synaptic transmission via glutamate,
calcitonin gene-related peptide, and substance P onto
ascending excitatory pathways, and/or (2) decreased
descending inhibitory modulation. In the brain, sensitization
can occur in the second-order spinal neurons, such as the
thalamus, periaqueductal gray (PAG), parabrachial nucleus,
and locus coeruleus. Increased signaling from those nuclei
then can promote neuroplasticity, similar to long-term
potentiation mechanisms, that strengthen and/or add syn-
aptic connectivity. The enhanced signaling then promotes
abnormal processing of pain within the extended pain ma-
trix (prefrontal cortex [PFC], anterior cingulate cortex,
amygdala, insula), which can amplify the discomfort and
negative emotions associated with chronic visceral pain,11
and/or a decrease in the descending pain inhibitory sys-
tem through the PAG and rostroventral medulla.12 In
particular, the amygdala is a key nucleus that integrates
noxious visceral signals with anxiety/fear behaviors and
hyperactivation could influence not only multiple nuclei in
the central pain matrix, but also descending brainstem
nuclei that modulate GI function.13 Multiple clinical imaging
studies also have shown differences in function, connectiv-
ity, and structure between IBS and healthy controls. Thus,
central sensitization can promote chronic abdominal pain in
IBS through remodeling of connections within both the
brain and spinal cord.
ENS Neurobiology
A universal perception of the enteric nervous system
(ENS) as a brain-in-the-gut implies that, similar to the brain
and spinal cord, the ENS is assembled in a hierarchy of
neural organization.14,15 Output from the ENS determines
May 2016
moment-to-moment behavior of the gastrointestinal
musculature, secretory glands, and blood vasculature. Inte-
gration of output to the muscles and secretory glands is
reflected by coordinated patterns of motility and secretion,
recognizable during clearly defined digestive states. Five
different behavioral states are recognizable in the small
intestine: (1) physiological absence of motility; (2) post-
prandial state with segmenting (mixing) motility integrated
with set-point feedback control of luminal pH and osmo-
larity; (3) migrating motor complex in the interdigestive
state also integrated with set-point feedback control of
luminal pH and osmolarity; (4) a defensive state with
copious neurogenic hypersecretion and orthograde or
retrograde power propulsion associated with urgency,
diarrhea, and cramping abdominal pain; and (5) emetic
program, which includes reversal of peristaltic propulsion in
the upper jejunum and duodenum to rapidly propel luminal
contents toward the open pylorus and relaxed antrum and
corpus. Coordinated neurogenic patterns of behavior in the
large intestine are recognized as haustral formation, physi-
ological absence of motility, defecatory power propulsion
and defense that also is associated with urgency, diarrhea,
and cramping lower abdominal pain.
Similar to the CNS, the ENS functions with chemical
synaptic connections between sensory neurons, in-
terneurons, and motor neurons. Interneurons are inter-
connected synaptically into neural networks, which process
information on the state of the gut, contain a library of
programs for different patterns of behavior, and control the
activity of motor neurons. Motor neurons innervate the
musculature, secretory glands, and blood vessels. Muscu-
lomotor neurons initiate or inhibit the contractile activity of
the musculature when they fire.15 Modulation of their firing
frequency, by input from interneuronal microcircuitry, de-
termines minute-to-minute contractile strength. Secreto-
motor neurons stimulate secretory glands to secrete
chloride, bicarbonate, and mucus,16,17 and determine the
osmolarity and liquidity in the lumen. Neurogenic control of
bicarbonate secretion maintains a physiological pH set-point
in the lumen and accounts for some of the mucosal pro-
tection against acid delivery from the stomach. A subset of
secretomotor neurons simultaneously innervates both
secretory glands and periglandular arterioles, and thereby
enhance blood flow with secretion.
Interaction of the ENS with ICC18 is a major determinant
of each of the motility programs stored in its library. Elec-
trically conducting junctions (gap junctions) connect smooth
muscle fibers one to another to form a functional electrical
syncytium. Action potentials propagate from muscle fiber to
muscle fiber in 3 dimensions and trigger a contraction as
they enter each neighboring muscle fiber. ICC are non-
neuronal pacemaker cells that also connect one to another
to form electrical syncytial networks that extend around the
circumference and throughout the longitudinal axis of the
small and large intestine. The ICC networks generate elec-
trical pacemaker potentials (also called electrical slow waves)
that spread via gap junctions into the intestinal circular
muscle, where they depolarize the muscle to action potential
threshold and thereby trigger contractions.
Neurogastroenterology Basic Science 1283
The functional characteristics of the circular muscle as a
self-excitable electrical syncytium implies that ICC networks
should continuously evoke contractions that spread in 3
dimensions throughout the entire syncytium, which is in
effect the entire length of the intestine. Nonetheless, in the
normal bowel, long stretches of intestine are found in a state
BASIC SCIENCE
of physiological ileus. Attention to the functional electrical
syncytial properties of the musculature suggests that
inhibitory musculomotor neurons and control of their ac-
tivity by the integrative microcircuits in the ENS have
evolved as a mechanism that determines when ongoing slow
waves initiate a contraction, as well as the distance and
direction of propagation after the contraction starts.
Overall, a normal ENS is essential for a healthy bowel
and absence of irritating symptoms, such as those associ-
ated with Rome-based diagnostic criteria for FGIDs. Any
neuropathic change in the ENS most likely will result in a
symptomatic bowel. Functional propulsive motility and its
integration with specialized secretory functions cannot
work in the absence of the ENS, as underscored in the
aganglionic terminal segment of Hirschsprung’s disease and
autoimmune ENS denervation of the lower esophageal
sphincter in achalasia.
ENS Neuroplasticity in
Pathophysiological Conditions
Gut functions are altered under various pathophysio-
logical conditions, and it has become increasingly clear that
alterations in the intrinsic reflex circuits of the gut are
involved. Over the past decade, much progress has been
made toward determining what elements of the circuits are
altered, the mechanisms of these alterations, which changes
persist after recovery from inflammation, and the effects of
neuroplasticity on propulsive motility.
Mucosal Serotonin Signaling
One mechanism of activating enteric neural reflex cir-
cuits is the release of 5-HT from EC cells in the intestinal
mucosa.19 Serotonin released from EC cells activates
intrinsic enteric reflexes and also sends signals related to
digestive reflexes, satiety, and pain to the CNS via vagal and
spinal afferents. Serotonin signaling is terminated by reup-
take into epithelial cells, all of which express the serotonin
selective reuptake transporter (SERT) on their basal surface.
A consistent feature of mucosal 5-HT signaling in the
inflamed bowels of human beings and experimental animals
is a decrease in SERT expression.19 This has been shown in
ulcerative colitis and diverticulitis in human beings, and also
in diarrhea-predominant and constipation-predominant IBS.
The effects of decreased SERT expression are likely to be
comparable with those related to serotonin-selective–
receptor inhibitor use, with increased mucosal 5-HT avail-
ability resulting in alterations in gut reflexes.
Decreased SERT expression in the inflamed bowel is likely
to involve the actions of the proinflammatory cytokines, tu-
mor necrosis factor a, and interferon g.20 The contributing
factors for decreased SERT in IBS have not been identified,
 1284 Vanner et al
but it may involve a genetic predisposition, given that certain
polymorphisms of the SERT gene are associated with
decreased SERT expression. It also is possible that altered
SERT expression in IBS develops as a compensatory response
to altered gut function; however, SERT expression is not
altered in opiate-induced constipation.21
BASIC SCIENCE
Impact of Enteric Neuroplasticity
on Gut Functions
Inflammation is associated with changes along the ENS
reflex circuitry that include increased 5-HT availability, hy-
perexcitability of AH (sensory) neurons, interneuronal syn-
aptic facilitation, and suppressed purinergic neuromuscular
transmission22 (Figure 2). It is highly likely that these alter-
ations lead to changes in neurogenic secretory and motor
functions in the bowel, but the nature of the changes probably
differs between secretory and motor responses. Neurogenic
secretion can be activated by 5-HT release from EC cells, and
involves a 2-neuron reflex circuit consisting of an AH neuron
and an S neuron. With increased 5-HT availability, AH neuron
hyperexcitability, and a strengthening of synaptic signals to
the secretomotor (S) neurons, it is likely that secretion is
enhanced. One potential pitfall in this scheme is that 5-HT
receptors on the processes of AH neurons could become
desensitized by increased exposure to 5-HT.
The effects of neuroplastic changes on motility are more
convoluted than secretion because the reflex circuitry is
more complicated, involving an excitatory signal passing
upstream from a given site and an inhibitory signal passing
downstream. For an unequivocal set of signals to be trans-
mitted, there cannot be much noise in the system. This
quiescent background state is disrupted in the inflamed
colon by increased 5-HT availability in the lamina propria
and by increased spontaneous activity of AH neurons
throughout the inflamed regions. This results in an overlap
Gastroenterology Vol. 150, No. 6
of contradictory ascending and descending signals at a given
site, and a decrease in the ability of the ENS to generate the
pressure gradient that result in propulsive motility, result-
ing in a form of pseudo-obstruction. Experimentally,
increasing AH neuron excitability in normal colons disrupts
motility whereas suppressing hyperexcitability of AH neu-
rons in inflamed preparations improves motility.23
Furthermore, when the inhibitory junction potential is
protected and AH neuron activity is attenuated in trini-
trobenzene sulfonic acid–inflamed colons, propulsive
motility is restored to its control velocity.24 These findings
underscore the delicate balance of enteric neural signaling,
especially as it relates to motor functions.
Neuroimmune Cross-Talk
No perfect animal model exists for investigating the
neurophysiological basis of altered motility in FGIDs, but
one approach that has been used is to determine what
inflammation-induced neuroplastic changes persist beyond
the recovery of inflammation. This approach is obviously
relevant to postinfectious IBS, but in the past decade a
number of studies have shown that IBS is accompanied by a
detectable increase in immune cells and inflammatory me-
diators in the mucosal layer. Furthermore, many inflam-
matory bowel disease patients show IBS-like symptoms
after resolution of their macroscopic inflammation. There-
fore, inflammation-induced changes in neuronal function
could be a contributing factor in IBS and refractory in-
flammatory bowel disease, but these changes in neuronal
excitability and synaptic strength would not be detectable
with current diagnostic techniques. Several inflammation-
induced changes in the ENS, including AH neuron hyper-
excitability, do persist beyond recovery of inflammation,25,26
supporting the possibility that long-term changes in enteric
circuitry could contribute to FGIDs.
Figure 2. Diagram show-
ing inflammation-induced
changes in the propulsive
motor circuitry of the
colon. Modified from
Mawe22 with permission
from Journal of Clinical
Investigation.
May 2016
Neuroimmune Function
For many years, the contribution of immune cells to the
pathogenesis of FGIDs largely was ignored. Recent evidence
derived from patient and animal studies, however, has
shown the untapped therapeutic potential of the mecha-
nisms involved in the cross-talk among immune cells,
epithelial cells, smooth muscle, enteric nerves, and their role
in the generation of symptoms in FGIDs.
The intestine is a unique compartment containing
enteric neurons and a large number of regionally distrib-
uted resident immune cells. The expression of receptors for
neurotransmitters on immune cells, and receptors for im-
mune mediators on neurons/nerves, provides a foundation
for neuroimmune interactions (Figure 3). Immune cells
synthesize and release mediators that alter neuronal activity
though neural expression of receptors for pathogen- and
damage-associated molecules and for cytokines generated
by resident and infiltrating cells. Immune cells also release
classic neurotransmitters, fostering the concept of the
“neuroimmune synapse.” Neuroimmune cross-talk is
involved in proinflammatory and anti-inflammatory neural
reflexes and is important for the full development of the gut
immune system and maintenance of mucosal homeostasis.
Amplification of the bidirectional communication among
epithelial cells, innate and adaptive immune cells, and ENS
provides a bridge to the adaptive immune response to
physiologic or pathogenic stimuli.
Cells Involved in Neuroimmune Interactions
Intestinal epithelial cells. Intestinal epithelial cells
(IECs) express pattern recognition receptors (PRRs),
including membrane-spanning Toll-like receptors, intracel-
lular nucleotide oligomerization domain-like receptors, and
retinoic acid-inducible gene 1–like receptors, all of which
respond to pathogen-derived signals to promote tissue-
specific innate immunity. Epithelial-derived cytokines (eg,
interleukin [IL]25, thymic stromal lymphopoietin) activate
Figure 3. Nerves express
receptors for immune cell
mediators. Immune medi-
ators bind to receptors on
nerves and can result in
either excitation or inhibi-
tion of gut function. PAR,
protease activated recep-
tor; TNF, tumor necrosis
factor; TRP, transient re-
ceptor potential; TTX-s,
tetrodotoxin sensitive Naþ
channels.
Neurogastroenterology Basic Science 1285
receptors on resident immune cells to initiate immune re-
sponses. IECs also amplify immune responses by producing
chemokines, such as IL8, that recruit immune cells. Immune
mediators binding to IEC receptors affect function through a
variety of signaling pathways or through activation of
transcription factors that control expression of specific
BASIC SCIENCE
genes. The close association of epithelial cells, nerves, and
immune cells greatly facilitates their interactions.
Intraepithelial lymphocytes. Intraepithelial lympho-
cytes (IELs) are a heterogeneous population of T-cell
subtypes—distinct from peripheral T cells—that are inter-
spersed among IECs. IELs express surface markers that play
a role in their migration and retention in the mucosal
compartment and generate molecules, allowing them to
tether epithelial cells. In human beings, the majority of IELs
are found in the proximal small intestine where they are
important in mucosal tolerance and in maintenance of
barrier function through the production of cytokines that
affect permeability.27
Innate lymphoid cells. Innate lymphoid cells (ILCs)
are a recent discovery, arise from a poorly defined precur-
sor pool, and generate cytokines identified with polarized
adaptive immune responses (T-helper [Th]1, Th2, or Th17).
Unlike T cells, ILCs lack antigen receptors and are not
involved in immune memory,28 but are important for the
initiation of host immune responses. ILC fate is modulated
by the cross-talk among epithelial cells, luminal factors, and
other immune cells, implicating them in both protective and
inappropriate immune responses.29
Dendritic cells. Intestinal dendritic cells (DCs) shape
adaptive immune responses to harmful or infectious intra-
luminal stimuli through acquisition of luminal antigens and
migration to mesenteric lymph nodes to present these an-
tigens to naive T cells. Sensory neuropeptides participate in
the recruitment of DCs during neurogenic inflammation, and
activation of vasoactive intestinal polypeptide (VIP) re-
ceptors inhibits the migration of mature DCs to sites of
inflammation, inducing a more tolerogenic phenotype. DCs
 1286 Vanner et al
express nicotinic and dopaminergic receptors that shift
function toward production-specific profiles of cytokines
and this neuromodulation may play a role in inflammatory
GI pathologies.
T cells. As central constituents of the adaptive immune
response, T cells are natural targets of the nervous system.
Specific cell markers subdivide populations of effector T
BASIC SCIENCE
cells into different phenotypes including cytotoxic (CD8þ),
T helper (CD4þ), memory (CD4þ or CD8þ, CD45RO), and
regulatory (CD25þ). Some effector cells are retained and
differentiate into resident tissue memory cells, which are
responsible for rapid responses to subsequent antigenic
stimuli. T cells express receptors for neurotransmitters
including 5-HT, dopamine, norepinephrine, glutamate, and
acetylcholine (muscarinic and nicotinic). Their ability to
release acetylcholine and produce choline acetyltransferase
allows them to function as a non-neuronal cholinergic
system.30
Mucosal mast cells. Mucosal mast cells reside in
healthy gut and are important in the transition from innate
to adaptive immunity. They release both preformed and
newly synthesized mediators including proteases, hista-
mine, prostaglandins, 5-HT, cytokines, and chemokines that
depend on the phenotype, which is influenced by the
microenvironment. The nature and timing of mediator
release is determined by the type of receptors activated and
the strength and duration of the stimuli. There is a well-
documented anatomic and functional interaction between
mucosal mast cells and nerves.
Macrophages. Macrophages are the largest population
of mononuclear phagocytes in the gut. Mucosal macro-
phages respond to luminal contents and to specific IEC-
derived mediators. Macrophages associated with smooth
muscle are implicated in inflammation- and infection-
induced changes in gut motility.31 Macrophage activation
by Th1 cytokines leads to the development of the proin-
flammatory classically activated phenotype, whereas Th2
cytokines promote the development of the anti-
inflammatory alternatively activated phenotype. Macro-
phages express nicotinic and muscarinic receptors for
acetylcholine and are in close contact with cholinergic
neurons. Activation of these receptors enhances or inhibits
macrophage phagocytosis and modulates production of cy-
tokines. Macrophages also express a- and b-adrenergic re-
ceptors as well as receptors for 5-HT, substance P, VIP,
adenosine, and a number of proteases that activate
protease-activated receptor 1 and protease-activated
receptor 2.
Immune Modulation of Integrated
Neural Responses
Activation of vagal nerves has beneficial effects that
include inhibition of proinflammatory cytokines and atten-
uation of tissue injury. Recent evidence has shown an
anatomic and functional interaction between macrophages
in the muscularis externa of the intestine with vagal efferent
fibers synapsing on cholinergic, nitric oxide, and VIP-
containing neurons in the ENS.32 Sympathetic nerves
Gastroenterology Vol. 150, No. 6
innervate gut-associated lymphoid structures and modulate
the responses of immune cells expressing adrenergic re-
ceptors. Proinflammatory actions of sympathetic nerves are
mediated by a2-adrenergic receptors whereas anti-
inflammatory effects are mediated by the b3-adrenergic
receptor. Catecholamines bind with higher affinity to a
than to b receptors, so the distance from the source of the
immune cells that express both receptors can influence the
response.
Neurogenic inflammation is a response triggered by
serine proteases, elaborated by enteric pathogens, mast
cells, and neutrophils. Cleavage of protease-activated re-
ceptor 2 on extrinsic primary afferents sensitizes TRP
channels and releases proinflammatory sensory neuropep-
tides such as substance P and calcitonin gene-related pep-
tide. There is also a neuronal and nerve fiber hyperplasia in
inflammation that also may contribute to the severity of the
response.33
Interaction of the Epithelial Barrier and
the ENS With Gut Luminal Content
The intestinal epithelial barrier plays a critical role in the
maintenance of homeostasis within the gut and there is
growing evidence that alterations in this barrier may be an
important factor in the pathogenesis of FGIDs. The epithe-
lium, along with underlying immune structures in the lam-
ina propria, plays a pivotal role in controlling the host
immune response to luminal antigens. These luminal factors
also may signal directly or indirectly, through the host im-
mune response, to other effector systems including the ENS.
These complex interactions, if dysregulated, can lead to gut
dysfunction and symptom onset.
Intestinal Barrier Structure
The intestinal barrier (Figure 4) consists of a single layer
of epithelial cells that physically separates the host from the
intestinal lumen.34 IECs are bound together by the epithelial
apical junctional complex, comprised of tight junctions,
adherens junctions, and other membrane complexes con-
taining the membrane proteins nectin and junctional adhe-
sion molecule. Overlying the apical side of epithelial cells is
a mucus layer primarily produced by goblet cells, antimi-
crobial peptides, and immunoglobulins.35
Intestinal Barrier Function
Water and ion transport. The gut is capable of
handling approximately 9 L of fluid per day, absorbed
mainly by the small intestine. This fluid movement involves
both absorptive and secretory processes, which can occur
through the paracellular or the transcellular route. The
paracellular pathway involves water movements coupled to
nutrient absorption (solvent drag), whereas the trans-
cellular route involves the passage of water through apical
and basolateral membranes of epithelial cells by passive
diffusion, cotransport with ions and nutrients, or through
aquaporins.
May 2016
Figure 4. Intestinal barrier
structure and function.
Adapted with permis-
sion from Natividad
et al.46 MAMP, microbe-
associated molecular
pattern; PRR, pattern
recognition receptors.
Antigen sampling. Immune sampling of luminal con-
tent is constant and key to mount an appropriate immune
response. Peyer’s patches are overlaid with specialized
epithelial cells called microfold cells, through which anti-
gens are transported and exposed to antigen-presenting
cells in the lamina propria. Direct sampling may occur
through extension of dendrites by specialized dendritic
cells. This process mainly occurs in the ileum, whereas in
the upper small intestine sampling may be more dependent
on changes in paracellular permeability.
Immune defense. Gastric and intestinal secretions,
and peristalsis, aid in digestion and immune defense by
flushing microbes and toxins. The outer layer of mucus in
the colon traps and contains large numbers of bacteria
whereas the inner layer is maintained relatively sterile, in
part by antimicrobial proteins (defensins, cathelicidins,
proteases, and C-type lectins) produced by various enter-
ocytes, Paneth cells, and innate immune cells. Some anti-
microbial proteins are expressed constitutively and others
are dependent on intestinal microbial colonization. Epithe-
lial cells also transport IgA produced by B cells into the gut
lumen. IgA deficiency is associated with increased pene-
tration of bacteria into host tissues.36 Epithelial cells also
are armed with antigen detection and immune signaling
mechanisms, and in some cases can even act as antigen-
presenting cells for neighboring IELs.
Molecular Mechanisms of Interactions Between
the Intestinal Barrier and Luminal Antigens
A key process in innate recognition of microbial antigens
is mediated by pattern recognition receptors (PRRs), which
include Toll-like receptors (TLRs), nucleotide binding oligo-
merization domain-like receptors, RNA helicases, C-type
Neurogastroenterology Basic Science 1287
BASIC SCIENCE
lectin receptors, and cytosolic DNA sensors. These receptors
recognize evolutionary conserved pathogen-associated
molecular patterns expressed by various microorganisms,
and shared by symbiotic microorganisms. Both epithelial and
immune cells express PRRs. Upon activation, PRRs trigger
sequential activation of intracellular signaling pathways and
lead to induction of a range of cytokines and chemokines that
promote immune and physiological responses. PRR signaling
also facilitates the differentiation of T cells and B cells to
establish antigen-specific adaptive immunity.
Critical intestinal barrier adaptations occur in response
to microbial signals after gut colonization.37 In germ-free
animals, expression of antimicrobial peptides is negligible,
low levels of IgA are secreted, the composition of the mucus
is altered, TLR expression is reduced, and zonula occludens
1 proteins are diminished. After bacterial colonization, there
is expansion of the lamina propria, along with increased cell
proliferation and increased expression of innate microbial
recognition receptors.
Interaction of the Intestinal Barrier
With Luminal Content
Gut microbiota. A key strategy of the mammalian in-
testine in maintaining homeostasis is to regulate the inter-
action between luminal microbiota and the intestinal
epithelial cell, as well as immune surveillance cells in the
barrier. However, disruption of the epithelial barrier, for
example, during acute gastroenteritis, could allow signaling
by the microbiota directly to the immune system in the
lamina propria and possibly directly to enteric and nerve
terminals of dorsal root ganglia neurons. Multiple TLRs also
are found on enteric and autonomic neurons and TLR acti-
vation can affect their excitability.
 1288 Vanner et al
BASIC SCIENCE
Figure 5. Chronic psychological stress plays a significant role in the pathophysiology of IBS. CRF, corticotropin releasing
factor. Reproduced from Barbara et al45 with permission from the Journal of Neurogastroenterology Motility.
Food components. There is increasing recognition
that luminal food components induce symptoms in many
patients with FGIDs.38 Enhanced signaling resulting from
altered intestinal barrier and/or exaggerated neuroimmune
responses could underlie these actions. One important
component is sensitivity to wheat-containing diets in some
IBS patients. This sensitivity could be related to gluten
because the gluten-derived peptide P31-43 increased IL15-
positive cells from biopsy specimens from celiac patients
and induced stress markers on epithelial cells. Other studies
have shown that gliadin, the storage protein in gluten, in-
creases permeability, and studies in animal models of gluten
sensitivity have shown that gliadin or gluten can increase
permeability, which then leads to increased uptake of
microbiota antigens that further amplify the immune and
functional responses to gluten. Other components in wheat
are capable of inducing innate immune responses that could
lead to gut dysfunction. Amylase trypsin inhibitors that
protect the grain from pests can activate the TLR-4 pathway.
Interestingly, amylase trypsin inhibitor reactivity has been
implicated in allergy and Baker’s asthma. Whether amylase
trypsin inhibitors alter the epithelial barrier and play a role
in a proportion of wheat-related IBS symptoms remains
unknown, but may explain some allergic reactions to wheat
components that potentially could lead to mast cell
degranulation and symptoms. Another important compo-
nent is the carbohydrates and smaller amounts of protein
Gastroenterology Vol. 150, No. 6
that are not absorbed in the small intestine. These are
metabolized by colonic bacteria to short-chain fatty acids
and intestinal gases. Studies suggest fermentable substances
can cause colonic epithelial cells to express receptors for
these short-chain fatty acids, potentially altering the prop-
erties of enteric neurons, leading to changes in motility and
secretion. Fermentable food components also produce a
number of gases, including H2, CH4, and CO2, which could
produce symptoms as a result of the gas-induced distension
of the colon and secondary activation of neural reflexes. H2S
gas, produced by sulfur-reducing bacteria in the intestinal
lumen, also has been implicated in the regulation of gut
function, including secretion, motility, and nociceptive
signaling. Finally, attention recently has centered on bile
acids, particularly in diarrhea-predominant IBS patients, in
whom such acids may induce alterations in intestinal
physiology, by signaling to the epithelium, immune cells,
blood vessels, smooth muscle, ENS, and autonomic nerves.
Stress
Although the etiology of FGIDs is unknown, there is
compelling evidence that psychological and physical
stressors play an important role (Figure 5). It is a generally
accepted hypothesis that dysfunction of the bidirectional
communication between the brain and the gut, in part
through activation of the principal neuroendocrine stress
May 2016
system, namely the hypothalamic–pituitary–adrenal (HPA)
axis, plays a role in the symptomatology of IBS. The HPA axis
is activated by stress, causing the release of corticotropin
releasing factor (CRF) from the paraventricular nucleus of
the hypothalamus into the hypophyseal portal circulation to
bind in the anterior pituitary. Adrenocorticotropic hormone
then is released from the pituitary into the systemic circu-
lation to cause the synthesis and release of the glucocorticoid
cortisol (corticosterone in rats) from the adrenal cortex.
Clinical studies have implicated HPA axis dysregulation
based on multiple reports of increased cortisol levels and
exaggerated HPA responses to stressors in IBS patients.
Multiple lines of evidence have shown activation of
central mechanism(s) resulting in colorectal hypersensitiv-
ity, involving descending facilitation from the brain to
induce remodeling of colorectal responsiveness via sensiti-
zation of spinal dorsal horn neurons. Brainstem regions
responsible for the modulation of descending inhibitory
pain signals are modulated by both pain and stress. The PAG
receives excitatory signaling from the PFC and inhibitory
signaling from the amygdala. The rostroventral medulla
receives not only direct nociceptive information from the
spinoreticular pathway but also integrated pain and stress
signals from the amygdala and PAG. In addition, the locus
coeruleus and amygdala form a circuit that can potentiate
both endocrine and autonomic stress responses. Central
structures regulating affective and sensory processes
including the amygdala, insula, cingulate, and PFC show
enhanced activation in IBS patients. In animal models and in
IBS patients, imaging studies have shown that limbic regions
regulating sensory processing and emotion, including the
amygdala, show greater responsiveness to visceral stimu-
lation. The amygdala is an important limbic structure
involved in the potentiation of the HPA axis, with diffuse
connections to pain-modulatory networks, and has been
implicated in visceral sensitivity and aberrant HPA activity
observed in IBS patients.13 The amygdala is sensitive to
corticosteroids but, in contrast to the hippocampus and PFC,
the amygdala facilitates behavioral, neuroendocrine, and
autonomic responses to stress. Thus, this altered balance in
stress modulation induced by amygdala hyperactivity may
represent an essential aspect of alterations in GI motor
function, colonic permeability, and colorectal sensitivity
apparent in IBS. In support, increasing amygdala cortico-
sterone in rats by stereotaxically implanting corticosterone
micropellets onto the central nucleus of the amygdala cau-
ses a persistent increase in the sensitivity to visceral stimuli
as well as inducing anxiety-like behavior.39 These findings
suggest that in IBS patients exposed to chronic stress,
increased amygdala activation dysregulates the HPA axis.
Clinical observations have suggested that abdominal
pain and altered bowel habits are more common in females,
and that menstrual cycle–linked differences are observed in
symptom reporting. Differences in CNS processing of
visceral information is a potential explanation because
studies using positron emission tomography imaging have
suggested that gender differences in regional brain re-
sponses to rectal pressure exist in IBS patients. Differences
in pain sensitivity may be the result of cyclic hormonal
Neurogastroenterology Basic Science 1289
changes in females, however, the mechanisms are poorly
understood. Effectively abolishing the activational role of
ovarian hormones via ovariectomy reverses the effects of
early life adversity (ELA) on adult visceral pain hypersen-
sitivity in female rats, whereas reintroduction of ovarian
hormones via a subcutaneous estradiol pellet was sufficient
to induce visceral hyperalgesia.40 These data provide sup-
BASIC SCIENCE
port that ovarian hormones play a prominent role in
maintaining the persistent effects of ELA on increased pain
sensitivity in human beings and rodent models. Studies of
neonatal maternal separation to induce ELA also have
shown features of the IBS phenotype including motility
abnormalities, colonic hypersensitivity, and enhanced gut
permeability.40
Remodeling of the epigenome by the environment or
chronic stress may result in long-term changes in gene
expression.41 A recent study showed the importance of his-
tone acetylation in stress-induced visceral pain by showing
that direct administration into the brain of a histone deace-
tylase inhibitor reversed visceral hypersensitivity induced by
stress or activation of the amygdala with corticosterone.42,43
In another study, exposure to ELA was associated with CRF
promoter hypomethylation and an increase in CRF tran-
scriptional responses to stress in adulthood suggesting that
neonatal stress causes long-lasting epigenetic changes in the
CRF expression within the HPA axis.44
In summary, stress plays an important role in functional
bowel disorders with recent evidence from experimental
models showing that chronic adult stress or early life stress
can recapitulate IBS phenotypes, and provide new insights
into the underlying mechanisms of IBS.
Conclusions and Future Directions
This review highlights many advances in our under-
standing of the cellular and molecular mechanisms under-
lying GI physiological and pathophysiological systems that
may play a role in FGIDs. Examples of important themes and
research questions for future research are as follows:
1. Sensory mechanisms underlying sensitization of
nociceptors and visceral hypersensitivity: which me-
diators act to sustain signaling in specific patients and
are there critical pathways? When and how are cen-
tral (CNS) and peripheral mechanisms (ENS/auto-
nomic nervous system) dominant?
2. Barrier function regulating intestinal permeability,
tight junction proteins, and microbiome signaling:
which pathways are involved in FGIDs and when?
Which mechanisms regulate them?
3. Neuroimmune function regulating immune mediators
and bidirectional neural signaling: which immune
cells are activated and which mediator(s) are most
important? What role do the vagal anti-inflammatory/
sympathetic proinflammatory and central pathways
play?
4. ENS preprogrammed synaptic networks and neuro-
plasticity: can peripheral (eg, microbiome) or central
 1290 Vanner et al
(eg, stress) pathways switch ENS networks to change
symptoms (eg, alternating diarrhea and con-
stipation)? When and how does ENS neuroplasticity
underlie FGIDs?
5. Psychological stress and the HPA axis/autonomic
nervous system response: how does it lead to visceral
BASIC SCIENCE
hypersensitivity and alter gut function in FGIDs?
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24. Roberts JA, Durnin L, Sharkey KA, et al. Oxidative stress
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Reprint requests
Address requests for reprints to: Stephen J. Vanner, MD, Gastrointestinal
Diseases Research Unit, 76 Stuart Street, Kingston General Hospital,
Kingston, Ontario, Canada. e-mail: vanners@hdh.kari.net; fax: (613) 544-3114.
Acknowledgments
All authors contributed to the organization and writing of the review.
Conflicts of interest
The authors disclose no conflicts.
Funding
Supported by Canadian Institute of Health Research grant 110986 (S.V.);
National Institutes of Health grant DK62267 (G.M.); National Institutes of
Health grant R01-DK083418 (T.S.-D.); and the European Community FP7
Program (D.G.).
 Gastroenterology 2016;150:1292–1304

Fundamentals of Neurogastroenterology:
Physiology/Motility – Sensation
Guy Boeckxstaens,1 Michael Camilleri,2 Daniel Sifrim,3 Lesley A. Houghton,4
Sigrid Elsenbruch,5 Greger Lindberg,6 Fernando Azpiroz,7 and Henry P. Parkman8
1
Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven,
PHYSIOLOGY

KU Leuven, Leuven, Belgium; 2Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Program,
Mayo Clinic, Rochester, Minnesota; 3Wingate Institute of Neurogastroenterology, Bart’s and the London School of Medicine,
Queen Mary, University of London, London, United Kingdom; 4Division of Gastroenterology and Hepatology, Mayo Clinic,
Jacksonville, Florida; 5Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of
Duisburg-Essen, Essen, Germany; 6Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge,
Stockholm, Sweden; 7Digestive Diseases Department, University Hospital Vall D’Hebron, Autonomous University of Barcelona,
Barcelona, Spain; 8Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania

The fundamental gastrointestinal functions include motility, Perception

sensation, absorption, secretion, digestion, and intestinal
barrier function. Digestion of food and absorption of nutri-
ents normally occurs without conscious perception. Symp-
toms of functional gastrointestinal disorders often are
triggered by meal intake, suggesting abnormalities in the
physiological processes are involved in the generation of
symptoms. In this article, normal physiology and patho-
physiology of gastrointestinal function, and the processes
underlying symptom generation, are critically reviewed. The
functions of each anatomic region of the digestive tract are
summarized. The pathophysiology of perception, motility,
mucosal barrier, and secretion in functional gastrointestinal
disorders as well as effects of food, meal intake, and
microbiota on gastrointestinal motility and sensation are
discussed. Genetic mechanisms associated with visceral
pain and motor functions in health and functional gastroin-
testinal disorders are reviewed. Understanding the basis for
digestive tract functions is essential to understand dysfunc-
tions in functional gastrointestinal disorders.
Keywords: Gastrointestinal Motility; Sensation; Absorption;
Secretion.
Peripheral nerves, afferent signaling. Human be-
ings have the capability to consciously perceive a variety of
highly differentiated sensations originating from the upper
and lower sections of the gut. In the upper gastrointestinal
(GI) tract, specific sensations amenable to conscious
awareness range from temperature, taste, hunger, fullness,
satiety, nausea, and pain. In the small and large bowel,
distensions and contractions cause aversive sensations such
as nausea, bloating, cramping, discomfort, and pain. Only a
minority of the sensory information arising from the
gastrointestinal tract is perceived consciously. The majority
(estimated to be >90%) of afferent sensory information
from the viscera serves homeostatic functions.
The gastrointestinal tract is densely innervated to pro-
vide information on its luminal contents, processes regu-
lating digestion and absorption, and potential threats.1 This
information was collected by intrinsic and extrinsic afferent
nerves and regulates physiological responses for homeo-
stasis and health. In brief, sensory neurons of the enteric
nervous system activate local responses. Extrinsic afferent
nerves transmit sensory information to the spinal cord or
brainstem for further processing and integration (for brain
processing, see later). In general, the extrinsic afferent
innervation of the gut is conducted through the vagus nerve

T he complex process of digestion of food and ab-

sorption of nutrients normally occurs without
conscious perception. Symptoms reported by patients with
functional gastrointestinal disorders often are triggered by
meal intake, suggesting that abnormalities in the physio-
logical processes involved in digestion are involved. Evalu-
ation of sensory function and gastrointestinal motility aims
to identify abnormalities in neuromuscular function to ul-
timately guide therapeutic management. In this article, more
general and region-specific aspects of normal physiology
and pathophysiology, and the processes underlying symp-
tom generation, are critically discussed.
Normal Physiology: Main Components
The fundamental gastrointestinal functions include
sensation, motility, digestion, absorption, and secretion.
and the spinal afferents. The cell bodies of the vagus affer-
ents are in the nodose ganglion, and mainly project to the
nucleus of the solitary tract. Vagovagal reflexes result in
stimulation of vagal efferents in the dorsal motor nucleus of
the vagus nerve. Two examples of vagovagal reflexes are
transient lower esophageal sphincter relaxations and meal-
induced gastric accommodation.
Abbreviations used in this paper: FGID, functional gastrointestinal disor-
der; GI, gastrointestinal; GNb3, Guanine nucleotide-binding protein G(I)/
G(S)/G(T) subunit b-3; IBS, irritable bowel syndrome; LES, lower esopha-
geal sphincter; LM, longitudinal muscle; MMC, migrating motor complex.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.030
May 2016
The spinal afferents have cell bodies in dorsal root
ganglia. These afferents are thoracolumbar (with neurons in
thoracolumbar dorsal root ganglia and projections via
splanchnic nerves and mesenteric/colonic/hypogastric
nerves) or lumbosacral (with cell bodies in lumbosacral
dorsal root ganglia and projections via pelvic nerves and
rectal nerves to the distal bowel) nerves, which synapse in
the spinal cord and send information to the brainstem. Of
note, each region of the GI tract receives dual sensory
innervation reflecting functional connectivity for the distri-
bution of extrinsic primary afferents in these pathways.
Elucidating the afferent and central mechanisms medi-
ating the specific sensation of visceral hyperalgesia or pain
is relevant in the context of the functional gastrointestinal
disorders (FGIDs), especially irritable bowel syndrome (IBS)
and functional dyspepsia.2,3 The sensation of pain appears
to be mediated by different afferents depending on the
location of the GI tract undergoing the noxious stimulus.
Pain from the rectum primarily involves pelvic pathways;
more proximal intestinal sensations are mediated by thor-
acolumbar spinal afferents. Inflammation (or inflammatory
mediators) can change both the response properties of
specific classes of sensory neurons and the involvement of
specific ascending pathways, which is relevant in post-
inflammatory hypersensitivity and postinfectious IBS.4
For the sensations of hunger, satiety, fullness, and nausea,
which play a prominent role in functional gastroduodenal
disorders, vagal afferent pathways play a primary role. Vagal
mucosal afferent pathways are activated by enteroendocrine
cell mediators including cholecystokinin, ghrelin, and
glucagon-like peptide-1, which regulate food intake and
satiety.1 Ghrelin is released from gastric endocrine cells
and inhibits intraganglionic laminar endings located in
myenteric ganglia. Abdominal vagal afferents can contribute
to nausea and vomiting, at least in part through effects of
5-hydroxytryptamine released by enterochromaffin cells.1
Multiple or multimodal ascending and descending
pathways are involved in gastrointestinal sensation through
bottom-up and top-down connections between the central
nervous system and the GI tract along the brain–gut axis.
Brain processing. Within the brain, the multiple facets
that define the conscious experience of pain or other sen-
sations are shaped, involving sensory–discriminative as well
as affective–motivational aspects, behavioral–motor re-
sponses, and cognitive components. Multiple brain regions
and interconnected networks mediate normal and disturbed
responses to visceral stimulation. From the spinal cord,
nociceptive ascending signals from the gut reach the brain
via the anterolateral and dorsal column pathways.5 The
spinothalamic tract projects to the ventral nuclei of the
thalamus and the medial thalamus and then to the primary
and secondary somatosensory cortices. These structures
primarily mediate the sensory–discriminatory aspects of
noxious stimulation, including information regarding
intensity, duration, and location. Affective–motivational as-
pects of pain probably are shaped via connections between
the medial thalamus and the limbic system, including the
anterior cingulate cortex as well as the midbrain, including
the periaqueductal gray.
Gastrointestinal Motility and Sensation 1293
The spinoreticular and spinomesencephalic tracts are
additional anterolateral afferent systems that conduct sen-
sory information to various loci within the brainstem,
mediating reflexive, affective, and motivational conse-
quences of noxious stimulation. Other cortical and subcor-
tical brain regions in normal and abnormal visceral stimulus
processing include the insula, the dorsolateral and ventro-
lateral prefrontal cortices, and the amygdala. These regions
play a role in modulation of the response to pain by emo-
tions such as stress and cognitions such as expectations in
healthy human beings, as well as in patients with chronic
PHYSIOLOGY
pain or hyperalgesia. Descending corticolimbic pain modu-
lation via inhibitory pathways involving the brainstem
modulates afferent visceral signaling. Disturbed endogenous
pain modulation probably plays a role in abnormal brain
responsiveness to visceral pain stimuli in FGIDs.6,7
Motility
The major functions of human digestive tract motility are
to accomplish propulsion along the gut, to mix gut contents
with digestive secretions and expose them to the absorptive
surface, to facilitate temporary storage in certain regions of
the gut, to prevent retrograde movement of contents from
one region to another, and to dispose of residues.
Anatomic and functional considerations. In each
region of the gastrointestinal tract, the muscle layers of the
gut wall and their innervation are adapted and organized to
produce the specific motor patterns that serve the motor
functions. The entire gastrointestinal tract interacts with the
central nervous system and communication between
various parts of the gut is facilitated by the longitudinal
transmission of myogenic and neurogenic signals through
the intrinsic neurons, as well as by reflex arcs through
autonomic neurons. The aspects of gut motility that appear
most relevant to the FGIDs are contractile activity and tone,
compliance, and transit.
Contractile activity and tone. Phasic (short-dura-
tion) contractions originate from electrical spikes on the
plateau phase of the slow-wave activity, and thus the fre-
quency of the phasic contractions in the stomach and small
intestine is dictated by the slow wave frequency. The slow-
wave frequency varies along the length of the gastrointes-
tinal tract; the maximum contractile frequency varies
similarly. The maximum contractile frequency in the stom-
ach is approximately 3 per minute, whereas in the small
intestine the frequency decreases gradually from approxi-
mately 12 per minute in the duodenum to 7 per minute in
the terminal ileum. A mixture of slow-wave frequencies is
found in the colon and ranges from 1 to 12 per minute
where the correlation between electrical and contractile
activities is less clear. Whether the gut phasic contractions
accomplish mainly mixing or propulsion depends on their
temporal (eg, frequency, duration) and spatial (eg, spread of
propagation) characteristics.8
A more prolonged state of contraction, referred to as
tone, is not regulated by slow waves and may be recognized
clearly in the proximal stomach (accommodation response
to a meal) and the colon (response to feeding), as well as in
 1294 Boeckxstaens et al
some sphincteric regions. Tone is regulated by actin–myosin
interaction mediated by cellular mechanisms that are
modulated by neurogenic and mechanical stimuli. Phasic
contractions, such as those regulating lumen occlusion, may
be superimposed on tonic activity. Thus, tone can increase
the efficiency of phasic contractions by diminishing the
diameter of the lumen. Tone also modifies wall tension in
response to gut filling, and is therefore one determinant of
perception of distension.9,10
Compliance. Compliance refers to the capability of a
region of the gut to adapt to intraluminal distension,
expressed as the ratio of the change in volume to the change
PHYSIOLOGY
in pressure. Several factors contribute to compliance
including the capacity (diameter) of the organ, the elastic
properties of the gut wall (ie, thickness, fibrotic component,
muscular activity), and the elasticity of surrounding
organs (which can be influenced by fibrosis, ascites,
abdominal masses). Although compliance sometimes has
been expressed as the pressure/volume ratio at one
distension step, it is expressed more accurately as the entire
pressure/volume curve. Compliance can differ markedly in
different regions of the gut, and even within an organ; for
example, the descending colon is less compliant than the
ascending colon, whereas the sigmoid colon is less
compliant than the transverse colon. Compliance decreases
during contraction and increases during relaxation, and in a
given organ is determined by the muscular activity of its
walls. Hence, short-term changes in compliance reflect the
tone of the organ. In that respect, compliance measurements
in vivo (volume/pressure relationship) reflect the elonga-
tion/tension relationship of the gut wall.
A distending intraluminal volume produces a stretch and
tension (force) on the gut wall, which determines the
intraluminal pressure increment. Perception of gut disten-
sion is in part determined by wall tension, rather than by
intraluminal volume or pressure. Hence, assessment of wall
tension may be important in assessing perception of visceral
stimuli.10–13
Transit. Although flow reflects the local movements of
intraluminal content, transit refers to the time taken for
food or other material to traverse a specified region of the
gastrointestinal tract. Transit represents the net interaction
of a number of parameters and is a relevant and convenient
index of organ function. Most measurements of transit are
based on detecting intraluminal movements of an extrinsic
marker labeling the luminal content. Transit depends on
many factors, such as the physical (eg, solid, liquid, gas) and
chemical (eg, pH, osmolality, and nutrient composition)
nature of both gut contents and the administered marker.
Transit measurement also is influenced by the state of gut
motility at the time of marker administration (eg, fasted vs
fed motility), and any preparation of the gut (eg, cleansing of
the colon). The transit times have been shown to be
abnormal in some FGIDs.
The relationship between transit and phasic activity or
tone is incompletely understood, but studies examining the
movement of radiolabeled colonic contents in healthy sub-
jects have shown that only 28% are associated with prop-
agating sequences, with the remainder associated with
Gastroenterology Vol. 150, No. 6
either nonpropagating activity (32%) or no pressure events
(40%).14 Moreover, patients with chronic constipation who
have normal transit can show reduced fasting and/or
postprandial colonic tone.15
Mucosal Barrier Integrity and Secretion
Interest in the role of abnormal barrier function in FGIDs
has increased since the observation that postinfectious IBS
is associated with increased permeability and increased
rectal mucosal enteroendocrine cells and T lymphocytes.16
The intestinal barrier. A tightly regulated intestinal
barrier is present to protect us against threats from the
intestinal lumen.16–18 At first, gastric acid and pancreatic
juice degrade bacteria and antigens in the lumen. Next, the
enterocytes are covered by an unstirred water layer, the
glycocalyx, and, finally, a mucus layer secreted by goblet
cells providing some kind of physical barrier against intra-
luminal bacteria. Together with secreted factors such as
defensins secreted by Paneth cells and secretory immuno-
globulins released by enterocytes, a subtle equilibrium with
the external milieu is created within this layer covering the
epithelium (Figure 1).
The epithelium is tightly sealed by 3 types of junctional
complexes between the enterocytes: (1) tight junctions, (2)
adherent junctions, and (3) desmosomes. Tight junctions are
the most apical intercellular protein complex formed by
transmembrane proteins such as claudins, occludin, and
tricellulin, which are connected to the actin cytoskeleton via
zona occludens. They are mainly responsible for the sealing
of the intercellular space and regulate the passage of par-
ticles in a rather complicated manner with sometimes
opposing functions.16 Interaction with the strength of the
tight junctions will increase permeability to large solutes
with no charge discrimination, a pathway referred to as the
leak pathway. Adherent junctions are located below the
tight junctions and are linked to the actin cytoskeleton
through multiprotein complexes consisting of the trans-
membrane protein E-cadherin and the intracellularly local-
ized catenins.17 Together with desmosomes, the third type
of junctional complexes located at the basal pole of the
intercellular space, they comprise strong adhesive bonds
between epithelial cells, providing mechanical strength to
the epithelial barrier. Stimuli modulating the strength of
these bonds also thus will contribute to a more leaky
barrier.
Factors leading to barrier dysfunction. Mainly from
animal work, several factors have been proposed, such as
genetic predisposition, alterations in the microbiome
(including bacterial infection), and psychological stress
(through mast cell activation). In human beings, the evi-
dence is limited.
Genetics. Patients carrying a single-nucleotide poly-
morphism in the gene encoding for cadherin-1, one of the
proteins of the adherent junctions, are at higher risk of
developing postinfectious IBS.19
Glutamine. Glutamine synthase, a key enzyme in the
synthesis of glutamine, is reduced in the intestinal mucosa
of diarrhea-predominant IBS patients with increased
May 2016 Gastrointestinal Motility and Sensation 1295

PHYSIOLOGY
Figure 1. The intestinal mucosal barrier. A layer of unstirred water and mucus (secreted by goblet cells), together with secreted
soluble immunoglobulin A (IgA), antimicrobial proteins (AMP), goblet cell–derived products (such as trefoil factor 3 [TFF3]) are
the first line of defense against commensals and pathogens. Intestinal epithelial cells (IECs) form a biochemical and physical
barrier that maintains segregation between luminal contents and the mucosal immune system. IESC, intestinal epithelial stem
cell. Modified from Peterson and Artis.117

permeability.20 Glutamine is a major energy source for
rapidly dividing mucosal cells such as enterocytes, and thus
important for the maintenance of intestinal barrier function.
Stress. In human beings, cold pain stress and psycho-
logical stress result in increased levels of mast cell media-
tors in jejunal fluid,21,22 whereas psychological stress and
infusion of corticotropin-releasing hormone induce
increased permeability in healthy subjects. Mast cell acti-
vation induced by stress may be one of the mechanisms
leading to barrier dysfunction in human beings (Figure 2).
Intraluminal proteolytic activity. Increased proteo-
lytic activity in the intestinal lumen,23,24 caused by either
pancreatic enzymes or bacterial proteases, can lead to bar-
rier dysfunction.24 Application of diarrhea-predominant IBS
fecal supernatant on colonic mucosa results in a rapid
increase in phosphorylation of myosin light chain and
delayed redistribution of zonula occludens-1 in colonocytes.
Secretion. Although abnormalities in secretion have
not been studied in depth in FGIDs, interest in mechanisms
triggering secretion has increased tremendously since the
observation that compounds activating secretion are effi-
cacious as treatment for functional constipation and
constipation-predominant IBS.25 Linaclotide, a 14–amino
acid peptide homologous to bacterial heat-stable entero-
toxins, activates receptor guanylyl cyclase C in the brush
border of intestinal mucosa cells from the duodenum to
rectum to open the cystic fibrosis transmembrane conduc-
tance regulator chloride channel, producing a net efflux of
ions and water into the intestinal lumen.26 Lubiprostone, an
activator of chloride channels, is a member of a class of
compounds called prostones,27 and results in increased
chloride secretion with associated passive transport of
sodium and water across the epithelium, thereby enhancing
fluid secretion.
Bile acids potently induce secretion and colonic
motility.28 Increased exposure of the colonic mucosa owing
to reduced reabsorption in the distal small intestine (bile
acid malabsorption) has been implicated in a subgroup of
patients with diarrhea-predominant IBS.29 Conversely, pa-
tients with constipation-predominant IBS or functional
constipation have impaired bile acid synthesis,30 indicating
that alterations in bile acid metabolism may be implicated in
the pathophysiology of functional gastrointestinal disorders.
Relevance of Motility, Secretion, and Barrier
Functions to FGID
In the context of the FGIDs, gastrointestinal dysmotility
can develop through several mechanisms involving the
brain–gut axis. First, various inflammatory, immune, infil-
trative, or degenerative processes may directly affect the
muscle and/or other elements of the enteric nervous sys-
tem effector system. Dysmotility also may be triggered
indirectly in response to excess stimulation by visceral
afferent (sensory) fibers that influence local gastrointes-
tinal motor function via modulation of motor neurons in
prevertebral ganglia. In addition, activation of visceral
afferent fibers induces autonomic changes integrated in the
brainstem, such as changes in heart rate, and alterations in
colonic tone (eg, vagally mediated gastrocolonic motor
response), which may be increased in certain FGIDs.
Finally, psychosocial stressors can induce mast cell acti-
vation affecting motility, mucosal permeability, and
visceral afferents (Figure 2).
 1296 Boeckxstaens et al Gastroenterology Vol. 150, No. 6
PHYSIOLOGY

Figure 2. Psychological stress induces changes in motility, secretion, and barrier function via the brain–eosinophil–mast cell
axis. Animal studies have indicated that stress indirectly activates mast cells via eosinophils. The latter cells release
corticotropin-releasing hormone (CRH), inducing mast cell activation. Mast cell mediators subsequently act on afferent nerve
fibers, barrier function, and blood vessels. Moreover, direct interaction between the brain and the enteric nervous system
(ENS) further contributes to stress-induced changes in physiology due to stress.

Food, Meal Intake, and Microbiota
The meal ingested is transformed from the mouth to the
ileum, first by digestion and then by absorption, so that only
nonabsorbed residues pass into the colon. The whole
digestive–absorptive process down to the terminal ileum is
finely regulated depending on the composition of intra-
luminal content; nutrients in the stomach and small bowel
have limited effects on colonic activity. Nonabsorbed meal
residues entering the colon serve as substrate to feed
microbiota and this interaction has several effects, including
the modulation of the digestive system.
Effect of Food on Gastric and
Small-Bowel Activity
During fasting, the gastrointestinal tract exerts cyclic
activity with alternating periods of quiescence and periods
of intense motor and secretory activity (Figure 3). This
stereotyped pattern develops in the absence of extrinsic
stimuli and its function seems to be the clearance of resi-
dues from the gut lumen. Ingestion of a meal stimulates the
digestive system, suppresses the intrinsic interdigestive
pattern, and activates reflexes that control the digestive
process. The presence of nutrients in the gastrointestinal
tract modulates gastrointestinal motility, barrier function
(secretion, absorption), as well as sensitivity. Even before
ingestion, the digestive system starts with a series of pre-
paratory procedures, which include the cephalic phase of
digestion and in normal conditions an anticipatory reward
sensation. Food ingestion and swallowing activates oral and
esophagogastric responses (salivation, esophageal peri-
stalsis, and receptive relaxation). Meal arrival into the
stomach induces an accommodative relaxation (gastric ac-
commodation), as well as secretion, while solid particles
activate the antral pump with peristaltic grinding activity.
Intraluminal nutrients modulate the activity (motility,
secretion, absorption) of the small bowel, adapting it to the
local requirements of the digestive process. Meal ingestion
exerts a profound influence down to the ileocecal junction,
but it also has a relatively mild distal effect, inducing colonic
contraction (gastrocolonic reflex).
The response to a meal is largely elicited by stimulation
of gut receptors and activation of neurohumoral pathways.
Some gut receptors are nutrient-specific. Meals are hetero-
geneous and their global effects depend on the nutrient
composition. Food components elicit antegrade and retro-
grade responses, which also might be different (ie, retro-
grade stimulation and antegrade relaxation). Furthermore,
the same component might elicit different effects when
passing through different regions of the gut (ie, stimulation
of gastric secretion in the proximal small bowel and inhi-
bition in the distal). Fat is a very active component of food
and has potent effects on motility, sensitivity, and barrier
function, but other food components also play a role.
Normally, the digestive response to a meal also involves
a cognitive–emotive component with a pleasant sensation of
satiation, digestive well-being, even a positive influence on
mood.31 Patients with FGIDs show abnormal gut function
and increased sensitivity owing to a mixed sensory–reflex
dysfunction, so that physiological, normally unperceived
stimuli induce symptoms.32 The type of symptoms depends
on the specific sensory–reflex pathways and region(s)
affected. Nutrients modulate the responses of the gut to
various stimuli and some of these modulatory mechanisms
are abnormal in patients with FGIDs, which may explain the
relationship between nutrients and functional GI symptoms.
For instance, it consistently has been shown that FGID pa-
tients are much more sensitive to small intestinal lipid
exposure than healthy controls. These effects seem to be
specific for fat because isocaloric administration of other
May 2016 Gastrointestinal Motility and Sensation 1297

PHYSIOLOGY
Figure 3. The MMC is the gastric and small intestinal motor pattern of the interdigestive state. The interdigestive pattern of
small intestinal motility begins after digestion and absorption of nutrients are complete 2–3 hours after a meal and is called the
migrating motor complex. Sensors in the stomach show that the MMC starts as large-amplitude contractions at 3 per minute in
the distal stomach. Activity in the stomach appears to migrate into the duodenum and on through the small intestine to the
ileum. At a given time, the MMC occupies a limited length of intestine called the activity front, which has an upper and lower
boundary. The activity front slowly advances (migrates) along the intestine.

nutrients does not result in comparable symptomatic
responses.33,34
Despite the general acceptance that functional gut
symptoms are induced, or exacerbated, by food ingestion, few
studies have been performed to evaluate the role of specific
foods. Dyspeptic patients report several foods such as fried
foods, pastry, or spices to be associated with their symp-
toms.35 Cognitive factors also may contribute to functional
digestive symptoms, especially because previous negative
experiences might influence a patient’s anticipation of
symptoms. A study in patients with functional dyspepsia
showed that information about the fat content of a test meal
increased the symptoms induced by a low-fat yogurt when
the patients were (mis)informed that the yogurt was high in
fat.36 Few studies have evaluated dietary habits in patients
with FGID and the global outcome is not clear-cut. Further-
more, it is not clear whether the differences observed are the
cause of symptoms, or whether the differences just reflect
dietary modifications to prevent symptoms.
Food and Microbiota
The human organism hosts a large community of mi-
croorganisms. A large proportion of this resides in the colon,
which provides a dedicated niche for this population of
symbiotic organisms. Meal residues that have not been
absorbed in the small bowel enter the colon and serve as
feeding substrate for the microbiota.
Although the human organism feeds and hosts the
microbiota, microbiota accomplish a series of important
functions, operating as another organ of the host. Microbiota
accomplish important biological functions for the host,37–39
such as: (1) development of the immune system, particu-
larly immune tolerance; (2) development of the central
nervous system and behavior; (3) modulation of metabolic
activity, energy balance, and growth; and (4) regulation of
the digestive system. On the other hand, the host also in-
fluences the microbiome. Hence, there is dynamic cross-talk
between the host and microbiota, but the messengers and
circuits for communication still are poorly understood. The
microbiota metabolize unabsorbed substrates delivered into
the colon and release a vast amount of metabolites that
could serve as messengers activating gut receptors or
crossing the gut-blood barrier and acting at different sites.
Some data indicate that microbiota may exert modulatory
effects on gut function, both motility and barrier function.
Prebiotic and probiotic treatment modify the microbiota
and accelerate intestinal transit. The microbiota also may
influence visceral sensitivity. Indeed, modulation of micro-
biota induces visceral hypersensitivity and visceral pain
perception in animals.
Genetics
Genetic mechanisms appear to be associated with
visceral pain and motor functions in health and functional
gastrointestinal disorders. Familial aggregation and twin
studies support a genetic factor in IBS. In addition, gene
variations have been described in association with the
symptom phenotype of IBS, biomarkers of visceral pain, and
motor function.
Familial aggregation and twin studies
Epidemiologic studies of familial aggregation40,41 and
twins42–46 suggest that there is a genetic component of IBS.
However, the data are conflicting, and the contribution of
common environment to the association of IBS within
studies presents a significant confounder that cannot be
completely resolved.
 1298 Boeckxstaens et al
Visceral pain
Genetic studies suggest that variation in the control of
candidate genes involved in ion channel function, neuro-
transmitter synthesis, reuptake or receptor functions, and
inflammatory disease susceptibility loci may impact varia-
tions in the prevalence of the symptom phenotype of
abdominal pain or IBS, or quantitative traits (intermediate
phenotypes) of rectal sensation. The candidate genes
include SLC6A4, CNR1, and TNFSF15 reflecting serotonin
reuptake, cannabinoid receptors, and inflammatory–barrier
functions. However, other than TNFSF15, the other candi-
PHYSIOLOGY
date genes are only univariately associated with pain, IBS
symptom complex, or quantitative traits of sensation.47
Motor and barrier functions
Genetic studies suggest that variation in the control of
candidate genes involved in neurotransmitter (serotonergic,
a2 adrenergic, and cannabinoid) mechanisms, inflammatory
pathways (interleukin 10, tumor necrosis factor a, GNb3,
susceptibility loci involved in Crohn’s disease), and bile acid
metabolism are associated with symptoms and disturbances
of motor function, particularly colonic transit.48
Region-Specific Physiology
The Esophagus
Physiology. Esophageal motility and lower esopha-
geal sphincter function. The coordinated motor pattern of
the esophagus initiated by the act of swallowing is called
primary peristalsis. Primary peristalsis usually clears most
contents of the esophagus into the stomach. Secondary
peristalsis is provoked by residual food or reflux events, and
it is not accompanied by pharyngeal contraction or upper
esophageal sphincter relaxation. Peristalsis in the striated
muscle part of the esophagus is dependent on central vagal
pathways. It is mediated by sequential excitation of motor
neurons in the nucleus ambiguous.49 Peristalsis in the
thoracic esophagus is mediated by both central and
peripheral mechanisms.50,51 The timing of peristalsis in
the smooth muscle segment is based on the duration of
the deglutitive inhibition that increases distally along the
esophagus followed by deglutitive rebound excitation.52 This
deglutitive inhibition results from a near-simultaneous acti-
vation of short-latency inhibitory vagal fibers,51 triggering a
wave of inhibition that precedes the arrival of the peristaltic
contraction.53 This inhibitory wave, mediated by myenteric
inhibitory neurons,54 also results in relaxation of the lower
esophageal sphincter, allowing passage of the bolus into the
stomach. The rebound excitation occurs after the sequential
termination of deglutitive inhibition. The balance of timing in
inhibition and excitation is the fundamental mechanism that
regulates esophageal peristalsis.
The esophageal peristaltic contractions are regulated by
predominantly cholinergic excitatory input in the proximal
but noncholinergic inhibitory (or nitrergic) in the distal
esophagus. As a consequence, cholinergic antagonists such
as atropine increase the latency and decrease the amplitude
of contraction in the proximal but not the distal parts of the
Gastroenterology Vol. 150, No. 6
esophagus. In contrast, antagonists of nitric oxide synthase
reduce the latency mainly in the distal segments and lead to
simultaneous contractions. The fact that impaired degluti-
tive inhibition is reported in the esophageal body of patients
with diffuse esophageal spasm55 and nonspecific esophageal
motility disorders suggest that decreased nitrergic input
may be involved in the pathogenesis of these disorders.
Longitudinal muscle contraction may be important in
esophageal bolus transport.56 Synchrony between circular
and longitudinal muscle (LM) contractions is important to
create maximal increase in esophageal muscle thickness and
efficiently show peak pressure contractility.57 Esophageal
shortening is important to produce lower esophageal
sphincter (LES) axial movement and opening. This is true
during swallowing and transient LES relaxation.58 Finally,
abnormal LM contraction and shortening may be associated
with pathology and symptoms. Studies using high-frequency
intraluminal ultrasound described long-lasting thickening of
the esophageal wall (sustained esophageal contraction)
associated with chest pain or heartburn.59
The junction between the esophagus and stomach is a
highly specialized region, composed of the LES and crural
diaphragm.60 Because the 2 components are anatomically
superimposed, contraction of the striated muscle of the
crural diaphragm during inspiration or straining exerts a
pressure on the LES, leading to a dynamic and powerful
increase in esophagogastric junction pressure.60 The
esophagogastric junction has to be able to relax briefly upon
swallowing to allow passage of ingested food toward the
stomach. The postganglionic inhibitory myenteric neurons
innervating the LES are nitrergic in nature, and act by
releasing nitric oxide.54
Secretion and sensation. The esophageal submucosal
glands secrete water, bicarbonate, mucins, epidermal
growth factor, and prostaglandins. These substances are
involved in mucosal clearance along with peristalsis and
salivary secretion. The most important secreted substance is
bicarbonate, which plays a protective role during gastro-
esophageal reflux.61
Vagal afferents merging from the esophageal smooth
muscle layer and serosa are sensitive to muscle stretch,
whereas vagal afferents in the mucosa are sensitive to
various stimuli including chemical (acid), thermal (cold or
hot), and mechanical intraluminal stimuli.62 In general,
vagal afferents do not play a direct role in visceral pain
transmission to the brainstem but rather transmit physio-
logical stimuli. In contrast, spinal afferents, which have their
cell bodies in the dorsal root ganglia, are acting predomi-
nantly as nociceptors.62 Spinal afferents terminate in the
dorsal column nuclei and project stimuli to the brain.63
Esophageal symptoms and pathophysiology. The
major esophageal symptoms are heartburn, chest pain,
dysphagia, belching, and rumination.
Heartburn. Heartburn, the most frequently encountered
symptom of esophageal origin, is characterized by discom-
fort or a burning sensation behind the sternum that arises
from the epigastrium and may radiate toward the neck.64
Heartburn is an intermittent symptom, most commonly
experienced within 60 minutes of eating, during exercise,
May 2016
and while lying recumbent. The most common cause of
heartburn is esophageal acidification. Other stimuli such as
esophageal distension also can provoke heartburn. In pa-
tients with esophagitis, luminal content easily can permeate
the mucosa and stimulate sensory nerves to produce
heartburn. In patients with nonerosive reflux disease, the
mechanism of heartburn involves microscopic alterations of
esophageal mucosa and esophageal hypersensitivity. In
nonerosive reflux disease, the basal layer of the esophageal
mucosal epithelium shows dilated intercellular spaces.65
Dilated intercellular spaces in the basal layer of the esoph-
ageal epithelium may facilitate the passage of acid or other
components in the refluxate into the mucosa, thereby trig-
gering symptoms and inducing peripheral sensitization.66,67
Chest pain. Chest pain is a common esophageal symp-
tom with characteristics similar to cardiac pain. Esophageal
pain usually is experienced as a pressure-type sensation in
the midchest, radiating to the midback, arms, or jaws.
Esophageal distention or chemostimulation (eg, with acid)
can be perceived as chest pain.68 The most important
mechanism for chest pain of esophageal origin is gastro-
esophageal reflux. Some patients perceive reflux as chest
pain instead of heartburn. The reason for such difference is
unknown, but higher reflux volume and esophageal disten-
sion have been proposed. Another mechanism associated
with esophageal chest pain is severe esophageal motility
disorders such as spastic achalasia (type 3) and severe
hypermotility such as jackhammer esophagus.69 Abnormal
LM contraction and shortening may be associated with chest
pain.59 Finally, patients with noncardiac chest pain
frequently have esophageal hypersensitivity and psycho-
logical comorbidity.62
Dysphagia. Esophageal dysphagia often is described as
a feeling of food sticking on the way down or even lodging in
the chest for a prolonged period. It can be caused by me-
chanical obstruction such as peptic stricture, absent
esophagogastric junction relaxation (achalasia) or a Schatzki
ring, by esophageal dysmotility either with significant
hypomotility (ineffective motility), or by motility dis-
coordination as very rapid contraction with short latency
after swallows,70 or a large gap between contractions at the
transitional zone between the striated and smooth muscle.71
Mucosal inflammation associated with esophagitis also can
be responsible for dysphagia in gastroesophageal reflux
disease. Finally, dysphagia can occur in the absence of any
identifiable abnormality, in which case it is likely the result
of hypersensitivity to bolus movement during peristalsis.
Belching. Gastric belching is a physiological mechanism
that enables venting of gas from the stomach to the
esophagus. In another type of belching, supragastric belch-
ing (identified with impedance), air is sucked rapidly into
the esophagus and is followed immediately by a rapid
expulsion of air without ever reaching the stomach. Both
gastric and supragastric belching are common symptoms in
gastroesophageal reflux disease patients. Supragastric
belches can induce reflux episodes.72
Rumination. Rumination is clinically suspected when
chronic, effortless regurgitation of recently ingested food oc-
curs, followed by re-mastication, re-swallowing, or
Gastrointestinal Motility and Sensation 1299
expulsion.73 The absence of nausea, discontinuation of
symptoms when the contents become acidic, and the
impression of pleasant taste of clearly recognizable food in the
regurgitate are supportive criteria to diagnose rumination
clinically. The characteristic high-resolution manometric
pattern of rumination shows an abrupt increase in intragastric
pressure (strain), followed by an increase in intraesophageal
pressure in all channels (common cavity), followed by primary
or secondary peristalsis. In some patients, however, it is
difficult to distinguish rumination from postprandial bel-
ching–regurgitation. Esophageal impedance combined with
PHYSIOLOGY
manometry allows recognition of liquid retrograde flow in
rumination and a better time definition between increased
abdominal pressure and regurgitation events.74
Stomach
Physiology. Gastric physiology often is described by
the different functions of the proximal and distal stomach.
During fasting, the stomach participates in the cyclic inter-
digestive motor pattern (migrating motor complex) with
alternating periods of quiescence and periods of activity
(Figure 3). During the periods of phase III activity, the
proximal stomach generates a high-level tonic contraction
with superimposed prolonged phasic contractions at a 1-
minute rhythm, whereas the antrum produces shorter 3
per minute phasic contractions.75 The antral phasic con-
tractions are timed by the gastric pacemaker in the body of
the stomach, emanating from the interstitial cells of Cajal.76
Ingestion of food suppresses interdigestive motility, and
the gut switches to a fed pattern. The stomach accommo-
dates an ingested heterogeneous meal, and delivers ho-
mogenized chyme into the small bowel at a rate adapted to
the intestinal processing capability. In response to ingestion,
the proximal stomach partially relaxes to accommodate the
meal. Later during this postprandial period, the proximal
stomach progressively regains tone, and this tonic contrac-
tion gently forces intragastric food distally. Solid particles
are retained and ground in the antrum by phasic contrac-
tions, whereas liquid chyme is squeezed through the pyloric
gate, which determines the final gastric outflow.
The motor responses of the proximal stomach during the
postprandial period are modulated by several mechanisms.
The motor response induced by swallowing produces a
transient and brief receptive relaxation not only of the
esophagogastric sphincter, but also of the fundus.77 Antral
filling releases antrofundal relaxatory reflexes, which may
play a major role in the early accommodation phase.78 Nu-
trients entering the intestine induce a variety of reflexes
depending on the type of nutrients and the region of the
intestine stimulated, which probably constitute a fine feed-
back control to adapt the nutrient delivered rate to the in-
testinal processing capability. Other chyme parameters,
such as pH and osmolality, also play a role. Gastric accom-
modation is modulated by vagovagal reflexes involving the
release of 5-hydroxytryptamine, probably at the level of the
enteric nervous system, and subsequent activation of
inhibitory nitrergic motor neurons to produce fundic
relaxation79 (Figure 4).
 1300 Boeckxstaens et al
The stomach has a rich sensory innervation, and in
normal conditions, meal ingestion not only induces diges-
tive, but also cognitive and emotive, responses involving
satiation and a pleasant sensation of digestive well-being.31
Symptoms and pathophysiology. The stomach has a
reservoir function. Symptoms may originate by 4 types of
pathophysiological mechanisms: delayed gastric emptying,
impaired accommodation, increased perception, or acceler-
ated gastric emptying. Of note, the symptomatic expression
of the stomach is limited and the manifestations may be
similar regardless of the underlying pathophysiological
PHYSIOLOGY
mechanisms involved.
Delayed gastric emptying. Gastric emptying is the net
output of the stomach, which is governed by 3 areas of the
stomach: proximal fundus, distal antrum, and the pyloric
sphincter. Neural and hormonal pathways from the small
intestine also influence gastric emptying. Because phasic
antral contractions produce the grinding of solid particles
required for passage through the pylorus into the intestine,
impaired antral contractions results in the delayed
emptying of solids.80 On the other hand, the tonic contrac-
tion of the proximal stomach pushes gastric content distally
and feeds the antral pump. Hence, impaired tonic contrac-
tion of the proximal stomach results in impaired grinding of
solids and also may produce an overall delay in the
emptying of both solids and liquids. During the phases of
activity of the interdigestive period (phase III), gastric
contractions propagating from the proximal to the distal
stomach coincide with pyloric opening and duodenal
quiescence, have a very propulsive effect and produce the
evacuation of indigestible particles retained into the stom-
ach after the digestive period. The absence of gastric phase
III activity may promote gastric bezoar formation.
Delayed gastric emptying produces symptoms if the
disturbance is relatively severe, resulting in chyme reten-
tion into the stomach. The symptoms vary from mild
symptoms (early satiety, epigastric fullness, vague nausea)
to severe manifestation of gastric stasis with retention-type
Gastroenterology Vol. 150, No. 6
emesis (ie, vomiting of food ingested many hours or even
days earlier) and nutritional compromise. Nausea and
vomiting may occur in some patients during fasting rather
than postprandially. In some patients, this may lead to an
inability to eat because of symptoms and resultant weight
loss. In severe cases, even endogenous fasting secretions
cannot be emptied.81 Delayed gastric emptying in the
absence of mechanical obstruction is called gastro-
paresis.82,83 Chronic idiopathic gastroparesis constitutes a
relatively uncommon but important entity. The diagnosis of
gastroparesis should be restricted to patients with objective
demonstration of grossly abnormal gastric emptying of
solids and liquids. Some patients with functional dyspepsia
show a delay of solid emptying with normal emptying
of liquids.
Impaired accommodation. Impaired accommodation of
the proximal stomach in response to food ingestion in-
creases gastric wall tension, which might activate sensory
endings in the gastric wall and produce symptoms. Inap-
propriate relaxation might be related to impaired enter-
ogastric and antrofundic reflexes that normally modulate
the gastric accommodation/emptying process.78,84 Reduced
proximal gastric relaxation in response to a meal can be
seen in some patients with functional dyspepsia and this
may be associated with more prevalent early satiety and
weight loss.85 Impaired accommodation is associated with
abnormal intragastric distribution of food in patients with
functional dyspepsia, with preferential accumulation in the
distal stomach or antral overload.86 The latter may explain
the impression of postprandial antral hypomotility in
dyspepsia because only occlusive contractions are recorded
by manometry. A distended antrum may produce a slower
grinding of solids, and lead to prolonged gastric retention
and delayed emptying of solids observed in a subpopulation
of these patients.
Increased gastric sensitivity. Distending the stomach
can produce conscious sensations similar to the symptoms
reported by patients with gastric functional disorders.
Figure 4. Adaptive relaxa-
tion in the gastric reservoir
is a vagovagal reflex. The
adaptive relaxation is trig-
gered by filling and
distension of the gastric
reservoir. It is a vagovagal
reflex that is triggered by
stretch receptors in the
gastric wall, transmission
over vagal afferents to the
dorsal vagal complex, and
efferent vagal transmission
to inhibitory motor neurons
in the gastric enteric ner-
vous system.
May 2016
Perception of gastric distension depends on activation of
tension rather than elongation or volume receptors in the
gastric wall.87 Some patients with functional dyspepsia
show increased perception of gastric distension or hyper-
sensitivity of the stomach, but not of the duodenum.
Moreover, somatic sensitivity in these patients is normal or
even decreased, with enhanced tolerance of aversive so-
matic stimuli characteristic of chronic pain conditions.78,88
Gastric hypersensitivity is more prevalent in patients with
predominant epigastric pain89 and may coexist with
impaired gastric accommodation to meal ingestion and/or
delayed gastric emptying.
The cause and mechanism of gastric hypersensitivity has
not been elucidated. In normal conditions, gastric sensitivity
is modulated by several mechanisms. For instance, lipids in
the small intestine increase perception of gastric distension.
This modulatory mechanism is up-regulated in patients with
functional dyspepsia, and, hence, contributes to the genesis
of symptoms. Some data indicate that altered perception in
a subset of patients with dyspepsia occurs as a consequence
of an acute (possibly viral) gastroenteritis, which leads to
impaired nitrergic nerve function in the proximal stom-
ach.90 Central mechanisms also may play a role. Anxiety is
correlated negatively with pain and discomfort threshold in
hypersensitive functional dyspeptic patients.91
Accelerated gastric emptying. In some patients, mainly
after partial or complete gastrectomy, rapid gastric
emptying is accompanied by vasomotor and gastrointestinal
symptoms. Dumping Syndrome also may be observed after
vagotomy, intentional or unintentional, at the time of sur-
gery at the gastroesophageal junction.
Symptoms typically occur after ingestion of liquids and
meals rich in carbohydrates, and usually occur within the
first weeks after surgery, when patients resume their
normal diet. Dumping symptoms can be subdivided into
early dumping and late dumping. Early dumping occurs in
the first hour after meal ingestion and is associated with
both abdominal and systemic symptoms owing to the rapid
passage of hyperosmolar contents into the small bowel,
leading to a shift of fluids from the intravascular compart-
ment to the gut lumen. This induces intestinal distension
and gastrointestinal symptoms such as bloating, abdominal
pain, and diarrhea.92 Enhanced release of several gastroin-
testinal hormones, including enteroglucagon, vasoactive in-
testinal polypeptide, peptide YY, pancreatic polypeptide,
and neurotensin are thought to cause a systemic and
splanchnic vasodilation, most likely explaining the vaso-
motor symptoms. Late dumping occurs 1–2 hours post-
prandially and results from reactive hypoglycemia. Rapid
gastric emptying induces high glycemic levels, which lead to
increased insulin secretion. Because of the long half-life of
insulin and the often very transient character of the initial
increase in glycemia, reactive hypoglycemia occurs when all
sugars have been absorbed.
Small Intestine
Small intestinal physiology. Motility and secre-
tion. The small intestine is where most of the digestion of
food to absorbable nutrients takes place. Digestion and
Gastrointestinal Motility and Sensation 1301
absorption require a combination of motor activity and
secretion of water, electrolytes, bile, and enzymes. The
pancreas delivers most of the enzymes needed for digestion
of lipids and proteins. It also delivers amylase for the
digestion of starch and glycogen, whereas the final digestion
of carbohydrates takes place at the microvilli of enterocytes
using brush-border enzymes. Little is known about the role
of small intestinal motility in digestion.
Phase III of the migrating motor complex (MMC) is co-
ordinated with intestinal, biliary, and pancreatic secre-
tion,93,94 and probably serves a housekeeper function in the
PHYSIOLOGY
small intestine. The MMC is a program that resides in the
enteric nervous system but can be influenced by extrinsic
control systems, such as the vagus nerve, and a number of
gut hormones and neurotransmitters.95 Motilin, which is
secreted from enteroendocrine M cells in the upper small
intestine, can induce premature activity complexes in the
stomach. Of note, the occurrence of the phase III portion of
the migrating motor complex in the antrum is associated
with a peak in plasma motilin level.96 However, phase IIIs
that originate in the upper small intestine are not associated
with changes in plasma motilin levels.97 Ghrelin is secreted
by P/D1-cells in the gastric fundus. Similar to motilin,
ghrelin induces premature activity complexes in the stom-
ach when given exogenously.98 Both motilin-induced and
ghrelin-induced activity complexes behave similar to phase
IIIs and are propagated to the small intestine.96,99 Prema-
ture activity complexes in the small intestine without acti-
vation of the stomach can be elicited using somatostatin100
or octreotide.101 Somatostatin is secreted from neuroendo-
crine neurons of the periventricular nucleus of hypothala-
mus but also from enteroendocrine cells in the small bowel
and the stomach and from v-cells of the pancreas. It is as yet
unclear if somatostatin has a direct effect on small intestinal
motility or if the effect is mediated by inhibition of
pancreatic polypeptide.100 An intact vagus nerve is required
for inhibition of MMC and conversion to fed motor activity
in the small intestine.
Sensation. In healthy people, the functions of the small
intestine are hardly perceived. Borborygmus sometimes can
be noticed after a meal and the audible noise is caused by
movement of swallowed air and fluids in the bowel, but it
also can arise during fasting in association with the migra-
tion of an activity complex. The gut usually is effective at
handling gas.102 Bloating is a feeling of being puffed up in
the abdomen and can be felt after eating.
Small intestinal symptoms and pathophysi-
ology. In pathologic conditions, dysfunction in the small
intestine can give rise to abdominal pain, bloating,
abdominal distension, and diarrhea. The mechanisms that
lead to pain and discomfort are somewhat unclear but
distension of the intestines is one such mechanism. Pain
caused by distension is mediated by stretch receptors in
muscle layers and serosa that project through splanchnic
and vagal nerves to the brain.103 Abnormal sensitivity
seems to involve other mechanisms including mast
cells.104,105 Bloating and abdominal distension are symp-
toms that recent research have ascribed to abnormal vis-
cerosomatic reflexes.106,107 Patients with enteric
 1302 Boeckxstaens et al
dysmotility as well as patients with IBS show a greater
retention of infused gas compared with healthy controls,
indicating impaired gas clearance as a mechanism for
distension in these patient groups.108 Diarrhea can be
caused by increased intestinal secretion (eg, from stimu-
lation of guanylate- or adenylate-cyclase receptors on the
enterocytes). Diarrhea also can follow from impaired
digestion of foods in the small intestine, resulting in an
osmotic increase in luminal water. Diarrhea caused by
maldigestion or malabsorption in the small intestine can be
enhanced further by colonic bacterial fermentation.
PHYSIOLOGY
Large Intestine and Anorectum
Physiology. Colon. Motor functions of the colon
include propulsion, accommodation, or storage, and rapid
emptying of a variable portion of the colon during defeca-
tion. Propulsion is achieved by a number of motor events
including individual contractions, contractile bursts, high-
amplitude propagated contractions, and possibly changes
in tone. High-amplitude propagated contractions have been
correlated with large-volume movements of the intra-
luminal content of the colon that initially were recognized
on barium studies as mass movements.
High-amplitude propagated contractions occur more
often in the morning, during the postprandial period, and
preceding defecation.109,110 Other colonic motor events
propel contents over short distances in either an orad or an
aborad direction, and their primary function appears to be
to facilitate mixing. It is likely that regular contractile
bursts—colonic motor complexes—do occur, each burst
occurring once or twice per hour and lasting approximately
6 minutes. Periodic or cyclic motor activity is evident more
clearly in the rectum, the so-called rectal motor complexes.
They do not appear to be synchronized with the small in-
testinal MMC and their precise function and regulation
remain unclear. In terms of sensitivity of the colon, experi-
mental distension of the descending or sigmoid colon is
perceived as a sensation of cramping, gas, or pressure in the
lower abdomen, lower back, or perineum.111
Gastroenterology Vol. 150, No. 6
Accommodation and storage are essential functions of
the colon so that fluids, electrolytes, and some products of
carbohydrate and fat digestion can be salvaged by bacterial
metabolism. Accommodation, storage, and distribution of
material within the colon are mediated by colonic tone
(Figure 5). Tone and phasic activity in the colon show
considerable diurnal variation, increasing slowly after a
meal, reducing during sleep, and increasing dramatically
upon waking.112,113 The colonic motor response to eating
consists of an increase in phasic and tonic contractile ac-
tivity that begins within several minutes of ingestion of a
meal and continues for a period of up to 3 hours. This
response is influenced by both the caloric content and
composition of the meal with fat and carbohydrate stimu-
lating colonic motor activity, while amino acids and protein
inhibit motor activity. The response of the proximal colon is
less than that of the distal colon.114
Anorectum. The anorectum functions in defecation and
continence. Defecation is achieved through the integration of
a series of motor events and involves both striated and
smooth muscle.115,116 A sensation of rectal fullness is
generated by rectal afferents when colonic contents reach the
rectum.13 Rectal filling also induces the rectoanal inhibitory
or rectosphincteric reflex that leads to internal anal sphincter
relaxation and external sphincter contractions. At this stage,
the individual can decide to postpone or proceed with defe-
cation. To facilitate defecation, the puborectalis muscle and
external anal sphincter relax, thereby straightening the rec-
toanal angle and opening the anal canal. The propulsive force
enabling defecation then is generated by contractions of the
rectosigmoid, diaphragm, and the muscles of the abdominal
wall to propel the rectal contents through the open sphincter.
The internal anal sphincter is a continuation of the smooth
muscle of the rectum and is under sympathetic control and
provides approximately 80% of normal resting anal tone,
whereas the external anal sphincter and pelvic floor muscles
are striated muscles innervated by sacral roots and the pu-
dendal nerve. Somatic and autonomic nervous system
convergence within the anorectum means that it is
Figure 5. Colonic motility:
normal tonic response of
sigmoid colon to a meal.
An example of the normal
postprandial increase in
tone in the descending
colon measured using the
electronic barostat is
shown. Note the reduction
in volume of the colonic
balloon (lower tracing) at
constant balloon pressure
(upper tracing) after the
meal, which represents an
increase in colonic tone.
May 2016
susceptible to disorders of both striated and smooth muscle,
as well as to diseases of the central, peripheral, and auto-
nomic nervous systems.
Main symptoms and pathophysiology. Main symp-
toms of dysfunction include constipation, diarrhea, urgency,
straining to defecate, sense of incomplete rectal evacuation,
and incontinence. Bloating and abdominal pain also are
features that often coexist, especially in patients with
dysfunction of the large intestine, but they also may arise as
a result of dysfunctions of the anorectum and pelvic floor.
Abdominal pain in the right and left lower quadrants of the
abdomen may suggest origin in the large intestine. Right
subcostal and epigastric pain may be symptoms of stasis in
the transverse colon. The pain also may become aggravated
postprandially, which often is mistaken for gastric origin
of the pain. In patients with constipation, the presence of
postprandial epigastric pain may arise from stimulation of
colonic contraction in the face of inadequate onward pro-
pulsion of colonic content as a result of fecal obstruction in
the left colon or rectosigmoid (eg, caused by rectal evacu-
ation disorders).
Concluding Remarks
Understanding the basis for digestive tract functions is
essential to understand dysfunctions in the functional
gastrointestinal disorders. This article has discussed and
critically assessed the normal physiology and pathophysi-
ology, and the processes underlying symptom generation.
From this careful review, the following recommendations
for future research in this area emerge.
 Define new characteristics of wall function other than
phasic and tonic contractions (eg, longitudinal muscle
contractions, elasticity, connective tissue).
 Improve differentiation of health from disease using
standardized stimuli when basal conditions are not
discriminatory.
 Conduct physiological measurements during times of
symptoms.
 Investigate luminal content (eg, microbiota, metab-
olomic factors), and contrast with the content juxta-
posed to the mucosa.
 Further characterization of peripheral and central
mechanisms of normal and abnormal sensory function.
 Apply physiological measurements as biomarkers in
epidemiology, phenotyping, and therapeutics.
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. To access the supplementary
material accompanying this article, visit the online version
of Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.030.
Gastrointestinal Motility and Sensation 1303
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Reprint requests
Address requests for reprints to: Henry P. Parkman, MD, Department of
Medicine, Temple University School of Medicine, 3401 North Broad Street,
Philadelphia, Pennsylvania 19140. e-mail: henry.parkman@temple.edu; fax:
(215) 707-2684.
Conflicts of interest
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 Gastroenterology 2016;150:1305–1318

The Intestinal Microenvironment and Functional

Gastrointestinal Disorders
Giovanni Barbara,1 Christine Feinle-Bisset,2 Uday C. Ghoshal,3 Javier Santos,4
Stepen J. Vanner,5 Nathalie Vergnolle,6 Erwin G. Zoetendal,7 and Eamonn M. Quigley8
1
Department of Medical and Surgical Sciences, School of Medicine, University of Bologna, Italy; 2University of Adelaide
Discipline of Medicine, and National Health and Medical Research Council of Australia Centre of Research Excellence in
Translating Nutritional Science to Good Health, University of Adelaide Discipline of Medicine, Adelaide, South Australia;
3
Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India;
4
Lab Neuro-Immune-Gastroenterology, Digestive System Research Unit, Department of Gastroenterology, Institut de Recerca

MICROENVIRONMENT
Vall d’Hebron, Hospital Vall d’Hebron, Barcelona, Spain; 5Gastrointestinal Diseases Research Unit, Queen’s University,
Kingston, Ontario, Canada; 6INSERM, U1220, Toulouse, France; Université de Toulouse, UPS, Institut de Recherche en Santé
Digestive, Toulouse, France; 7Laboratory of Microbiology, Department of Agrotechnology and Food Sciences, Wageningen
University, the Netherlands; and 8Lynda K and David M. Underwood Center for Digestive Disorders, Division of
Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas

For decades, interactions between the enteric neuromus-
cular apparatus and the central nervous system have served
as the primary focus of pathophysiological research in the
functional gastrointestinal disorders. The accumulation of
patient reports, as well as clinical observations, has belat-
edly led to an interest in the role of various luminal factors
and their interactions with each other and the host in func-
tional gastrointestinal disorders. Most prominent among
these factors has been the role of food. As a consequence,
although not always evidence-based, dietary interventions
are enjoying a renaissance in irritable bowel syndrome
management. Not surprisingly, given its exploration in many
disease states, the gut microbiota has also been studied in
functional gastrointestinal disorders; data remain incon-
clusive. Likewise, there is also a considerable body of
experimental and some clinical data to link the pathogenesis
of functional gastrointestinal disorders to disturbances in
epithelial barrier integrity, abnormal enteroendocrine
signaling, and immune activation. These data provide
growing evidence supporting the existence of micro-organic
changes, particularly in subgroups of patients with func-
tional dyspepsia and irritable bowel syndrome. However,
their exact role in the complex pathophysiology and symp-
tom generation of functional gastrointestinal disorders
needs to be further studied and elucidated, particularly with
longitudinal and interventional studies.
research had been performed on interactions with diet and/or
the products of digestion in the FGID sufferer. As the com-
plexities of the human microbiota are increasingly under-
stood, the possibility that microbe-host interactions, including
immune and metabolic responses, might be relevant to the
FGIDs has emerged. How any one or a combination of these
luminal factors interact with each other and with the host is a
subject of considerable research interest and putative path-
ophysiological mechanisms have been postulated (Figure 1).
These will be explored further in this review. Caveats
that might limit the outcomes of the current review must be
acknowledged. Although we aim to refer to human studies,
animal data could be mentioned when instrumental to
better understand the role of microenvironmental factors in
FGID. As most studies have been conducted in patients
suffering from functional dyspepsia (FD) and irritable bowel
syndrome (IBS), we will address other FGIDs only margin-
ally. Pharmacological and other interventional approaches
involving the intestinal microenvironment will not be sys-
tematically reviewed here.
Food
There is increasing recognition that dietary factors can
play a major role in the etiology and the pathogenesis of

Keywords: Microbiota; Bile Acids; Serotonin; Immune System;
Food; Irritable Bowel Syndrome; Functional Dyspepsia.
Abbreviations used in this paper: BA, bile acid; BAM, bile acid malab-
sorption; CRF, corticotropin-releasing factor; EC, enterochromaffin cell;
FD, functional dyspepsia; FGID, functional gastrointestinal disorder;
FODMAP, fermentable oligosaccharides, disaccharides, mono-
saccharides, and polyol; GI, gastrointestinal; 5-HT, 5-hydroxytryptamine,
serotonin; IBS, irritable bowel syndrome; IBS-C, irritable bowel syndrome

A
lthough the focus of studies on the pathophysiology
of functional gastrointestinal disorders (FGIDs) has
largely been on the enteric neuromuscular apparatus and its
central connections through the gut
brain axis, the potential
importance of the luminal environment was noted many de-
cades ago in the first descriptions of FGID-type symptoms
developing de novo in the aftermath of an enteric infection.1
Clinical experience informed us of the importance of food as
a symptom precipitant yet, up until very recently, little
with constipation; IBS-D, irritable bowel syndrome with diarrhea; IBS-M,
irritable bowel syndrome with mixed bowel habits; IFN, interferon; IL,
interleukin; JAM, junctional adhesion molecules; MC, mast cell; NCGS,
nonceliac gluten sensitivity; NGF, nerve growth factor; PI, post-infectious;
SCFA, short-chain fatty acids; SERT, serotonin reuptake transporter;
SIBO, small intestinal bacterial overgrowth; TJ, tight junction; TLR, toll-like
receptor; TNF, tumor necrosis factor; TpH, tryptophan hydroxylase; ZO,
zonula occludens.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.028
 1306 Barbara et al Gastroenterology Vol. 150, No. 6
MICROENVIRONMENT

Figure 1. Schematic representation of the putative interplay between luminal and mucosal factors in FGIDs. Microenviron-
mental factors (eg, food, microbiota, bile acids) may permeate in excess through a leaky epithelial barrier, allowing amplifi-
cation of signaling from the lumen to deeper mucosal and muscle layers, including overstimulation of the mucosal immune
system. These factors may determine abnormal signaling to neural circuits (intrinsic primary afferent nerves and extrinsic
primary afferent nerves), which in turn may affect intestinal physiology and sensory perception.

symptoms in both FD and IBS. Their impact could be
mediated through direct interactions between dietary
components and mucosal receptors that may have been
sensitized to these stimuli, or via down-stream events trig-
gered by dietary components, such as the release of gut
hormones, changes in epithelial morphology, generation of
immune responses, or altered signaling between the gut and
the brain.
Dietary factors that reportedly trigger symptoms include
eating patterns as well as specific foods and/or food com-
ponents. Only a few small studies have evaluated the direct
effects of administering specific foods or nutrients on
symptom provocation. No intervention studies have evalu-
ated the impact of targeted dietary changes on symptom
improvement in FD.
Although patients with IBS have long associated their
symptoms with food ingestion, a focused scientific and
clinical interest in the potential role of food in IBS has
emerged only recently.
Role of Diet
No major differences have been found in eating patterns
between FD patients and controls, although limited evi-
dence suggests that patients eat fewer meals per week, and
tend to eat more smaller meals/snacks, than controls.2
While up to 80% of patients report that fatty foods/
meals induce their symptoms, and approximately 30%
exclude fried foods to avoid symptoms, many other foods
are also reported to induce symptoms.3 Data on dietary
nutrient composition in FD are limited and inconsistent,
possibly because some patients modify their diets in an
attempt to alleviate symptoms. The only available pro-
spective study in FD patients noted trends toward lower fat
and energy intakes and direct relationships between, on
the one hand, postprandial fullness and fat and energy
intake and, on the other hand, bloating and fat intake.2
Wheat- and carbohydrate-containing foods have been
identified as triggers for symptoms, and FD patients
frequently report symptoms on exposure to milk and dairy
products, although their role remains unclear. Data on fiber
intake in FD are inconsistent.
The majority of IBS patients associate ingestion of a wide
range of foods with symptoms, particularly abdominal
bloating and pain.4 Patients frequently report making di-
etary adjustments, including reduced consumption of milk
products, wheat products, alcohol, and certain fruits or
vegetables that are high in poorly absorbed short-chain
carbohydrates and sugar alcohols (eg, onions) and an
increased intake of other fruits high in fermentable oligo-
saccharides, disaccharides, monosaccharides, and polyols
(FODMAPs; eg, grapes and pears).5 Data on such dietary
adjustments in IBS are not consistent. Many IBS patients
report symptoms in response to wheat-containing products,
reminiscent of the sensitivity to gluten that characterizes
celiac disease, despite negative celiac serology and normal
small intestinal morphology, a phenomenon that has
been termed nonceliac gluten sensitivity (NCGS). Subsets of
May 2016
patients also report symptoms after consumption of milk
and dairy products, or spicy foods. The view that a lack of
dietary fiber was the main cause of IBS has been largely
revised. While soluble fiber can have some beneficial effects,
insoluble fibers, including bran, appear to be of neither
benefit nor harm.
Provocation of Symptoms
Prospective studies in FD have only evaluated the effects
of fat on symptoms. While equicaloric high-fat and high-
carbohydrate yogurt-based meals both increased FD symp-
toms; pain, fullness, and nausea were greatest after the
high-fat meal.3
Studies that manipulate dietary constituents provide
further insights. Ingestion of a high-FODMAP diet wors-
ened symptoms (eg, abdominal pain, bloating, and exces-
sive flatus) in IBS patients, compared with healthy
controls or a low-FODMAP diet. In addition, in patients on
a low-FODMAP diet, blinded rechallenge with fructose
and/or fructan, but not glucose, exacerbated symptoms.6
The role of gluten in IBS remains uncertain. While one
recent study in patients with diarrhea-predominant IBS
(IBD-D) and NCGS found an improvement in symptoms on
a gluten-free diet, and their relapse when gluten was
reintroduced in a blinded fashion, another study was un-
able to confirm gluten-specific, as distinct from FODMAP-
related, effects on symptoms.7 In another study, exposure
to gluten increased stool frequency and altered gut barrier
function; mainly in IBS-D subjects who were human
leukocyte antigen DQ2 or DQ8 positive. While some
studies have found an improvement in symptoms on a
milk- or dairy-free diet, these trials were often not blin-
ded. Intolerance might also exist toward other compo-
nents of milk. Acute ingestion of hot chili powder in a
capsule with a meal increased abdominal pain and burning
in IBS patients compared with healthy controls.
Potential Mechanisms
The limited research that has been performed suggests
that symptoms generated by food ingestion in FD may be
due to exaggerated signals originating in the upper GI tract,
including gastric hypersensitivity to distension, small in-
testinal hypersensitivity to fat, and hypersensitivity to the
effects of gut hormones (particularly cholecystokinin), acid,
capsaicin, and the products of colonic fermentation.3
Several factors could contribute to the pathophysiology of
food-related symptoms. An enhanced phasic
colonic motor
response to food ingestion and colonic hypersensitivity to
distension can both contribute to a nonspecific increase in
abdominal symptoms postprandially in IBS. FODMAPs are
osmotically active and increase water content in the intestinal
lumen. They are rapidly fermented to hydrogen, carbon di-
oxide, methane, short-chain fatty acids (SCFAs), and lactate.
Such responses could be exaggerated in IBS, the resulting
distension of the intestinal lumen may exacerbate visceral
hypersensitivity. Gluten can cause a mild immune response in
IBS patients, associated with exaggerated responses in
enteric and sensory nerves and compromised intestinal
Microenvironment and FGID 1307
barrier function.8 Some of the adverse reactions attributed to
“gluten” might reflect a hypersensitivity to wheat or intoler-
ance to FODMAPs. GI symptoms attributed to wheat (the
largest dietary fructan source) can also relate to FODMAPs,
rather than gluten.7,8 Thus, the term wheat intolerance or
sensitivity might be more appropriate than NCGS. A high
prevalence of autoimmune disease among patients with
wheat sensitivity has been described.9 Lipids can exacerbate
IBS symptoms through modulation of distal gut motor func-
tions and sensitivity. An increase in the density of sensory
fibers expressing transient receptor potential cation channel,
subfamily V-1 receptors in IBS patients with visceral hyper-
sensitivity can enhance transmission of pain signals,
including those generated by spicy foods. Recently, a role for
transient receptor potential cation channel, subfamily V-4 has
MICROENVIRONMENT
also been proposed as a possible pathway of pain trans-
mission in patients with IBS (see Impact of Immune Activa-
tion on Gut Sensorimotor Function).10
Translational Research
Prospective studies evaluating the effects of dietary in-
terventions in FD are urgently required.
While recent studies have reported beneficial effects of a
low-FODMAP diet on symptoms,11 stool habits, and quality
of life in IBS, studies were small in size and further evidence
is required to determine whether a low-FODMAP diet is
better than a standard diet in controlling symptoms.
Furthermore, the observed effects on the reduction of fecal
commensal bifidobacteria, and detrimental effects on gut
microbiota composition,12 require further investigation. A
gluten-free diet improves IBS symptoms and reduces bowel
frequency and intestinal permeability.13,14 The gluten-
specificity of these effects remains to be established.
Comprehensive dietary counseling, including the adoption
of healthy eating habits, avoidance of foods rich in FOD-
MAPs, insoluble fiber and artificial sweeteners, replacing
wheat with spelt products, and the importance of ingesting
dairy products, has been reported to be associated with a
significant reduction in IBS symptoms, including abdominal
pain, diarrhea (in IBS-D) and constipation (in IBS-C), and a
marked improvement in the quality of life.15
The Microbiota and its Metabolic
Interactions
When food enters our intestine, the undigested compo-
nents are utilized by the intestinal microbes, collectively
called the GI microbiota. The microbiota is dominated by
bacteria belonging to the phyla Firmicutes, Bacteroidetes,
and Actinobacteria. These microbes inhabit the various re-
gions in the GI tract, of which the colon is most densely
populated. The microbiota has a major impact, not only on
processes that occur in the GI tract, but also on systemic
functions, and thus plays a key role in our overall health.
Impact of Diet and Lifestyle on Microbiota
It is evident that lifestyle and diet are crucial de-
terminants of microbiota composition and function in
 1308 Barbara et al
humans. Comparative studies have demonstrated huge dif-
ferences in microbiota composition between human pop-
ulations in Western and those in developing countries and
suggested that these are based on lifestyle and long-term
dietary pattern differences.16 Short-term dietary changes
have also been shown to impact the composition of the
microbiota. To date, such alterations have been shown in
intervention studies that involve quite drastic changes in
diets, while more subtle, short-term dietary interventions
have, in general, only a minor impact on microbiota
composition.17 The impact of diet on the microbiota can be
direct, through changes in its composition or total energy
supply, or indirect, via the induction of changes in intestinal
transit time or intraluminal pH. Of note, the impact of diet
on the microbiota is also highly dependent on the intestinal
MICROENVIRONMENT
location. For example, the conversion of complex indigest-
ible carbohydrates is the driving force for the microbiota in
the colon, while the microbiota in the small intestine is
largely driven by the fast uptake and conversion of
sugars that are likely derived from digested dietary
polysaccharides.18
Microbiota Metabolism of Dietary Substrates
in Functional Gastrointestinal Disorders
Carbohydrate. Complex dietary components can be
converted by the microbiota to a wide variety of metabo-
lites that might involve cross-feeding and synthrophic in-
teractions between individual microbes.17,19 Which
metabolites are produced and in what quantities, is
dependent on the dietary components. The fermentation of
complex carbohydrates, such as fibers and resistant
starches, results, in general, in the production of SCFAs,
notably acetate, propionate, and butyrate; on a Western
diet approximately 300 mmol SCFA are produced daily.
Because SCFAs are fuels for our intestinal cells and serve as
signaling molecules, they are considered as beneficial,
particularly butyrate and propionate. Butyrate can be pro-
duced by a wide variety of bacteria, and most well-known
are Faecalibacterium prausnitzii, Eubacterium rectale, Eu-
bacterium hallii, and Roseburia intestinalis.19 Sources for
butyrate production include sugars, lactate, acetate, as well
as amino acids, such as lysine.20 This allows butyrate pro-
ducers to engage in metabolic cross-feeding interactions
with organisms that convert complex food components.
Propionate fermentation occurs via three distinct pathways,
of which the succinate pathway is the most commonly
utilized route in the gut, mainly performed by Bacteroides
spp. and Veillonella spp.19 Acetate can be produced by a
wide variety of microbes in the gut from fermentation of
carbohydrates in a so-called mixed fermentation with
lactate or other SCFAs, such as propionate. Acetate may also
be generated via reductive acetogenesis, the reduction of
carbon dioxide with hydrogen, a process that is estimated
to be responsible for one third of total acetate production in
the intestine.21
A few human studies suggest a role for SCFAs in FGIDs
and imply that nerves are involved. For example, a
reduction in abdominal pain in IBS patients administered
Gastroenterology Vol. 150, No. 6
sodium butyrate was observed.22,23 It was speculated that
butyrate reduced the hypersensitivity of intestinal mech-
anoreceptors and altered neurotransmitter release,
resulting in a reduction in luminal pressure and/or peri-
stalsis. Others have observed higher levels of acetic acid,
propionic acid, and total organic acids in IBS patients, with
higher acetic acid levels being associated with greater GI
symptoms.23,24
Carbohydrate fermentation also results in the produc-
tion of hydrogen and carbon dioxide, which are the main
intestinal gases formed in the intestine by the microbiota.
Whereas impaired handling of intestinal gases has been
consistently described in IBS, the contribution of the
microbiota to this phenomenon is far from clear. Hydrogen
is thought to inhibit fermentation, but can also serve as an
energy source for a variety of microbes, including meth-
anogenic Archaea, reductive acetogens, and sulfate reduc-
ers.17
19 The latter group produces sulfide, a toxic
component that is regarded as harmful to our health. Po-
tential sources of the required sulfate include dietary com-
ponents and host-derived substrates, such as mucin.
Although the relative volumes of intestinally derived gases
excreted in the breath have been used to relate FGID
symptoms to microbial fermentation rates in situ in the gut,
this extrapolation is fraught with problems due to cross-
feeding between different microbial populations, such as
has been described here, resulting in altered relative con-
centrations of intestinal gasses that together determine the
total volume.
Relatively few data are available on qualitative
changes in gas composition in FGIDs. Increased methane
production in constipation-predominant IBS-C25 is well
known, but it is unclear whether this is a cause or effect.
One study correlated methane with a higher motility in-
dex in IBS patients.25,26 Hydrogen sulfide signals through
multiple pathways, including nerves, but human studies
are lacking.
Protein. Protein utilization requires protease activity,
which is available in both humans and microbes. Although
less frequently studied than carbohydrate fermentation,
microbial fermentation of protein is, in general, considered
as potentially harmful to health, because amino acid
fermentation can lead to toxic products, such as amines and
ammonia, as well as N-nitroso, indolic, sulfur, and phenolic
compounds.27 Potential sources of proteins for fermentation
include diet and host-derived compounds. Although most
proteins are digested and taken up by the small intestine, a
high-protein diet could lead to the arrival of significant
protein loads in the colon. Because microbes favor carbo-
hydrate fermentation over protein fermentation, it has been
speculated that low carbohydrate diets can promote protein
fermentation in the intestine.
A recent study showed that concentrations of fecal
proteases were higher in IBS-D patients compared with
healthy controls, suggesting enhanced protein metabolism
in the colon.28 Remarkably, most of these proteases were of
human origin. Nevertheless, it is conceivable that increased
protease activity in the colon may lead to higher rates of
amino acid fermentation.
May 2016
Fat. Dietary fat content has also been negatively corre-
lated with health status. In contrast to carbohydrates and
proteins, however, fat is not believed to reach the colon and
be exposed to its microbiota in significant amounts because
most is digested and absorbed in the small intestine. One
indirect effect of dietary fat assimilation is its facilitation of
the diffusion of bacterial components, such as lipopolysac-
charide, across the epithelium, which could lead to low-grade
inflammation, such as some have described in IBS.29
Microbiota Structure and Functional
Gastrointestinal Disorders
A recent report of the Rome Foundation on the micro-
biota in FGIDs provided an excellent overview of the
importance of the microbiota in health and disease and,
especially, in relation to FGIDs.30 Figure 2 provides a sche-
matic representation on the role of the intestinal microbiota
in conversion of dietary components and their potential
impact on the pathophysiology of FGIDs. Several lines of
evidence suggest the involvement of the intestinal micro-
biota in the pathogenesis of FGIDs in general and IBS in
particular: gastrointestinal (GI) infections are strong risk
factors for the development of FD and IBS (see Post-Infec-
tious Functional Gastrointestinal Disorders); fecal micro-
biota is substantially different in IBS and post-infectious
(PI)-IBS compared with healthy controls, and shows
reduced microbiota diversity30; innate and adaptive immu-
nity directed to microbiota-derived molecules, including the
expression of toll-like receptors (TLRs) in the mucosa, the
production of human b-defensin-2 and antibodies to bac-
terial flagellin are substantially different in IBS compared
with controls30; some evidence indicates the existence of
abnormal concentrations of fermentation end products,
such as SCFAs, which might participate in symptom pro-
duction in some patients with in IBS (see Microbiota
Metabolism of Dietary Substrates in Functional Gastroin-
testinal Disorders); one recent study showed that total SCFA
level was significantly lower in IBS-C patients than in IBS-D
and IBS with mixed bowel habit (IBM-M) patients and
Figure 2. Overview of di-
etary components and
metabolites produced in
the GI tract, and their as-
sociation with irritable
bowel syndrome or its
symptoms. *Increased
levels in irritable bowel
syndrome patients. In-
creases in methane (CH4)
and hydrogen (H2) con-
centrations contribute to
bloating and distension
and intraluminal concen-
trations of bile acids and
proteases will promote
diarrhea. BDFA, branched-
chain fatty acid.
Microenvironment and FGID 1309
healthy controls; case
control studies show that systemic
antibiotic use is a risk factor for de novo development of
FGIDs31; and in 43 randomized controlled trials, the relative
risk of IBS symptoms persisting with probiotics vs placebo
was 0.79 (95% confidence interval: 0.70
0.89), with posi-
tive effects on global IBS, abdominal pain, bloating, and
flatulence scores.32
Nonetheless, major limitations still hamper the defini-
tion of the role of the microbiota in FGIDs. Indeed, there is
no consensus on the nature of the microbial signatures that
may be consistently (either positively or negatively) corre-
lated to FGIDs. These inconsistencies may relate to several
factors, including methodological differences, variations in
sample sources, intrinsic variability between subjects, dif-
ferences in subject selection and definition of study pop-
MICROENVIRONMENT
ulations, overlap between the various FGIDs, and differences
in diet, therapy or other environmental exposures. It needs
to be recognized that many studies described comparisons
between different groups of subjects on the basis of a single
fecal sample per subject, which only represents a snapshot
of the microbiota and, as a result, such comparative analyses
cannot differentiate between cause, consequence, or coin-
cidence. Given the large heterogeneity in the human popu-
lation and the extent of microbial diversity, it is likely that
many significant correlations are just coincidence. This may,
in part, explain why there has been no consensus regarding
whether a specific microbe or groups of microbes is asso-
ciated with a given FGID.30 Therefore, it is evident that
longitudinal studies involving repeated sampling of the
microbiota will be crucial to differentiate cause from
consequence or coincidence. Such studies could include in-
terventions with dedicated diets or dietary supplements,
specific pharmacological interventions, or novel therapies,
such as fecal microbiota transplantation.
Bile Acids
Bile acids (BAs) play a central and critical role in the
digestion and absorption of fat and fat-soluble vitamins,
and a highly efficient enterohepatic circulation ensures the
 1310 Barbara et al Gastroenterology Vol. 150, No. 6

conservation of secreted BAs; the primary means of BA
conservation being active absorption via the apical
sodium-dependent ileal BA transporter located on the
apical surface of ileal enterocytes. BA absorption and
secretion are closely linked through a feed-back loop,
which involves a number of receptors and mediators that
ultimately impact on the rate-limiting enzyme in BA syn-
thesis (Figure 3).33
BAs have a variety of physiological effects of relevance to
the FGIDs; on motility, intestinal secretion, membrane
permeability, and visceral sensation,34 and act as important
signaling molecules with effects well beyond the GI tract. As
BAs repress bacterial growth in the intestine, the develop-
ment of microbial enzyme pathways capable of deconju-
gating and transforming BAs is an important adaptive
MICROENVIRONMENT
malabsorb BAs37,38 and infusion of BAs in the colon
disproportionately stimulated motility compared with con-
trols. In idiopathic BA malabsorption (BAM),39 phase
3
induced neurogenic secretions were increased in the
jejunum, and prostigmine increased the colonic motility
index, implying involvement of the enteric nervous sys-
tem.40 Genetic variants of the G protein
coupled bile acid
receptor (TGR5), found on multiple cells, including enteric
nerves, have also been linked to transit time in patients with
FGIDs.38 Altered metabolism of BAs by colonic bacteria
might also be involved, as constipation and increased transit
time correlated with a reduction of colonic BAs, possibly the
result of bacterial sulfation.41

response by commensal bacteria.35 In contrast, antibacterial Epithelium and Mucosal Barrier

and mucosal immune-stimulating effects of BAs play an
important role in the prevention of small intestinal bacterial
overgrowth (SIBO).36
Human physiological studies suggest a role for luminal
BA signaling to enteric nerves in causing altered small
bowel motility and increased sigmoid and rectal motility. In
IBS-D, it was estimated that as many as 10% of patients
The intestinal luminal-mucosal interface represents the
first location where toxic and immunogenic particles face
the scrutiny of the mucosa-associated immune system. Loss
of molecular and functional integrity of the epithelial barrier
could lead to activation of mucosal immune responses and
set in motion events that are closely related to the origin
and clinical manifestations of several FGIDs.

Figure 3. Schematic representation of the interactions between the microbiota and bile acids as illustrated by a comparison
of germ-free and normally colonized animals. The scheme shows increased activity and expression of cholesterol
7a-hydroxylase and levels of taurine-conjugated b-muricholic acid in germ-free mice. In contrast, the expression and activity
of sterol 12a-hydroxylase and cholic acid levels are similar in germ-free and normally colonized mice. Taurine-conjugated b-
muricholic acid is a natural antagonist of the farnesoid X receptor (FXR), which, in turn, may elicit reduced inhibition of rate-
limiting enzyme cholesterol 7a-hydroxylase in germ-free animals mice. In contrast, normally colonized animals show a
reduction in taurine-conjugated b-muricholic acid. This leads to increased activation of farnesoid X receptor in enterocytes,
thus up-regulating the fibroblast growth factor 15 (FGF15), which in turn suppresses cholesterol 7a-hydroxylase in the liver. In
addition, the microbiota affects intestinal bile acid metabolism and increases their excretion. BACS, bile acyl-CoA synthetase;
C4, cholesterol-4; CYP7A1, cholesterol 7a-hydroxylase; CA, cholic acid; FGFR4, fibroblast growth factor receptor 4; FGF15,
fibroblast growth factor 15; b-MCA, b-muricholic acid; TCA, taurine-conjugated cholic acid; DCA, deoxy cholic acid; LCA,
lithocholic acid; CYP8B1, sterol 12a-hydroxylase; TbMCA, taurine-conjugated b-muricholic acid. Reproduced with permission
from Sayin et al.120
May 2016
Molecular Structure
The apical junctional complex keeps enterocytes tightly
sealed and regulates paracellular permeability.42 This
complex is composed of tight junctions (TJs), adherens
junctions, and desmosomes. Intracellular (zonula occludens
[ZO]-1, ZO-2, and ZO-3, and cingulin) and surface-membrane
proteins (occludin, claudins, and junctional adhesion mole-
cules [JAMs]) are major components of TJs.42 Adherens
junctions are mainly composed of e-cadherin, catenin, and
actin filaments.42 Occludin seems to regulate the integrity of
TJs, while claudins determine their strength, size, and ion
selectivity, and JAMs their construction and assembly.43 All
are linked to actomyosin fibers by members of the ZO family
and, in this way, control the opening/closing of TJs at par-
acellular spaces.44 Zonulin transactivates the epithelial
growth factor receptor via proteinase-activated receptor 2
activation and reversibly regulates intestinal permeability.
Intestinal Permeability and Barrier Dysfunction
The passage of molecules across the epithelium takes
place mainly via two distinct routes: the paracellular
pathway, which allows small molecules (<600 Da) to diffuse
through TJs, and the transcellular pathway, which facilitates
the transit of larger particles via the processes of endocy-
tosis or exocytosis. Rapid changes in permeability usually
occur via myosin light-chain kinase-mediated cytoskeleton
contraction and endocytosis of TJ proteins. In contrast, more
sustained changes in permeability involve the transcrip-
tional modulation of TJ proteins, epithelial cell apoptosis,
and ultrastructural alterations in the epithelium.42
Acute stress either reduces net water absorption or in-
creases jejunal secretion in healthy subjects through the
parasympathetic nervous system and mast cell (MC) acti-
vation.45 In addition, higher background levels of stress
have been related to decreased water secretion in healthy
female volunteers exposed to cold pain stress.46 Stronger
stresses, like abdominal surgery, GI infections, hemorrhagic
shock or intensive exercise, increase intestinal permeability.
Corticotropin-releasing factor (CRF) enhances transcellular
uptake of macromolecules in the human colon via CRF-R1
and CRF-R2 receptors on subepithelial MCs.47 Acute psy-
chological stress also increases small intestinal permeability
in humans; peripherally administered CRF reproduces this
effect and MC stabilization blocks the effects of both stress
and CRF.48
In-depth reviews on the role of physiological and path-
ophysiological stimuli controlling the gut barrier have been
published recently.42,49 Vasoactive intestinal polypeptide
regulates chloride secretion, mucin release, and paracellular
permeability, partly through a direct effect on ZO-1. Sub-
stance P stimulates the release of pro-inflammatory
cytokines and vasoactive mediators by macrophages,
eosinophils, and MCs, contributing to chloride secretion,
increased intestinal permeability, and vascular leakiness.
Nerve growth factor has been involved in nerve- and
MC-mediated stress-induced barrier dysfunction. Both pro-
gesterone and estradiol have been shown to reduce chloride
secretion in intestinal epithelial cells, whereas estradiol
Microenvironment and FGID 1311
reinforced epithelial permeability and up-regulated JAM-A
and occludin expression. Other mediators, including CRF,
leptin, and cholecystokinin, may increase permeability,
while insulin-like growth factor, ghrelin, KdPT and
glucagon-like peptide 2, may decrease intestinal
permeability.42,49
Various strains of Vibrio cholera, Clostridium difficile, and
toxin-producing strains of Escherichia coli have been shown
to enhance intestinal permeability through direct TJ
disruption, the production of toxins or proteases, and the
activation of the inflammatory cascade. In contrast, pro-
biotics promote barrier integrity by increasing occludin,
claudin 3, and ZO-1 and ZO-2 expression.50
Interferon (IFN)-gamma and tumor necrosis factor
(TNF)
a induce barrier dysfunction through myosin
MICROENVIRONMENT
light-chain kinase and claudin-2 up-regulation and down-
regulation of occludin. Many other cytokines and pro-
teases have effects on barrier function, including interleukin
(IL)-3, IL-4, IL-17, IL-22, and IL-26, IFN-alfa, IFN-beta, and
transforming growth factors
a, and
b.51
The impact of nutritional factors on the intestinal barrier
have been reviewed recently.49 In predisposed individuals,
gluten and other specific food components can lead to
increased intestinal permeability through the zonulin
pathway and MC-mediated enhancement of both passage
routes. Whey proteins can improve barrier function by a
transforming growth factor
b-mediated increase in intes-
tinal claudin-4 expression. Other nutritional products, such
as glutamine, butyrate, arginine, fatty acids, and prebiotics,
have been shown, to some extent, to exert a protective effect
on the intestinal barrier.
Ethanol promotes separation of ZO-1 proteins, disas-
sembly of actin and myosin filaments and myosin light-chain
kinase activation. Nonsteroidal anti-inflammatory drugs,
methotrexate, tacrolimus, omeprazole, and corticosteroids
can also enhance intestinal permeability, but heparin,
vitamin D, and larazotide can decrease permeability.
Mucosal Barrier and Functional
Gastrointestinal Disorders
There is little information on the status of mucus pro-
duction in IBS other than isolated reports on the potentially
beneficial effects of probiotics or mesalazine on mucus
quality and production, higher levels of trefoil factor 3 in the
urinary IBS proteome, and increased expression of genes
involved in the production of mucin 20 in the colon of IBS.
Enhanced intestinal permeability has been reported in FD
and in subsets of patients with IBS (Supplementary Table 1)
and linked to alterations in JAM-A, ZO-1, e-cadherin,
claudins, and occludin (Supplementary Table 2), and these
changes were associated with MC activation and clinical
manifestations.
Enteroendocrine System
The enteroendocrine system, the largest endocrine
organ, constitutes 1% of the gut epithelium. Fourteen cell
populations, including enteroendocrine cells and enteric
 1312 Barbara et al
nerves, produce transmitter substances that signal to
neighboring cells (paracrine), distant targets via the
vascular system (endocrine) or through intrinsic/extrinsic
nerves (neurocrine). These effector targets, in turn, control
gut motility, secretion, sensation, absorption, vascular tone,
microcirculation, immunity, and cell proliferation (Figure 4,
Supplementary Table 3).52
54
Serotonin Metabolism and Receptors
Serotonin (5-hydroxytryptamine [5-HT]), is a paracrine/
neurocrine amine primarily contained in the gut (95%) and
only minimally in the brain (5%). Serotonin is synthesized
from tryptophan, in enterochromaffin cells (EC) (90%) and
autonomic nerves (10%).55,56 Synthesis and release of
MICROENVIRONMENT
serotonin involves conversion of dietary tryptophan to
5-hydroxy-L-tryptophan (catalyzed by tryptophan hydroxy-
lase [TpH], isoforms, TpH1 [in gut] and TpH2 [in
brain]),56
58 granular packaging by vesicular monoamine
transporter 159 and release, mainly determined by bowel
wall distension, mucosal stroking, food, amino acids, hypo-
or hyper-osmotic solutions, glucose, galactose, adenosine,
cholera toxin, and chemotherapeutic agents.59,60 SCFA,
which may be produced in increased amounts by intestinal
microbiota fermentation of carbohydrate substrates, can
also promote the release of serotonin.59 An alternative
metabolic pathway leads to the production of kynurenic
acid, and not serotonin, from tryptophan, and results in
reduced serotonin synthesis.61 The serotonin reuptake
transporter (SERT) terminates serotonin action (Figure 4).57
Figure 4. Mechanism of action of serotonin and its re-uptake in IBS. ACh, acetylcholine; GABA, gamma amino butyric acid;
5-HT, serotonin.
Gastroenterology Vol. 150, No. 6
In the gut, serotonin stimulates intrinsic primary
afferent neurons, which synapse in the myenteric plexus
with ascending and descending inter-neurons to evoke
motility- and secretion-induced reflexes and also transmit
information to the brain.55,57,62
Serotonin Metabolism in Functional
Gastrointestinal Disorders
SERT hyperactivity may lead to increased reuptake of
serotonin, hence reducing the effects of the amine on target
tissues. In contrast, hypofunction of SERT may increase
serotonin concentrations, leading to gut hypercontractility,
hypersensitivity, diarrhea, and pain.57,60 Accordingly, in cell
lines, infection with enteropathogenic E coli reduced SERT
activity.63 The SERT protein is encoded by a gene on chro-
mosome 17q11 and is composed of 14 exons encoding 630
amino acids. Insertion/deletion of 44 base pairs in the 5-HT-
transporter-gene-linked polymorphic region, leading to
reduced SERT expression, has been reported in IBS-D.64 The
5-HT-transporter-gene-linked polymorphic region (S/L)
was more common than the S/S polymorphism in FD,
particularly in the postprandrial distress syndrome.65 In an
Indian study, solute carrier family 6 (neurotransmitter
transporter), member 4 (SLC6A4) polymorphism and higher
levels of 5-HT were associated with IBS, particularly PI-IBS
and IBS-D.66 The homozygous S genotype (reducing SERT
expression) was more common in IBS-D.64 A meta-analysis
on 25 studies, including 3443 IBS patients and 3359 con-
trols, showed that the 5-HT-transporter-gene-linked
May 2016
polymorphic region mutation was associated with IBS-C, but
not with IBS-D and IBS-M, and, particularly, among East
Asians.67 More studies are needed to clarify this issue.
The implications of serotonin in FGID have been
reviewed previously.59,68 Data suggest that subgroups of
patients with FGIDs show altered serotonergic signaling
(Figure 4). Accordingly, the epigastric pain syndrome sub-
type may have higher basal serotonin levels.65 In contrast,
some data suggest that subsets of patients with FD may
have low basal and postprandial plasma levels of seroto-
nin.69 Studies suggest that IBS-D is associated with elevated,
and IBS-C with reduced, serotonin plasma levels.59,70 In one
study, both serotonin and kynurenic acid levels were lower
in the duodenal mucosa and higher in plasma in IBS, than
controls, suggesting a contribution from the kynurenic acid
pathway.61 As chili ingestion increases FGID symptoms and
granisetron, a 5-HT 3-receptor antagonist, prevents it;
serotonin is suggested as the mediator of chili-induced
symptoms.71 Although a low-FODMAP diet has been
shown to improve IBS symptoms,12 data on its effect on
brain and gut serotonin levels are lacking.
In PI-IBS (see Post-Infectious Functional Gastrointestinal
Disorders), altered EC cell numbers have been reported.60,72
PI-IBS patients had higher rectal mucosal serotonin than
non
PI IBS-D and non-diarrheal IBS. The enteroendocrine
and immune systems are widely interconnected, as sug-
gested by the proximity of immune cells to EC cells.59,68
Furthermore, immune cells, including B and T lympho-
cytes, monocytes, macrophages, and dendritic cells, express
serotonergic receptors and MCs; macrophages and T cells
synthesize serotonin from tryptophan.59 Serotonin is
chemotactic for dendritic cells, MCs, and eosinophils and
may participate in the recruitment of these immune cells in
Figure 5. Post-infectious IBS and related risk factors. RR, relative risk.
Microenvironment and FGID 1313
the intestinal mucosa (see Mucosal Immune Activation).59
Low-grade inflammation, such as has been detected in
FGIDs can, in turn, contribute to altered serotonin synthesis
and reuptake through changes in SERT expression.73,74 Th1
responses generate IFN-gamma and TNF-a, which inhibit
SERT; Th2 responses, such as occur in parasitic infestations,
stimulate IL13, which increases EC numbers and TNF-a and,
therefore, inhibit SERT.75
Efficacy for serotonergic agents, such as 5-HT3 receptor
antagonists (alosetron, cilansetron, and ondansetron),
including a large multicenter trial on ramosetron in female
IBS-D patients with promising results,76 and 5-HT4 agonists
(cisapride, tegaserod, and prucalopride) in the treatment of
IBS-D and IBS-C, respectively, also provide evidence for a
role for serotonin in the pathogenesis of FGIDs.56,57
MICROENVIRONMENT
Immune System and Neuro-Immune
Interactions
Post-Infectious Functional Gastrointestinal
Disorders
The observation that FD and IBS can develop after an
episode of acute infectious gastroenteritis supports the
involvement of the immune system in the pathophysiology
of FGIDs. The mean incidences of PI-FD and PI-IBS after
infection with diverse pathogens (bacteria, parasites, or
virus) are 9.6% and 10%, respectively, with an overall odds
ratio of 2.5 for the presence of an FGID at 6 months post
infection compared with controls.32,77 Risk factors for PI-IBS
include the severity and duration of the acute infection,
female sex, psychological comorbidity (eg, hypochondriasis,
neuroticism, depression, adverse live events, perceived
 1314 Barbara et al
stress, negative illness beliefs78), smoking, and being a child
at the time of the infection79 (Figure 5). The pathogenesis of
PI-FGIDs is multifactorial and involves both pathogen and
host factors.78 In PI-IBS, the colorectal mucosa shows
increased infiltration of macrophages, MCs, and intra-
epithelial lymphocytes, as well as PYY-containing enter-
oendocrine cells.72,78 The association of the TNF-a SNP
rs1800629 with PI-IBS supports the hypothesis of a genetic
predisposition possibly contributing to increased epithelial
permeability and an inability to resolve an acute inflam-
matory process.80
Mucosal Immune Activation
Numerous studies have shown increased numbers of
mucosal immunocytes (ie, MCs, eosinophils, and T cells) in
MICROENVIRONMENT
adult and pediatric patients with FD and IBS. Several
precipitating factors have been claimed, including food
allergy, an abnormal microbiota, BAM, and increased in-
testinal permeability. The magnitude of the inflammatory
response is several-fold less than that seen in acute
inflammation in inflammatory bowel disease. The wide
overlap with healthy controls, possible geographic and di-
etary variation, and lack of methodological standardization
might explain the failure of some studies to confirm the
presence of increased immune cells in FGIDs. The nature of
the inflammatory process is also different from that seen in
acute GI inflammation in inflammatory bowel disease, with
no involvement of neutrophils or frank tissue distortion.30,81
Eosinophils, usually linked to allergic reactions, have been
associated with postprandial distress syndrome and early
satiety.82,83 Increased MC numbers have been detected in
the stomach and duodenum of patients with FD,83 in the
esophagus of patients with noncardiac chest pain,84 and
throughout the gut in IBS-D and IBS-C,85 particularly in fe-
males, in PI-FD and PI-IBS (for review, see Barbara et al81).
Genetic factor, such as the TNFa rs1800629 genotype,80
have also been implicated. Microbial molecular pattern-
mediated activation of innate immunity suggests a patho-
genic contribution of the gut microbiota.86 TLRs are
expressed on human submucosal and myenteric neuro-
ns87–89 and altered TLR expression has been observed in
IBS tissues. For example, TLR4 expression in colonic
mucosal biopsies from IBS patients was increased, particu-
larly in those with alternating-type IBS.90 TLRs 5 and 2
were also up-regulated, while TLRs 7 and 8 were down-
regulated.86,90 Biopsy studies have provided evidence of
epithelial permeability changes in IBS patients and bacterial
proteases may play a role.91 Thus, in some IBS patients,
there may be increased expression of TLRs and/or a
disruption of the mucosal barrier and increased bacterial
translocation resulting in increased TLR signaling and/or an
abnormal immune response to luminal microbes.86,90
Impact of Immune Activation on
Gut Sensorimotor Function
Supernatants obtained after incubation of mucosal
biopsies from IBS subjects contained increased
amounts of histamine, serotonin, polyunsaturated fatty acid
Gastroenterology Vol. 150, No. 6
metabolites,81 and proteases, including tryptase and
trypsin.10 The exact source of proteases remains unclear;
they may originate from mucosal MCs, gut bacteria,92 or
pancreatic secretions.28 In adoptive transfer experiments,
biopsy supernatants from IBS subjects evoked abnormal
functional responses in enteric and sensory nerves of
recipient rodents93–95 and human tissues.96 These effects
were at least partly related to immune and endocrine fac-
tors, including proteases, histamine, and serotonin.73,93,95
Application of biopsy supernatants to human or rodent
tissues suggests that, in IBS, serine proteases, or poly-
unsaturated fatty acid metabolites, act respectively on
proteinase-activated receptors93 and transient receptor
potential cation channel, subfamily V-4,10 to mediate
visceral pain. In addition to these acute effects, a recent
study suggested that the chronic release of immune me-
tabolites could affect the structure of mucosal neural net-
works in IBS, that is, increased neuronal density and
outgrowth, as well as increased expression of MC nerve
growth factor in the colonic mucosa of patients with IBS
compared with controls.97 Mucosal supernatants of patients
with IBS evoked increased neurite growth and expression of
GAP43 (a key neuronal growth protein) when applied to
primary cell cultures of rat myenteric plexus or to neuro-
blastoma cell line SH-SY5Y cultures.97
Probiotics can have beneficial effects in IBS, through the
modulation of immune function. Indeed, Bifidobacterium
infantis 35624, but not strains of Lactobacillus salivarius,
was able to reduce a systemic proinflammatory cytokine
profile along with symptom improvement.98
Immune Activation and Symptoms
Although several studies have demonstrated intestinal
immune activation in FGIDs, reports of correlations with
symptoms have been limited. Correlations were found be-
tween colonic MC density close to nerves and abdominal
pain and bloating, and between bowel habit dissatisfaction,
global IBS symptoms, and circulating T cells.85,99,100 In
addition, immune activation featuring increased small bowel
homing T cells has been associated with the intensity of
pain, nausea, and vomiting in FD.101 Mucosal MCs
were associated with fatigue and depression, suggesting
the potential role of psychological factors in the
brain
gut
immune axis in IBS.
Implications for Management
Diet and Food Components
Food has long been recognized as an important precip-
itant of symptoms in FD and IBS. Exaggerated GI and colonic
electrophysiological and motor responses to food ingestion
have been extensively documented and a variety of hy-
potheses have been advanced to explain these responses,
particularly in IBS. This process has also generated various
diagnostic strategies, which will be briefly reviewed here.
Food allergy. Although up to 20% of the population
and much higher proportions of IBS patients are convinced
that they are allergic to certain foods, and this is a major
May 2016
contribution to their problem, food allergy, traditionally
denoted by an activation of IgE-mediated antibodies to a
food protein, has not been linked convincingly to IBS
pathogenesis and the status of IgG-based testing remains
unclear.102 Although confocal endomicroscopy studies
suggest the existence of rapid morphological and functional
changes in the epithelium and immune system of the small
intestine after challenge with foods to which the patients
reported intolerance, and symptomatic improvement were
recorded following avoidance of these foods, this approach
seems to be too cumbersome to be applied on a large
scale.103
Food intolerance. The contribution of lactose maldi-
gestion to IBS depends on the prevalence of lactose maldi-
gestion in the population studied. Furthermore, subjective
reports of lactose intolerance correlate poorly with formal
tests of lactose malabsorption, rendering such tests of
limited value in the evaluation of IBS.104 Lactose intolerance
should be identified in patients with FGID and milk products
avoided accordingly.
Although IBS subjects appear, both subjectively and
objectively, to be intolerant of fructose,105 formal tests of
fructose malabsorption failed to discriminate between IBS
subjects and healthy controls.106 Again, it does not seem
possible to recommend testing or dietary fructose elimina-
tion alone as an evidence-based treatment strategy for IBS
or other FGIDs.
Sorbitol intolerance has also been reported in IBS and it
is likely that sorbitol has an additive effect to fructose, with
further exacerbation of symptoms.106 Here again rates of
intolerance and malabsorption do not tally, thereby, limiting
the value of diagnostic testing or dietary advice.
Gluten intolerance/sensitivity. The relationships
between celiac disease, “gluten-sensitivity,” and IBS remain
unclear, with various studies reporting increased107 or
expected108 rates of celiac disease among IBS subjects. The
status of that entity which has come to be referred to as
NCGS109 is particularly unclear. Other than excluding celiac
disease, and providing evidence of intolerance after double-
blind challenge, there are no currently validated diagnostic
methods for diagnosing this entity.
The Microbiota and its Metabolic Interactions
Small intestinal bacterial overgrowth, fecal and
colonic mucosal microbiota. The status of SIBO in IBS
remains highly controversial. Two factors contributing to
variations in prevalence of SIBO among IBS subjects have
been the test modality and diagnostic criteria used to di-
agnose SIBO.110 Although some patients with SIBO may
present with IBS-type symptoms, it does not appear that
SIBO is a major contributor to the pathogenesis of IBS, in
general.111 The lactulose breath test has shown poor diag-
nostic performance to detect SIBO. While the glucose breath
test performs slightly better, routine testing for SIBO cannot
be currently recommended.30
Although abnormalities in the fecal and colonic micro-
biota have been identified among IBS subjects and microbial
signatures associated with certain demographic and etio-
logical features in IBS, a fecal or mucosal microbial signal
Microenvironment and FGID 1315
diagnostic of IBS or of an IBS subtype or subpopulation has
yet to be validated.30 Approaches aimed at modifying the
microbiota, mainly with probiotics and nonabsorbable an-
tibiotics, are now widely applied in clinical practice,
particularly in patients with IBS, however, several questions
remain to be elucidated, including, type of probiotics,
dosage, relevant subgroups, therapeutic gain over placebo,
treatment and retreatment schedules, as well as mode of
action.30
Bile acids. Abnormalities in fecal BAs, as well as in
serum markers of BA synthesis, have been reported in a
subgroup of IBS-D,112 and BAM may be responsible for a
significant proportion of those with IBS-D.113 The 23-
seleno-25-homo-tauro-cholic acid test, the most widely
employed and validated test for the diagnosis of BAM, is not
MICROENVIRONMENT
universally available. Alternate approaches include the
measurement of fecal BAs, or serum levels of 7 a-hydroxy-4-
cholesten-3-one (C4), or a therapeutic trial of a bile salt
sequestering agent.34,41
Epithelium and Mucosal Barrier
The usefulness of measures of barrier integrity (such as
the lactulose-to-mannitol excretion ratio) in the diagnosis or
assessment of FGIDs has not been established,114 nor have
the diagnostic role of ex vivo approaches on biopsies
(Ussing chambers) and assays for molecular markers or
surrogates of altered permeability (eg, endotoxin, anti-
lipopolysaccharide antibodies, bacterial lactate, butyrate
production, and hemolysin test).49,114 The use of endoscopic
endomicroscopy detecting rapid functional/structural
mucosal changes after challenge with food allergens,
although attractive, remains to be confirmed in future
studies.103 Strategies to modify mucosal permeability
include the use of probiotics and dietary interventions,
although there is still uncertainty on the potential
benefits.49
Enteroendocrine System
Although changes in basal or stimulated levels of a
number of enteric hormones and neurotransmitters (such
as postprandial levels of 5-HT) have been described in IBS
and other FGIDs, and manipulations of 5-HT metabolism
have been shown to provoke symptoms, none have achieved
the status of a diagnostic test. The use of drugs acting on
serotonin agents remains a field of interest, now generating
new potential therapeutic approaches for IBS-D with older
products with a new indication (eg, ondansetron)115 or
newer products (eg, ramosetron)76 being tested in large
clinical trials.
Immune System and Neuro-Immune Interactions
That the engagement between luminal contents on one
hand, and the microbiota and the immune system on the
other hand, might be relevant to the pathogenesis of IBS is
suggested by studies documenting the up-regulation of im-
mune biomarkers and various members of the Toll receptor
family in this disorder. However, given the variability in
results between studies, it is not possible at this time to
 1316 Barbara et al
employ measures of the mucosal or systemic responses in
the diagnosis of an FGID or in the delineation of a subgroup
thereof.116 Two recent large placebo-controlled studies in
IBS patients showed that mesalazine was not clinically su-
perior over placebo, although both studies suggested
that subgroups, including PI-IBS, showed sustained
responses.117,118
With respect to gases released in the process of bacterial
fermentation, it should be noted that with some, but not
complete, consistency, the detection of methane in the
breath has been linked to the predominance of constipation
in IBS.119 The therapeutic implications of these findings
remain unclear.
MICROENVIRONMENT
Conclusions and Future Directions
While the role of food and dietary components is, at last,
attracting the attention it has long deserved, many questions
persist. While dietary studies are challenging, only large-
scale, prospective studies using validated instruments can
provide much needed information on the food habits of
FGID subjects and also address such questions as to what
extent dietary preferences in FGID subjects reflect the
subconscious exclusion of items to which they are intol-
erant. Of the multiple factors that have been proposed,
intolerance to poorly absorbed dietary carbohydrates has
emerged as a major contributor in IBS, with the status of
true food allergy and gluten sensitivity remaining unclear.
Different mechanisms may be relevant to various subjects
or subject groups. Long-term studies of dietary in-
terventions will be important by defining, not just their
beneficial effects on symptoms, but also identifying any
negative consequences.
Although some tantalizing findings have been reported,
studies of the gut microbiota and the host immune response
in FGIDs have yielded variable and sometimes conflicting
results: there is a need for longitudinal studies that include
functional profiling of the microbiota, its metabolites
(including gases and SCFAs) and related immunological
responses in well-characterized IBS populations. Such in-
formation will be critical to guiding therapeutic strategies
that aim to modulate the microbiota, its products, and/or
the immune response.
The signal transduction mechanisms that generate re-
sponses to BAs need to be delineated, that is, whether they
are receptor-mediated or generated by paracrine or
nonspecific effects. Above all, in relation to BAs, the current
paucity of human studies needs to be addressed. Further-
more, microbiota
BA interactions in FGIDs need to be
explored.
While functional and molecular alterations of factors
involved in intestinal permeability might explain IBS path-
ophysiology and symptom generation, and could yield
innovative biomarkers valuable in both diagnosis and
assessment of therapeutic response in FGIDs, further
studies using validated and preferably noninvasive markers
are needed to more precisely define the mechanisms and
functional consequences of these alterations and their pri-
macy in a given FGID.
Gastroenterology Vol. 150, No. 6
Well-designed studies on large numbers of patients and
controls evaluating the enteroendocrine system, including
changes in serotonergic responses, are also lacking in pa-
tients with FGIDs. Dietary, behavioral, pharmacological, and
gut-microbiota
directed manipulations of enteroendocrine
responses are likely to be important approaches to the
management of these disorders.
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. To access the supplementary
material accompanying this article, visit the online version
of Gastroenterology at www.gastrojournal.org, and at
http://dxdoi.org/10.1053/j.gastro.2016.02.028.
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Reprint requests
Address requests for reprints to: Giovanni Barbara, MD, Department of Medical
and Surgical Sciences, St Orsola-Malpighi Hospital, Via Massarenti, 9, Building
#5, I-40138 Bologna, Italy. e-mail: giovanni.barbara@unibo.it; fax: (39) 051
345864.
Acknowledgments
The authors would like to thank Maria Raffaella Barbaro for editing the
manuscript.
Conflicts of interest
The authors disclose no conflicts.
Supplementary Table 1.Evidence of Altered Intestinal Permeability in IBS.

May 2016
Proportion of
Magnitude abnormal Diagnostic
Findings of change Site Methods Clinical subtype N (IBS:HC) values (IBS) criteria

Intestinal permeability
Increased ns small intestine and 5h and 24h urinary recoveries of orally D-IBS 19:10 42% (8/19) Rome III
colon administered sugars (lactulose/
mannitol urinary ratio)
ns ns 24h urinary recoveries of orally D-IBS 54:22 39% (21/54) Rome III
administered sugars (lactulose/
mannitol urinary ratio)
þþ proximal 3h urinary recoveries of orally FAP/IBS (children) 93:52 ns Rome II
gastrointestinal administered sugars (sucrose/
tract lactulose urinary ratio)
þ colon 3h urinary recoveries of orally FAP/IBS (children) 93:52 ns Rome II
administered sugars (sucralose/
lactulose urinary ratio)
þþþ small intestine 5h urinary recoveries of orally PI-D-IBS but not C-IBS 15:15 ns Rome II
administered 51Cr-EDTA
þþ small intestine 5h urinary recoveries of orally D-IBS þ PI-D-IBS 15:16 ns Rome II
administered 51Cr-EDTA
þþþ small intestine 6h urinary recoveries of orally PI-IBS 31:12 23% (7/31) Rome I
administered sugars (lactulose/
mannitol urinary ratio)
Unchanged - small intestine 3h urinary recoveries of orally FAP/IBS (children) 93:52 ns Rome II
administered sugars (lactulose/
mannitol urinary ratio)
- colon 24h urinary recoveries of orally IBS 14:15 ns Rome II
administered polyethylene glycols or
sugars (lactulose/mannitol urinary
ratio)
- colon 24h urinary recoveries of orally PI-D-IBS þ C-IBS 15:12 ns Rome II
administered 51Cr-EDTA
Increased in response to þ rectum HRP diffusion through the rectal biopsies D-IBS 20:30 ns Rome II
tryptase in Ussing chambers

Microenvironment and FGID 1318.e1

Increased paracellular þþ colon FITC diffusion through the colon biopsies IBS 13:5 77% (10/13) Rome II
permeability in Ussing chambers
þ colon FITC diffusion through the colon biopsies C-IBS þ D-IBS þ A-IBS 34:15 ns Rome III
in Ussing chambers
Increased in response to ns colon 24h urinary recoveries of orally IBS 14:15 ns Rome II
NSAIDs administered sugars (lactulose/
mannitol urinary ratio)
Decreased transepithelial þþ colon FITC diffusion through the colon biopsies IBS 13:5 ns Rome II
resistance in Ussing chambers
Supplementary Table 1. Continued

1318.e2 Barbara et al
Proportion of
Magnitude abnormal Diagnostic
Findings of change Site Methods Clinical subtype N (IBS:HC) values (IBS) criteria

Epithelial barrier integrity

Decreased tight junction þþ colon mucosa WB D-IBS but neither C-IBS 50:33 32% (6/19) ; Rome III
protein occludin nor A-IBS 18% (9/50
total IBS)
þþ colon mucosa WB (no change in qRT-PCR) IBS 25:18 ns Rome II
Decreased tight junction þþ colon mucosa WB (no change in qRT-PCR) D-IBS but neither C-IBS 50:33 53% (10/19) ; Rome III
protein claudin-1 nor A-IBS 36% (18/50
total IBS)
Decreased tight junction þþþ colon mucosa qRT-PCR IBS 21:12 ns Rome II
protein zonula þþ colon mucosa WB IBS 50:33 ns Rome III
occludens-1

NOTE. Data from Matricon J, Meleine M, Gelot A, et al. Review article: Associations between immune activation, intestinal permeability and the irritable bowel syndrome.
Aliment Pharmacol Ther 2012;36:1009-31.

Gastroenterology Vol. 150, No. 6

May 2016 Microenvironment and FGID 1318.e3

Supplementary Table 2.Molecular alterations in patients with IBS and FD2

Molecular alterations Localization Clinical subtype

Reduced ZO-1 expression Cecum IBS-A and IBS-D

Reduced E-cadherin expression Cecum IBS-A
Decreased occludin expression Colon IBS-C
Reduced JAM-A expression Cecum IBS
Decreased ZO-1 expression Small intestine IBS-D
Decreased ZO-1, claudin-1 and occludin expression Rectosigmoid IBS-D
Decreased ZO-1 and occludin expression Rectosigmoid IBS-D
Increased claudin-2 expression Jujunum IBS-D
Reduced occludin phosphorylation and enhanced redistribution
from the member to the cytoplasm
Increased myosin kinase expression
Reduced myosin phosphatase expression
Enhanced phosphorylation of myosin
Reduced ZO-1 expression Jejunum IBS-D
ZO-1 redistribution from the TJ to the cytoplasm
Decreased occludin and claudin-1 expression Descending colon IBS-D
Altered subcellular distribution of occluding and claudin-1 Descending colon IBS-C and IBS-D
Decreased occludin expression Descending colon IBS
Reduced ZO-1 expression Colon IBS
Reduced ZO-1 expression Duodenum FD
Decreased occludin expression
Reduced phosphorylation of serine / threonine residues (p-OCLN)
Reduced b-catenin expression
Reduced E-cadherin expression
Reduced desmocollin-2 and desmoglein-2 expression

NOTE. Data from Martinez C, Gonzalez-Castro A, Vicario M, et al. Cellular and molecular basis of intestinal barrier dysfunction
in the irritable bowel syndrome. Gut Liver 2012;6:305-315.
Supplementary Table 3.Summary of Major Chemical Messengers Controlling Gastrointestinal Function

1318.e4 Barbara et al
Known abnormalities in
Name Chemical nature Cell of origin Action Mechanism of action patients with IBS

Serotonin 5-hydroxytryptamine Enterochromaffin cells and Increases motility and Paracrine and neurocrine Increased and reduced
enteric neurones visceral sensation activity in IBS-D and
IBS-C
Nitric oxide (NO) Gas Enteric nitrinergic nerves Relaxation of gut and Inhibitory neurotransmitter Alters gut motility
vascular smooth
muscles
Vasoactive intestinal 28 amino acid (AA) peptide Enteric neurones Relaxation of gut and Inhibitory neurotransmitter Higher levels in IBS than
peptide (VIP) vascular smooth healthy controls
muscles
Ghrelin 28 AA peptide Oxyntic cells of stomach Stimulation of gastric and Endocrine Lower density of ghrelin
intestinal motility cells in IBS-C and
higher in IBS-D
Neurotensin 13 AA peptide Intestinal N cell and enteric Induces ileal brake, colonic Endocrine
neurones motility, pancreatic
secretion and inhibits
gastric secretion
Substance P 11 AA peptide Enteric neurones Smooth muscle Neurotransmitter Increased substance P
contraction and containing nerves in
inhibition of gastric acid IBS than controls
secretion
Somatostatin 14 and 28 AA peptides Intestinal D cells and enteric Inhibits digestive secretion Paracrine and endocrine Reduced D cell density in
neurones and post-prandial gut IBS-C and IBS-D
motility
Neuropeptide Y (NYY) 36 AA peptide Enteric neurones Decreases gut motility and Neurotransmitter Lower NYY in IBS-D than
digestive secretion IBS-C
Gastric inhibitory peptide 42 AA peptide Small intestinal cells Inhibits gastric acid Endocrine Reduced GIP cell density in
(GIP) secretion IBS-C and IBS-D
Peptide YY (PYY) 36 AA peptide Intestinal H/L cell Reduces gut motility and Endocrine and paracrine Reduced PYY cell density
digestive secretion in IBS-C and IBS-D
Secretin 27 AA peptide Intestinal S cell Reduced gastric, small and Endocrine Reduced S cell density in
large bowel motility IBS-D, but not in IBS-C
Enteroglucagon 69 AA peptide Intestinal L cell Inhibits gastric, pancreatic Endocrine
secretion and mediates
ileal brake

Gastroenterology Vol. 150, No. 6

Cholecystokinin (CCK) 8, 33, 39, 58 AA peptides Intestinal I-cell and neurones Delay gastric but enhance Endocrine and Reduced CCK cell density
gallbladder and gut neurotransmitter in IBS-D, but not in
motility IBS-C
Galanin 30 AA peptide Enteric neurones Inhibits gastric, pancreatic Neurotransmitter
and intestinal secretion
Motilin 22 AA peptide Intestinal M cell Induces migrating motor Reduction in IBS than
complex healthy control
Supplementary Table 3. Continued

May 2016
Known abnormalities in
Name Chemical nature Cell of origin Action Mechanism of action patients with IBS

Gastrin 17 and 34 AA peptide Gastric G-cell Stimulates gastric acid Endocrine

secretion
Pancreatic polypepdide 36 AA peptide Intestinal PP cell Relaxation of gallbladder Endocrine Higher in IBS-D and
(PP) and stimulation of gut reduced in IBS-C
motility

NOTE. Data from: El-Salhy M, Gundersen D, Gilja OH, et al. Is irritable bowel syndrome an organic disorder? World J Gastroenterol 2014;20:384-400; Miller LJ.
Gastrointestinal hormones and receptors. Philadelphia, Pa: Lippincott-Williams and Wilkins, 1999; Furness JB, Rivera LR, Cho HJ, et al. The gut as a sensory organ. Nat
Rev Gastroenterol Hepatol 2013;10:729-740.

Microenvironment and FGID 1318.e5

1318.e6 Barbara et al
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Pharmacologic, Pharmacokinetic, and Pharmacogenomic
Aspects of Functional Gastrointestinal Disorders
Michael Camilleri,1 Lionel Buéno,2,† Viola Andresen,3 Fabrizio De Ponti,4 Myung-Gyu Choi,5
and Anthony Lembo6
1
Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota; 2INRA, Toulouse, France; 3Israelitic Hospital, University
of Hamburg, Hamburg, Germany; 4Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy;
5
Department of Gastroenterology, The Catholic University of Korea College of Medicine Internal Medicine, Seoul, Korea; and
6
GI Motility Laboratory, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
This article reviews medications commonly used for the
treatment of patients with functional gastrointestinal disor-
ders. Specifically, we review the animal models that have been
validated for the study of drug effects on sensation and
motility; the preclinical pharmacology, pharmacokinetics,
and toxicology usually required for introduction of new
drugs; the biomarkers that are validated for studies of
sensation and motility end points with experimental medica-
tions in humans; the pharmacogenomics applied to these
medications and their relevance to the FGIDs; and the phar-
macology of agents that are applied or have potential for the
treatment of FGIDs, including psychopharmacologic drugs.
Keywords: Pain; Diarrhea; Constipation; Animal Models;
Dyspepsia; Transit; Sensation.
M edications are commonly used for the treatment of
patients with functional gastrointestinal disorders
(FGIDs). This article summarizes the pharmacokinetics and
pharmacology of medications used to treat FGIDs. Methods
included literature review, consensus evaluation of the ev-
idence for each topic assigned originally to 1 or 2 authors,
and broader review at a harmonization session as part of
the Rome IV process. Clinicians and basic scientists involved
in the treatment or investigation of FGIDs or disease models
need to have a comprehensive understanding of a vast range
of medications.
Preclinical Pharmacology: Animal
Models Validated for Study of Sensation
and Motility
The development of new drugs for the treatment of
patients with FGIDs is facilitated by preclinical animal
models that must reproduce the pathophysiology of FGIDs
as closely as possible. This section reviews the most
commonly used animal models of visceral pain and
disturbed gastrointestinal motility (Figure 1).
Visceral Pain
Mechanical Stimuli. Experiments are performed in
awake or anesthetized rats, and the most frequently used
stimulus of pain in animals is distention of a gut segment
Gastroenterology 2016;150:1319–1331
with a balloon connected to a barostat to measure simul-
taneously compliance and the response to gastrointestinal
distention. Balloons can be acutely or chronically implanted
in the gut.1 A number of factors influence reproducibility of
balloon distention studies across laboratories: balloon con-
PHARMACOLOGY
struction and unfolding, distention protocols, and frequency
of balloon distentions in the same animal (which can lead to
sensitization), and species (eg, rats vs mice) or strain dif-
ferences within species.
Chemical Stimuli. In rats, infusion of glycerol into the
colon through an implanted catheter induces abdominal
cramps that are typically demonstrated by observed be-
haviors (eg, back arching or writhing) or by psychoactive
responses, including reflex electromyographic activity
measured in the abdominal wall muscles (discussed in the
section End Points Used to Evaluate Sensation).2 Intra-
colonic injection of glycerol results in an increase in long
spike burst activity, which was eliminated by previous
administration of lidocaine, suggesting there is an induction
of a viscerovisceral reflex.3 Two separate studies provide
contradictory results regarding the role of glycerol-induced
activation of serotonin/5-hydroxytryptamine (5-HT) type 3
receptors on visceral afferent pathways. The 5-HT3 antag-
onist granisetron did not modify this reflex in a human
study, whereas alosetron significantly attenuated the
glycerol-induced visceral pain in rats.2,3 It is conceivable
that glycerol’s effects on contractile activity and tone might
be inhibited by alosetron independently of any effects on
visceral afferents or viscus compliance.4 Other stimuli are
used to sensitize the colon to balloon distention in order to
investigate visceral pain modulation in animal models; they
produce an initial inflammatory response5 that resolves, but
†
Deceased.
Abbreviations used in this paper: CFTR, cystic fibrosis transmembrane
regulator; cGMP, cyclic guanosine monophosphate; CYP, cytochrome
P450; FD, functional dyspepsia; FDA, Food and Drug Administration; FGID,
functional gastrointestinal disorder; GC-C, guanylate cyclase-C; GI,
gastrointestinal; 5-HT, 5-hydroxytryptamine; IBS, irritable bowel syn-
drome; IBS-C, constipation-predominant irritable bowel syndrome; IBS-D,
diarrhea-predominant irritable bowel syndrome; OIC, opioid-induced
constipation.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.029
 1320 Camilleri et al
later leads to sensitization of visceral afferents. Other
PHARMACOLOGY
chemical irritants include trinitrobenzene sulfonic acid,
dioctyl sodium sulfosuccinate, and zymogen and parasite
infestations (such as Nippostrongylus brasiliensis or Trichi-
nella spiralis). Long-term colonic hyperalgesia may also be
induced by colonic inflammation.6 At present, there is no
consensus on the best model to study visceral pain.
Nonchemical Models Used to Study
Visceral Sensitivity
Other models used to study colonic and rectal hyper-
sensitivity are stress (eg, maternal deprivation, water
avoidance models) and lipopolysaccharide injection.7,8
Long-term colonic hyperalgesia may be induced by
neonatal maternal deprivation.9
End Points Used to Evaluate Sensation
Nociceptive responses to stimuli, called “pseudo-
affective” responses, are brainstem or spinal reflexes that
cease when the noxious stimulus is terminated. The most
commonly used end point in the rat is the contraction of
abdominal muscles induced by rectal or colorectal disten-
tion; the contractions are typically recorded by electromy-
ography.2,5,10 The numbers of spike bursts or integrated
signals correspond to abdominal contractions during the
period of distension, and they correlate with the intensity of
the stimulus applied.5
In mice, colorectal distention triggers only one sustained
contraction at the onset of the distention.11 It is, however,
also possible that the electromyographic recording may
reflect contractions associated with a distention-induced
defecation reflex, rather than being a measure of pain.
This inference is supported by the observation that gastric
distention in rats does not induce abdominal contractions.
In contrast, stretching of the body or lifting of the head and
electromyography of neck muscles appear to reflect noci-
ceptive responses to gastric distention.12
Gastroenterology Vol. 150, No. 6
Figure 1. End points in
experimental animal
models of sensitivity and
motility are applied in pre-
clinical pharmacology of
lead compounds.
Visceral distension also induces viscerovisceral reflexes,
such as relaxation of anal sphincters during rectal distention
or rectocolonic inhibition of gastric emptying.13
Change in blood pressure is a pseudo-affective response
widely used to assess visceral pain. Cardiovascular and
muscular responses are mediated via brainstem reflexes;
both are vigorous in decerebrated, but not spinalized, rats.
Electrophysiologic recordings from sensory neurons or
second order neurons in the spinal cord may provide the
most direct evidence that a drug alters afferent
function.14,15
Measurements of the effect of the medication on viscus
compliance are essential to differentiate effects on volume
thresholds to activate sensory fibers from drug-induced
contraction or relaxation.16
Several behavioral end points have been used and
involve brain centers higher than the brainstem. They do
not cease when the noxious stimulus is terminated and,
therefore, are not pseudo-affective responses. Referred
somatic hyperalgesia is evaluated in mice by application
of von Frey hairs on the abdomen; the subsequent
behavioral response is a measure of sensation. Functional
magnetic resonance imaging studies of rat brain activity in
response to colorectal distention have also been
reported.17
Allodynia and Hyperalgesia
Several models permit evaluation of allodynia (decrease
in the sensitivity threshold to distention) and hyperalgesia
(enhanced response to painful stimulus). Gastric hypersen-
sitivity to distention has been induced by inflammation and
intestinal hypersensitivity by helminth infection.12,18
Motility
The techniques used to record motility or measure
transit in animals may differ from techniques used in
humans, but the end points are identical.
May 2016
Delayed Gastric Emptying
Numerous stressors have been proposed to inhibit
gastric emptying in rats, including restraint, acoustic
stress, cold stress, combined acoustic and cold stress, and
passive avoidance. Prolonged colonic distension inhibits
gastric emptying, and this is considered relevant because,
in humans, voluntary suppression of defecation for 4 days
inhibits gastric emptying.19,20 Another experimental
method used to inhibit gastric emptying is duodenal infu-
sion of lipids in humans or animals (reviewed in Lee and
Tack21).
Altered Duodenojejunal Migrating Motor
Complex Pattern
Acute stress affects migrating motor complex patterns22;
however, there are no models of chronic disruption of the
migrating motor complex in animals.
Altered Colonic Motility and Transit
Intestinal motility can be measured in animal models
of gastrointestinal (GI) transit. A traditional model is the
charcoal meal model, where animals are administered
test agents before or followed by a bolus of a charcoal
meal. The distance traveled by this charcoal along the GI
tract is measured and quantified as a percentage of
distance traveled after administering vehicle alone.23
Colonic transit in response to fluid hypersecretion is
harder to measure in rodents due to the high fluid
reabsorption in the cecum; however, preclinical models
to study distal colonic propulsion have been described in
rodents.24 Colonic motility can be inhibited by drugs
such as a2-adrenoceptor and m-opioid receptor agonists.
Stress has been used to stimulate colonic motility,
colonic transit, and fecal excretion in rats.25 Induction of
intestinal peristalsis by pharmacologic agents has also
been modeled using isolated guinea pig colonic
segments.26
In summary, because the present knowledge of the
pathophysiology of FGIDs is limited, selection of one or
more reliable animal models is not possible. It is also
difficult, based on results in a single animal model, to
predict efficacy of a compound in clinical trials. Studying
more than one animal model can enhance the probability
of selecting effective drugs for further development.
Several medications with track records of proven efficacy
in animal models (for both transit and sensation) were
subsequently shown to have clinical efficacy (eg, 5-HT4
agonists, 5-HT3 antagonists, opioid agonists, guanylate
cyclase-C receptor agonists); however, other classes of
medications that appeared to influence sensory functions
in animal models were not efficacious in clinical trials (eg,
NK2 antagonist, b3-adrenergic agonist). In addition, it is
worth emphasizing that pain is not the only symptom of
FGIDs affecting quality of life, and animal models providing
information on motility effects may be relevant to the
assessment of new drugs.
Pharmacology in FGID 1321
Human Studies of Motility and
Sensation: Utility in Drug Development
for Functional Gastrointestinal
Disorders
This section reviews the application of physiologic tests as
potential biomarkers used to understand the mode of action
and to predict efficacy of new drug treatments of FGIDs.
Measurements of Colonic Transit
The radiopaque marker test for colonic transit is a
commonly performed and widely available test used to
assess whole-gut transit time. Studies with fiber or loper-
amide suggest that overall effects of these therapies can be
predicted by the marker transit test, although there was
considerable overlap.27,28 Examples from the literature
support the use of detailed scintigraphic colonic transit
measurement in the development of medications for irrita-
ble bowel syndrome (IBS)
associated changes in bowel
function. Alosetron, a 5-HT3 receptor antagonist that slows
PHARMACOLOGY
colonic transit, was shown to be effective in female
diarrhea-predominant IBS (IBS-D) patients,29 and tegaserod
and prucalopride, 5-HT4 receptor agonists that accelerate
colonic transit, are effective in constipation-predominant
IBS (IBS-C) and functional constipation.30–34 Linaclotide, a
novel agonist of guanylate cyclase-C, accelerated ascending
colonic transit and altered bowel function; thus, it was
shown to be effective in IBS-C.35–37
Intraluminal Measurements of Rectal or Colonic
Motility and Sensation
Intracolonic measurements of postprandial tone showed
the potential of 5-HT3 receptor antagonists to prevent diar-
rhea and other postprandial symptoms in IBS and carcinoid
diarrhea.38 However, measurements of rectal or colonic
sensation in human subjects do not reliably predict clinical
efficacy. Changes in rectal sensitivity are observed with
octreotide and opiates, but rectal sensory thresholds are not
altered by tegaserod when using rapid distention.39–44
Gastric Biomarkers in Functional Dyspepsia
Gastric emptying rates, gastric electrical rhythm, gastric
sensitivity, and gastric accommodation are targets for
testing new drugs. Gastric emptying rates can explain
symptoms and aid in diagnosis of gastroparesis. Scinti-
graphic gastric emptying has been a classic measurement
for testing drug efficacy in gastroparesis; however, the
prediction of clinical efficacy is not consistent.45,46 A recent
extensive review questions the use of gastric emptying
measurement to direct drug development for gastro-
paresis.47 This analysis is also complicated by the occur-
rence of tachyphylaxis to some medications and by changes
in gastric emptying rate with placebo.48–51
Gastric accommodation is a new target for treatment, as
it reflects meal-related satiety. The gastric barostat is the
gold standard test used to measure compliance, tone, and
 1322 Camilleri et al
sensitivity. The k-opioid agonist fedotozine and the 5-HT1A
receptor agonist R-137696 produced acute effects on
barostat measurements of sensitivity or tone that did not
translate into significant clinical benefit during placebo-
controlled studies of several weeks in functional dyspepsia
(FD).52,53 Single-photon emission computed tomography
and magnetic resonance imaging can evaluate accommoda-
tion by measuring gastric volume, but their usefulness has
not been proven in clinical trials.
Induction of symptoms by a standardized provocative
meal of water or a liquid nutrient drink or a solid meal
shows differences between healthy controls and FD, and
was used in clinical trials.54–56 One open trial of the
dopamine-2 receptor antagonist and acetylcholinesterase
inhibitor itopride (discussed further in the subsection
Dopamine Receptor Antagonists) demonstrated that a pro-
vocative meal can quantify dyspeptic symptoms and re-
flected therapeutic effects of itopride treatment in FD.
However, it is still unclear whether changes in symptom
severity after meal provocative tests will prove effective
PHARMACOLOGY
predictors of the clinical efficacy of medications.
Combined use of the nutrient drink test with assessment
of symptoms, and measurement of gastric volume and
emptying or intragastric pressure monitoring, may simul-
taneously measure several potential biomarkers.57–59
Improved methods or further validation of those
mentioned will more accurately assess changes in symp-
toms and sensorimotor function in future trials.
Preclinical Considerations
An outline of some general pharmacodynamic, pharma-
cokinetic, and safety aspects that are important for the
development of new drugs for FGIDs is included in the
Supplementary Material.
Pharmacokinetics
Ideal pharmacokinetics features of a drug with systemic
action are the ability to reach clinically relevant drug con-
centrations at the target receptor; half-life or dosage
formulation suitable for once daily administration; not a
cytochrome P450 (CYP) substrate (lack of drug in-
teractions); no metabolites with different or unwanted
pharmacologic actions; and no interactions with food.
CYP2D6, CYP3A4, and CYP2C19 are important iso-
enzymes because of their involvement in the metabolism of
many drugs and drug
drug interactions. The prevalence of
altered CYP450 differs among different populations.
Figure 2 shows the distribution of CYP2 altered activity
variants in different geographic regions.60
Significant interactions with these enzymes should be
ruled out in early drug discovery and may be achieved by
computational prediction. Specifically, it is important to
distinguish between pharmacokinetic modification resulting
from drug metabolism by one of the enzymes vs drug in-
teractions, which may be inhibition or induction, at one of the
enzymes. In both situations, drug
drug interactions can occur,
if inhibition or induction occurs at clinically relevant doses.
Gastroenterology Vol. 150, No. 6
Principles of Pharmacogenomics in
Functional Gastrointestinal Disorders
Pharmacogenetics refers to the study of individual
variations in DNA sequence related to drug response.
Pharmacogenomics is the study of the variability of the
expression of individual genes relevant to disease suscep-
tibility as well as drug response at cellular, tissue, individ-
ual, or population levels.
Polymorphisms may be markers associated with pre-
disposition to FGIDs. For example, there may be an in-
flammatory or genetic component (eg, serotonin
transporter, polymorphism in 5-hydroxytryptamine trans-
porter linked polymorphic region) in some cases of IBS,61,62
or polymorphism (C825T) in the gene controlling G-protein
synthesis in functional dyspepsia and IBS.63 Such genetic
variations can influence response to medications. There may
also be genetic polymorphisms in drug metabolism. For
instance, the number of functional CYP2D6 genes de-
termines the pharmacokinetics and plasma levels of the
commonly used tricyclic agent, nortriptyline,64 or the action
of codeine (which is converted to morphine by the CYP2D6
isoenzyme to be effective). Note also that several antide-
pressants are metabolized by these enzymes, and this might
affect their clinical efficacy and safety.
Genetic polymorphisms may also involve transporters65
that may influence drug response. Two examples of
pharmacodynamic variation in FGIDs are provided.
5-Hydroxytryptamine transporter linked polymorphic
region polymorphisms in the gene SLC6A4 (solute carrier
family 6 [neurotransmitter transporter], member 4) were
associated with a greater colonic transit response in those
with long homozygous polymorphisms compared to those
with heterozygous or short homozygous polymorphisms in
IBS-D.66 Conversely, IBS-C patients carrying the S allele of
5-hydroxytryptamine transporter linked polymorphic region
have greater response to the 5-HT4 agonist tegaserod.67
Holtmann et al63 found that GNB3 polymorphisms were
predictors of symptom outcomes in FD, based on the
rationale that G proteins act as second messengers and may
influence multiple receptor-mediated mechanisms.
Thus, pharmacogenetics may affect drug response and
need to be considered in drug development programs and in
clinical therapeutics in FGIDs. Further examples and dis-
cussion of pharmacogenetics in IBS are provided in the
Supplementary Materials.
The conclusion as far as pharmacodynamics is that cli-
nicians and basic investigators involved in the treatment or
investigation of FGIDs or disease models need to have a
comprehensive understanding of a vast range of medica-
tions. It is anticipated that the interactions among basic
scientists, applied pharmacologists, and clinical trials will
lead to better treatment for these disorders.
Human Pharmacology:
Nonpsychotropic Agents
Gastrointestinal motor and sensory functions can be
altered through several pharmacologic approaches; the
May 2016 Pharmacology in FGID 1323

Figure 2. Cytochrome
P450 (CYP) refers to a
family of enzymes that are
responsible for the meta-
bolism of endogenous and
exogenous compounds.
CYP2 is associated pri-
marily with metabolism
(including oxidation, dehy-
drogenation, and esterifi-
cation) of a large number
of exogenous compounds.
The CYP2 metabolizing
enzymes are encoded by
polymorphic genes. Mo-
lecular variations in the
genes encoding CYP2D6,
CYP2C19, and CYP2C9
have the greatest clinical
impact. The figure shows
the distribution of CYP2
altered activity variants in
different geographic re-

PHARMACOLOGY
gions: (A) CYP2C9, (B)
CYP2C19, and (C)
CYP2D6. This suggests
that population substruc-
ture can strongly affect the
variation in pharmacoge-
netic loci and therefore,
the metabolism of drugs.
Adapted from Sistonen
et al,60 with permission.

most important are summarized in Supplementary Table 1
and are discussed in this section. However, it is also
important to recognize 2 other classes of agents commonly
used in FGIDs: laxatives in the treatment of constipation
(alone or in IBS-C68) and probiotics.69 Several meta-analyses
of pharmacologic treatments for IBS have been published in
recent years.70 Although not a focus of this article, the
pharmacologic actions of psychotropic drugs on monoamine
reuptake and receptors are summarized in Supplementary
Table 2. Figure 3 shows potential cellular and mechanistic
targets for drug action in functional and motility disorders.
Figure 4 provides a summary of receptors located on
different cellular targets and their potential as treatments
for FGIDs. Figure 5 summarizes the interaction of gut
mucosal barrier, microbiome, and gut
brain interactions in
FGIDs, focusing on colonic disorders.
Upper Gastrointestinal Tract:
Gastroparesis, Functional Dyspepsia
Current Drug Treatments for Gastroparesis or
Functional Dyspepsia
Serotonergic agents. Serotonin, or 5-HT, plays a key
role in the control of gastrointestinal motility, sensitivity,
and secretion. Actions of 5-HT are terminated by the action
of the serotonin transporter, which is inhibited by selective
serotonin reuptake inhibitor antidepressants.71 Selective
serotonin reuptake inhibitor alter motility in the stomach,
small bowel, and colon,72 but, to date, no convincing bene-
ficial therapeutic effects have been reported in FGIDs.
Several 5-HT receptor types are present on nerves and
smooth muscle and mediate multiple effects on gut motility,
secretion, and sensation.73
5-HT4 receptor agonists, such as prucalopride or
mosapride, act on intrinsic neurons to stimulate esophageal,
gastric, small bowel, and colonic transit in health, in
gastroesophageal reflux disease, in FD, in constipation, and
in IBS-C.74–80
In the stomach, 5-HT4 receptor agonists enhance (post-
prandial) proximal gastric volumes in health, but do not
alter sensation.81 While prucalopride has been studied
mainly in the lower GI tract and is primarily approved for
the treatment of constipation (outside the United States),
mosapride has also been investigated in the upper GI tract
and is approved for the treatment of dyspepsia and
gastroesophageal reflux disease in a variety of Asian and
South American countries. Supplementary Table 3 shows a
comparison of novel 5-HT4 agonists that are efficacious in
stimulating gut motility or transit and are sufficiently se-
lective to predict clinical safety from cardiovascular per-
spectives (discussed in section on constipation and IBS-C).
Dopamine receptor antagonists. Dopamine-2 receptor
antagonists have gastroprokinetic effects and central
 1324 Camilleri et al Gastroenterology Vol. 150, No. 6

Figure 3. Potential local

therapeutic targets for
drug action in the gut
include visceral sensitivity,
microbiome, motility,
secretion, immune activa-
tion, and barrier function.
PHARMACOLOGY

antiemetic properties resulting in suppression of nausea and
vomiting. Although metoclopramide and domperidone are
used clinically in the treatment of FGIDs and gastroparesis,
efficacy has not been established by high-quality studies.82–84
and treatment is recommended for short periods. A recent 4-
week trial of oral dissolving metoclopramide shows efficacy
in gastroparesis compared with placebo.85 It should be kept
in mind that domperidone is listed among drugs with known
risk of torsades de pointes, and the European Medicines
Agency Pharmacovigilance Committee recommended re-
strictions on its use86,87 (www.crediblemeds.org).
Itopride is a benzamide that acts as a dopamine-2
receptor antagonist and an acetylcholinesterase inhibitor.
Itopride has been investigated in FD with conflicting
results.88–90 It is approved for the treatment of FD in Asia.
Motilides. Activation of motilin receptors on smooth
muscle and cholinergic nerves enhances gastric contrac-
tility.91 Motilin receptor agonists, such as erythromycin,
azithromycin, and clarithromycin enhance antral contrac-
tility, fundic tone, and gastric emptying in health and in
gastroparesis.48,92–95 However, the symptomatic impact of
enhanced empting by erythromycin in gastroparesis has

Figure 4. Localization and nature of major targeted receptors in the treatment of functional bowel disorders. a2, alpha-2
adrenoceptor; a2d, calcium channel a2d, subunit; b3, beta adrenoceptor 3; CB2, cannabinoid receptor 2; CCK1, cholecys-
tokinin receptor 1 (or A); CB1, cannabinoid receptor 1; ClC2, chloride channel 2; D2, dopamine receptor 2; FXR, farnesoid X
receptor; GHSR1a, ghrelin receptor; GLP1, glucagon-like peptide1 receptor; H1, histamine receptor 1; 5-HT3, 5HT4, 5-HT1A,
serotonin receptors; IBAT, ileal bile acid transporter; M1, M3, muscarinic receptors 1 and 3; M3, muscarinic receptor 3; Mot-R,
motilin receptor; NHE3, Naþ/Hþ exchanger receptor 3; NK2, NK3, tachykinin receptor 2 and 3; NMDA, N-methyl-D-aspartate
receptor; SST2, somatostatin receptor 2; TRPV1, transient receptor potential vanilloid 1.
May 2016 Pharmacology in FGID 1325

PHARMACOLOGY
Figure 5. Site of action of different classes of medications on the brain
gut axis to alter colonic motility, secretion, immune
activation, and sensation. For example, the sites of action of different drug classes are shown in the myenteric plexus,
submucosal plexus and ion channels or receptors in enterocytes. H, histamine; 5-HT, serotonin; NHE, sodium-hydrogen
exchanger; NK, neurokinin; OR, opioid receptor; PAMORA ¼ peripherally active mu-opioid receptor antagonist. Adapted
from Camilleri,268, with permission.

been questioned.46 The occurrence of tachyphylaxis with
erythromycin and some motilides (eg, ABT-229) may also
be an important factor.96 A novel motilin receptor agonist
(that does not appear to be associated with tachyphylaxis) is
the experimental drug, camicinal.97 It is efficacious in vitro98
and has been shown to induce phasic contractions and in-
crease gastrointestinal motility in conscious dogs.99
Acetylcholinesterase inhibitor. Acotiamide is an
acetylcholinesterase inhibitor that was recently approved in
Japan for the treatment of FD. In phase 2 trials conducted in
Europe, United States, and Japan, acotiamide had beneficial
effects in FD, particularly for meal-related FD symptoms,
such as postprandial fullness, upper abdominal bloating,
and/or early satiation. A 4-week, phase 3 trial conducted in
Japan in patients with postprandial distress syndrome
confirmed the efficacy of acotiamide, 100 mg 3 times a day,
in meal-related symptoms (ie, postprandial fullness, upper
abdominal bloating and early satiation) compared with
placebo.100–102
New Drugs for Treatment of Gastroparesis and
Functional Dysplasia
Ghrelin agonists: RM-131. TZP-101 (ulimorelin, an
intravenous formulation ) and TZP-102 (oral) were not
consistently efficacious in early trials.103–108
Relamorelin, a pentapeptide synthetic ghrelin agonist,
has a longer plasma half-life and >100 times greater po-
tency than native ghrelin in reversing ileus in rats and pri-
mates. In a randomized, placebo-controlled single-dose
study, relamorelin accelerated gastric emptying in type 2
diabetes mellitus patients with gastrointestinal cardinal
symptoms and prior documentation of delayed gastric
emptying.109 In a large (n ¼ 204) 4-week, phase 2b study in
patients with diabetic gastroparesis, relamorelin, 10 mg
given subcutaneously twice daily, improved gastric
emptying and reduced vomiting episodes.110 Larger studies
with longer treatment duration for the assessment of
symptom improvement in gastroparesis are warranted.
Motilin receptor agonists. Camicinal (GSK962040) is
a small molecule, non-motilide motilin receptor agonist that
selectively activates the motilin receptor in humans and has
been evaluated to determine safety and tolerability in
humans.111 It is currently being investigated in phase 2
trials (NCT01262898).112
Motilin agonists may increase gastric tone or inhibit
gastric accommodation and, potentially, worsen symptoms,
even when gastric emptying improves.
Cholecystokinin. Cholecystokinin has multiple effects
on gastrointestinal motility and secretion.113 Clinical use-
fulness of cholecystokinin-1 receptor antagonists, such as
loxiglumide and dexloxiglumide, is uncertain.114,115
 1326 Camilleri et al
Capsaicin. The transient receptor potential ion channel
of the vanilloid type 1 (transient receptor potential cation
channel, vanilloid member 1), expressed by primary afferent
neurons, is a chemo- and thermoreceptor that may be up-
regulated in some FGIDs.116 Long-term administration of
capsaicin, which is a transient receptor potential cation
channel, vanilloid member 1 agonist, was more effective
than placebo in decreasing symptoms in FD.117
Cannabinoids. Cannabinoid CB1 receptors are
expressed on nociceptive primary afferents and some
enteric neurons. CB1 receptor agonists slow gastrointestinal
transit in animals by inhibiting acetylcholine release. d-9-
Tetrahydrocannabinol has strong antiemetic properties
and delays gastric emptying in humans.118,119 It is unclear
whether the abuse potential of CB1 agonists would preclude
regulatory approval for treatment of FGIDs.
Chronic Constipation and Irritable Bowel
Syndrome With Constipation
PHARMACOLOGY
Current drug treatments. A discussion of the large
number of available laxatives for chronic constipation is
beyond the scope of this article. Among treatments for
IBS-C, there is one large randomized controlled trial of
polyethylene glycol showing improvement of constipation,
but not pain.120
Novel drug developments. There are 3 drug cate-
gories under development for treating chronic idiopathic
constipation and IBS-C: 5-HT4 receptor agonists, intestinal
secretagogues, and bile acid modulators. Medications are
being developed for specific treatment of opioid-induced
constipation (OIC). Enhancing coordinated motor function
is conceptually attractive, based on the demonstration of
increased but uncoordinated motility, or retrograde or
nonpropagated colonic contractility in disorders associated
with constipation.121,122
5-Hydroxytryptamine type 4 receptor agonists. 5-
HT is an important neurotransmitter and paracrine
signaling molecule involved in gastrointesintal secretion,
sensation, and motility.123 5-HT4 receptors are expressed by
enteric neurons and in the heart. 5-HT4 receptor agonists
facilitate fast excitatory cholinergic synaptic transmission
between enteric neurons, which stimulates gastrointestinal
motility and secretion.34,77 Activation of colonic mucosal 5-
HT4 receptors can inhibit visceral hypersensitivity in
rodents.124
Prucalopride, a new 5-HT4 receptor agonist, has >150-
fold greater selectivity for the 5-HT4 receptors than for
the IKr channel and other 5-HT receptors.125 Prucalopride,
mosapride, and 3 other 5-HT4 receptor agonists (velusetrag,
naronapride, and YKP10811) in recent and current devel-
opment, including human trials are summarized in
Supplementary Table 3. With high intrinsic activity and
great specificity at intestinal 5-HT4 receptors and with low
intrinsic activity in cardiac muscle, these drugs have greater
cardiovascular safety in comparison with older 5-HT4
agonists.125
There is considerable evidence supporting pruca-
lopride’s pharmacodynamic and clinical efficacy and safety
Gastroenterology Vol. 150, No. 6
in patients with chronic constipation.126–132 Prucalopride
did not show significant adverse effects in a study of elderly
patients.133 Doses of 2 mg per day in adults and 1 mg per
day in the elderly were approved for chronic constipation
by the European Medicines Agency and a number of other
regulatory bodies outside the United States.
Velusetrag and naronapride are in development stages
(see Supplementary Table 3).134–136
YKP10811 is a 5-HT4 receptor agonist that enhances
colonic transit and improves stool consistency, and it
reduced pain in an animal model of IBS.137,138
Intestinal ClL secretagogues. Cl
secretagogues
enter enterocytes through the basolateral Naþ-Kþ-2Cl
co-
transporter. Naþ and Kþ are then exported through the
Naþ/Kþ, ATPase, and KCNQ1/KCNE3 heteromeric Kþ
channels. Cl
secretion in the apical membrane of epithelial
cells occurs through cystic fibrosis transmembrane regu-
lator (CFTR) and ClC-2 Cl
channels139 and is activated by
intracellular Ca2þ and cyclic guanosine monophosphate
(cGMP).
Lubiprostone and linaclotide are approved drugs, while
plecanatide and tenapanor are still in drug development
(Supplementary Table 4).140
Lubiprostone is a bicyclic fatty acid, most closely related
in structure to 15-keto-13,14-dihydro-PGE1, without the
functional characteristics of PGE1.141,142 It stimulates intes-
tinal Cl
secretion through apical membrane ClC-2 channels
and CFTR143; the action on CFTR is still controversial, with
recent data suggesting CFTR is not a target of lubiprostone at
relevant concentrations.144 Lubiprostone has demonstrated
efficacy in chronic constipation (24 mg bid) and in IBS-C (8 mg
bid), and is approved by the US Food and Drug Administra-
tion (FDA) and several other countries.143,145–150 Lubipro-
stone is also approved for treatment of OIC (discussed in the
section Other Medications for OIC).
Linaclotide and plecanatide activate guanylate cyclase-C
(GC-C) receptors in intestinal epithelium, resulting in the
elevation of cGMP intracellularly and extracellularly. This
receptor is the target for heat-stable enterotoxin (STa) of
Escherichia coli. Activation of GC-C results in stimulation of
chloride and bicarbonate secretion through cGMP-
dependent phosphorylation of CFTR, resulting in the open-
ing of chloride channels, and it results in inhibition of Naþ
absorption through blockade of an apical Naþ/Hþ
exchanger.151,152 The principal effector of ion transport is
cGMP-dependent protein kinase type II. In addition to the
secretory effects, linaclotide induces extracellular release of
cGMP that inhibited visceral nociceptors.153 Linaclotide ac-
celerates colonic transit, enhances intestinal secretion, and
improves symptoms of constipation and abdominal pain in
phase 2b and phase 3 trials of patients with chronic con-
stipation and IBS-C.154–162 It is approved for the treatment
of IBS-C (290 mg/d) by the FDA, the European Medicines
Agency, Health Canada, COFEPRIS (Mexico), and the Swiss
Agency for Therapeutic Products (Swissmedic), and for the
treatment of chronic constipation (145 mg/d ) by the FDA,
Health Canada, and COFEPRIS (Mexico).
Plecanatide is another GC-C currently being developed
for IBS-C and chronic constipation.163 In a large (n ¼ 946)
May 2016
12-week, phase 2b study, plecanatide was effective in
treating the symptoms of constipation, particularly at the
highest dose (3 mg once daily).164
Tenapanor is an inhibitor of sodium-hydrogen exchanger
3 that blocks absorption of Naþ through the sodium-
hydrogen exchanger 3 transporter. In a phase 2b clinical
trial in IBS-C, tenapanor, 50 mg twice daily, increased
spontaneous bowel movements responder rate and was
well tolerated.165
Bile Acid Modulation
Delivery of bile acids into the colon due to inadequate
(less than the normal approximately 95%) ileal reabsorp-
tion results in secretory diarrhea by increasing perme-
ability, activating adenylate cyclase, and increasing colonic
motility.166 It is estimated that approximately 25% of
patients diagnosed with IBS-D actually have bile acid
malabsorption.167 Treatment of these patients with bile acid
sequestrants may be helpful, although well-controlled
studies are lacking (see in subsection Bile acid binders).
Given the pharmacologic effects of bile acids on GI
function, a novel approach for treatment of chronic con-
stipation involves selective inhibition of the ileal bile acid
transporter (also called apical Naþ-dependent bile acid
transporter) with elobixibat, resulting in greater delivery of
bile acids to the colon. This drug accelerated colonic transit,
significantly improved stool consistency, constipation rat-
ing, ease of stool passage, and reduction of straining; and
significantly increased stool frequency and improved
contipation-related symptoms over 8 weeks of treat-
ment.168,169 Long-term exposure of patients to high colonic
bile acids after partial ileal bypass for hyperlipidemia is not
associated with increased prevalence of colorectal cancer at
5-year or 25-year follow-up.170
Peripherally Acting m-Opioid Receptor
Antagonists in Opioid-Induced Constipation
Peripherally acting m-opioid receptor antagonists, such
as N-methylnaltrexone and naloxegol are designed to
reverse the peripheral effects of opioids without compro-
mising central opioid analgesia.
Although efficacy in OIC has been demonstrated,171,172
alvimopan has only been approved by the FDA for the
short-term treatment of postoperative ileus because of a
suspected increase of cardiovascular events in one long-
term trial.
Methylnaltrexone is currently available in subcutaneous
injection and approved for use in palliative care patients
and chronic noncancer pain. An oral form of methylnal-
trexone also appears to be effective for OIC, but is not yet
approved by regulators.
Naloxegol is an oral therapy that is approved by the FDA
for treatment of OIC in adult patients with chronic non-
cancer pain. In 2 large phase 3 clinical trials, 25 mg once
daily of naloxegol significantly improved OIC response rates
compared with placebo. Naloxegol, 12.5 mg once-daily dose,
also showed efficacy, though it met statistical significance in
only 1 of the 2 trials.173,174 Other peripherally acting
Pharmacology in FGID 1327
m-opioid receptor antagonists in clinical development are
naldemedine and TD-1211. These agents are summarized in
Supplementary Table 5.
Other Medications in Opioid-Induced
Constipation
Prucalopride,175 lubiprostone,176,177 and the experi-
mental GC-C agonist, SP-333,178 are also potentially effica-
cious in treatment of OIC. Of these, only lubiprostone at a
dose of 24 mg twice daily is approved by the FDA for the
treatment of OIC.
Chronic Diarrhea and Diarrhea-
Predominant Irritable Bowel Syndrome
In the absence of mucosal diseases, such as celiac and
inflammatory bowel diseases, chronic diarrhea generally
results from increased intestinal or colonic motility or
secretion, increased colorectal sensitivity, or alterations of
PHARMACOLOGY
the intestinal content (bile and short-chain fatty acids or the
microbiome) and barrier function.
Current Drug Treatments for Chronic
Diarrhea and Diarrhea-Predominant
Irritable Bowel Syndrome
m-Opioid receptor agonists. The m-opioid receptor
agonist loperamide has limited ability to penetrate the
blood
brain barrier and inhibits secretion, reduces colonic
transit, and increases resting anal sphincter tone.179 In
contrast to loperamide, which is available over-the-counter,
diphenoxylate can cross the blood
brain barrier and,
therefore, is combined with atropine to reduce abuse po-
tential and is available only by prescription. While both m-
opioid receptor agonists reduce diarrhea, particularly acute
diarrhea, neither has been subjected to high-quality clinical
trials in IBS-D.180 In the case of loperamide, several small
studies have shown improvement in diarrhea-related
symptoms associated with IBS-D, but have not evaluated
individual or global symptoms in IBS-D. Adverse effects are
rare, but include bladder dysfunction, glaucoma, and
tachycardia.
Bile acid binders. Bile acid binders (cholestyramine,
4 g 3 times daily, and off-label colesevelam, 625 mg, 1
3
tablets bid) are indicated for bile acid diarrhea and those
with IBS-D and bile acid diarrhea.181 Cholestyramine gran-
ules are often poorly tolerated, owing to poor taste and
sticking to teeth.
5-Hydroxytryptamine type 3 receptor antago-
nists. 5-HT3 receptor antagonists, such as alosetron, delay
orocecal and colonic transit times and reduce colonic
compliance, but not sensitivity to isobaric distention.182–184
Several clinical studies confirmed the efficacy of alosetron in
IBS-D.29 Alosetron was temporarily withdrawn due to sus-
pected association with ischemic colitis185; it is now avail-
able for restricted use only in the United States. Other 5-HT3
antagonists (such as ondansetron), approved for the treat-
ment of chemotherapy-induced nausea and vomiting, are
 1328 Camilleri et al
often used as off-label treatment for IBS-D. Ondansetron
was shown to be effective in IBS-D.186
Psychoactive agents. Psychoactive agents with anti-
cholinergic effects are commonly used off label in IBS-D.
These are reviewed elsewhere (Biopsychosocial Aspects of
FGIDs).
Novel Drugs in Development or Recently
Approved for Chronic Diarrhea and Diarrhea-
Predomination Irritable Bowel Syndrome
5-Hydroxytryptamine type 3 receptor antago-
nists. Ramosetron slows colonic transit and reduces pain
sensation in animal models subjected to stress.187,188
Ramosetron (5 mg and 10 mg) was tested in 4 studies of
approximately 1300 patients with IBS-D and was superior
to placebo in global relief of symptoms, with similar efficacy
in men and women. Constipation and hard stool occurred in
approximately 5% of patients.189–193 Ramosetron, 5 mg once
daily, is as effective as the antispasmodic, mebeverine, 135
mg 3 times daily, in male patients with IBS-D.194 To date,
PHARMACOLOGY
ramosetron has not caused ischemic colitis.
Nonabsorbable antibiotics. Rifaximin is a minimally
absorbed antibiotic that is FDA-approved for treating trav-
eler’s diarrhea and hepatic encephalopathy; it is also
approved for IBS-D. In 2 large, phase 3 trials, rifaximin, 550
mg tid for 2 weeks, significantly improved adequate relief of
IBS symptoms and abdominal bloating, as well as the FDA
Responder End point for IBS-D during the 10 weeks after
treatment. Patients receiving rifaximin had an approxi-
mately 10% greater likelihood of being a responder for
adequate relief of IBS symptoms and bloating than patients
receiving placebo.195 A meta-analysis that included 3 addi-
tional clinical trials also found improvement of global IBS
symptoms and bloating, but no significant effect on
bowel function.196 Retreatment with rifaximin is also
efficacious.197
Mixed m-opioid receptor agonist and d-opioid
receptor antagonist (eluxadoline). The combination of
mixed m-opioid receptor agonist and d-opioid receptor
antagonist eluxadoline has been studied in phase 2 and two
phase 3 clinical trials for 26 and 52 weeks in IBS-D pa-
tients.198,199 A greater percentage of patients receiving 100
mg eluxadoline met responder definitions proposed by
regulatory agencies, compared with patients receiving pla-
cebo. Few cases of pancreatitis and sphincter of Oddi spasm
were reported in patients at high risk (eg, history of alcohol
abuse or history cholecystectomy). The drug is approved by
the FDA, and risk
benefit is being carefully watched.
Serotonin synthesis inhibition. LX-1031 is an oral
tryptophan hydroxylase (TPH) inhibitor that reduces syn-
thesis of 5-HT peripherally,200 as it does not cross the
blood
brain barrier and, thus, avoids risk of depression. In
a 4-week, phase 2 trial, LX-1031 dose-dependently reduced
5-HT, and there was correlation with adequate relief and
improved stool consistency with the 1000-mg dose
group.201 There appears to be wide variability in effect of
the drug, possibly related to TPH1 polymorphisms and the
observation that 15 of 43 patients who showed a fall in
urinary 5-hydroxyindoleacetic acid excretion responded
Gastroenterology Vol. 150, No. 6
better than those who did not show a fall in urine 5-
hydroxyindoleacetic acid. No phase 3 trials have been re-
ported to date.
Tachykinin receptor antagonists. Three distinct re-
ceptors, neurokinin-1, neurokinin-2, and neurokinin-3,
mediate the biological effects of endogenous tachykinins,
substance P, and neurokinin A and B in the gastrointestinal
tract. Through their locations on intrinsic nerves, extrinsic
nerves, inflammatory cells, and smooth muscle, inhibition of
tachykinin receptors has the potential to inhibit motility,
sensitivity, secretion, and inflammation in the gastrointes-
tinal tract.202,203 Tachykinin 1 receptor antagonists also
have antiemetic properties.202
An NK2 receptor antagonist, ibodutant (1, 3, and 10 mg,
once daily), was compared with placebo for 8 weeks in 559
patients with IBS-D. There was significant effect of the 1
mg/d dose in females in a prespecified analysis.204 Ibodu-
tant is currently being evaluated in phase 3 studies in fe-
male patients with IBS-D.
Muscarinic type 3 receptor antagonists. There are
beneficial pharmacodynamic effects of this class of medi-
cations that can relieve chronic diarrhea: darifenacin
retarded human small bowel and colonic transit, otilonium
reduced rectal sensation, and hyoscine (nonselective)
reduced enterocyte secretion.205–207 Clinical trials show
greatest effect of otilonium on abdominal sensation
rather than bowel dysfunction in IBS.208,209 A cross-over
design trial showed similar efficacy of solifenacin and
ramosetron.210
Carbon adsorbent: AST-120. AST-120 consists of
porous, spherical carbon particles that adsorb substances in
the lumen that can cause secretion (eg, bacterial toxins and
bile acid products).211 In a phase 2, 8-week treatment trial,
AST-120 transiently reduced pain and bloating in 115 pa-
tients with IBS-D or IBS-alternating; however, stool consis-
tency was not significantly improved.212
Mast cell stabilizers. The rationale for this class of
medications is supported by mast cell activation and
hyperplasia in the jejunal mucosal biopsies in IBS-D
patients.213
Disodium cromoglycate reduced release of tryptase from
jejunal biopsies, reduced expression of toll-like receptor
2 and 4, and improved bowel function in IBS-D.214,215 In an
earlier study of 66 IBS-D patients with food intolerance
assessed by skin prick test, disodium cromoglycate, 250 mg
4 times daily, plus exclusion diet, was associated with pro-
longed symptomatic benefit compared with exclusion
diet alone.216
Ketotifen, a mast cell stabilizer with antihistamine
effects,217 had beneficial effects on pain, bloating, flatulence,
diarrhea, quality of life, sleep, and sexual functioning, but it
induced sedation and drowsiness. The precise mechanism of
action is unclear, because increased mast cell tryptase
release from rectal biopsies was not observed in the IBS
patients and histamine and tryptase release were not
altered by ketotifen.217
Mesalamine derivatives. Mesalamine reduced total
colonic mucosal immunocytes and mast cells and mucosal
release of interleukin 1b, histamine, and tryptase in IBS
May 2016
patients.218 Clinical efficacy is unclear: 2 of 4 small clinical
trials suggest it may be beneficial in IBS patients, including
some benefit on bowel function.218–221 Two recent larger
trials both failed to demonstrate significant efficacy in
IBS-D.222,223
Farnesoid X receptor agonist obeticholic acid. In
an open-label trial, obeticholic acid improved stool consis-
tency and bowel function index in patients with bile acid
diarrhea.224
Glutamine. Patients with IBS-D have increased
permeability, and symptomatic IBS patients have decreased
intestinal glutamine synthetase levels.225,226 In a pre-
liminary report of a placebo-controlled trial of 10 g gluta-
mine tid in 61 IBS-D patients with high intestinal
permeability and reduced claudin-1 expression in intestinal
biopsies,227 the glutamine arm was associated with
improved abdominal pain, bloating, and diarrhea, and
restored intestinal permeability.
Visceral Sensation, Functional
Abdominal Pain, and Irritable Bowel
SyndromeLRelated Pain
Some medications that are discussed here because of
their efficacy in the treatment of bowel dysfunction may
also be independently efficacious in the relief of pain.228,229.
Current Treatments
Antispasmodics. Muscarinic receptor antagonists and
smooth muscle relaxants are used in most countries for the
treatment of IBS. Meta-analysis suggests they are superior
to placebo in IBS-related pain,230,231 although the quality of
trials has been questioned.
Guanylate cyclase-C agonist. Linaclotide has
demonstrated improvement in abdominal pain in 2 large,
phase 3 studies in IBS-C, with one trial extending treatment
out to 26 weeks.157,232
Psychoactive agents. Antidepressants are commonly
used to treat chronic functional abdominal pain syndromes,
and a Cochrane meta-analysis suggests efficacy of antide-
pressants in IBS.233,234 In randomized controlled trials, low-
dose tricyclic antidepressants have demonstrated some
improvement in global improvement in abdominal pain.234
However, the quality of the evidence is considered low235
due to the generally weak trial designs.
There is no approval of any psychoactive drug for spe-
cific IBS therapy, but some agents, such as amitriptyline,
have approval in many countries for neuropathic pain
therapy.
Future Treatments for Centrally Mediated
Abdominal Pain or Irritable Bowel
Syndrome
Related Pain
Pregabalin. The a2d-ligand pregabalin was shown to
increase distension sensory thresholds to normal levels in
IBS patients with rectal hypersensitivity.236 Studies evalu-
ating effects on clinical symptom end points in centrally
mediated abdominal pain syndrome, formerly known in
Pharmacology in FGID 1329
Rome III as functional abdominal pain syndrome, are
awaited (ClinicalTrials.gov Identifier: NCT00977197).
Histamine1-receptor antagonists. A nonsedating,
histamine H1-receptor antagonist, ebastin, was tested in a
12-week, placebo-controlled trial of 55 patients237 and was
associated with considerable relief of symptoms in 46% of
the ebastin group and 12% of the placebo group. There
were also lower average abdominal pain scores with
ebastin.
Other Agents for Motility and Functional
Gastrointestinal Disorders
Supplementary Table 6 and Figure 4 summarize new or
promising drugs targeting motility and secretion.
Role of Biomarkers in Individualizing Therapy in
Irritable Bowel Syndrome
The article “Design of Treatment Trials” addresses the
PHARMACOLOGY
potential of biomarkers in individualizing therapy for IBS.
There have been a number of reviews discussing the po-
tential role of biomarkers in IBS.238–240 Biomarkers are
objectively measurable indicators of normal or pathologic
processes or pharmacologic responses to a therapeutic
intervention.241
Biomarkers should meet basic requirements, such as a
reasonable diagnostic performance, noninvasiveness,
reproducibility, low costs, and applicability on a large scale.
Biomarkers may identify pathophysiologic mechanisms that
are present only in subsets of patients. Clearly, the multi-
factorial nature of IBS will necessitate the development of
biomarkers for subgroups, just as bowel function subtype
can identify only a subgroup of patients with IBS-C, IBS-D, or
IBS with mixed bowel habits.
For example, the biomarker for total fecal bile acid
excretion over 48 hours (low 75SeHCAT [selenium-75
labeled homocholic acid taurocholate] retention, or high
fecal bile acid excretion) may allow selection of IBS-D
patients to receive interventions that alter bile acid
excretion, such as bile acid sequestrants. The proof of this
principle is demonstrated by the recent observation in
IBS-D patients with high fecal bile acid excretion that
colesevelam, 1.875 g bid, improved stool consistency and
increased hepatic bile acid synthesis, thereby avoiding
worsening of steatorrhea.242 Future research may target
patients with specific pathophysiology (eg, increased
expression of mast cells, high mucosal serotonin levels,
high fecal proteases, alterations in the microbiome, or
barrier function).
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. Visit the online version of
Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.029.
 1330 Camilleri et al
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Reprint requests
Address requests for reprints to: Michael Camilleri, MD, Mayo Clinic, Charlton
8-110, 200 First Street SW, Rochester, Minnesota 55905.
Acknowledgments
This article is dedicated to the memory of Professor Lionel Buéno, who passed
away a few weeks after the completion of this manuscript. The authors salute
his leadership, mentoring, academic contributions, and friendship over 3
decades.
The authors appreciate reviews provided by Drs J. J. Galligan and R. C.
Spiller, which enhanced the quality of the manuscript.
Conflicts of interest
The authors disclose no conflicts.
1331.e1 Camilleri et al
Glossary
Acetylcholinesterase: an enzyme (more precisely a hy-
drolase) that hydrolyzes acetylcholine.
Allodynia: a form of hypersensitivity with an abnormal
pain response to an innocuous or non-noxious afferent
signal.
ASBT: apical sodium dependent bile acid transporter.
Bioavailability: one of the main pharmacokinetic prop-
erties of a drug: it is the fraction of an administered dose of
drug that reaches the systemic circulation, eg, after oral
administration, with respect to the dose that would be
available if the drug were given by the intravenous route
(which implies 100% bioavailability).
Biomarker: objectively measurable indicator of normal
or pathological processes, or pharmacological responses to a
therapeutic intervention; it may be used for diagnostic
purposes or to evaluate drug activity/efficacy.
Blood
brain barrier: a highly selective barrier that
separates the circulating blood from the extracellular fluid
in the central nervous system.
CYP450: cytochrome P450 enzyme system, responsible
for drug metabolism.
FXR: farnesoid X receptor, also known as bile acid re-
ceptor; it is highly expressed in the liver and in the intestine.
G proteins: G proteins (guanine nucleotide-binding pro-
teins) are a family of proteins acting as molecular switches
in cells; they are involved in the transmission of signals
from stimuli arising outside a cell to the inside.
hERG: human ether-a-go-go related gene, encoding a
potassium channel responsible for cardiac repolarization; its
blockade may cause arrhythmias.
5-HT: serotonin, or 5-hydroxytryptamine.
Hyperalgesia: increased sensitivity to pain.
Hypersensitivity: enhanced sensitivity.
Intestinal permeability: a normal function of the gut
wall, which exhibits “permeability,” ie, allows nutrients to
pass through the gut, while also maintaining a barrier
function to keep away potentially harmful substances (such
as antigens).
PAMORA: peripherally active m-opioid receptor
antagonist.
Pharmacodynamics: the branch of pharmacology study-
ing the mechanisms of drug action and the relationship
between a drug concentration and its effect.
Pharmacogenetics: the study of individual variations in
DNA sequence related to drug response.
Pharmacogenomics: the study of the variability of the
expression of individual genes relevant to disease suscep-
tibility as well as drug response at cellular, tissue, individ-
ual, or population levels (a broader term when compared to
pharmacogenetics).
Pharmacokinetics: the branch of pharmacology studying
the fate of substances (absorption, distribution, metabolism,
and elimination) administered externally to a living organ-
ism: substances may be drugs as well as toxic substances.
Polymorphism: natural variations in a gene, DNA
sequence, or chromosome that have no adverse effects on
the individual and occur with fairly high frequency in the
Gastroenterology Vol. 150, No. 6
general population. However, single nucleotide poly-
morphisms in the human genome may correlate with dis-
ease, drug response, and other phenotype.
Pseudo-affective response: response to nociceptive
stimuli mediated by brainstem or spinal reflexes that cease
when the noxious stimulus is terminated, eg, a change in
blood pressure after a noxious stimulus is a pseudo-
affective response widely used to assess visceral pain.
Psychoactive: of an agent affecting the central nervous
system.
Reverse pharmacokinetics: in contrast to classical
pharmacokinetics (which is performed well in advance of
clinical development of a new drug), reverse pharmacoki-
netics is based on the thorough pharmacokinetics assess-
ment of natural medicines, for which purported clinical
benefits are documented by historical use, while target tis-
sues and mechanisms remain unclear; its goal is to provide
clues for the target identification and mechanistic under-
standing of pharmacodynamics.
SERT: serotonin transporter.
SNRI: serotonin-norepinephrine reuptake inhibitor.
SSRI: selective serotonin reuptake inhibitor.
SPECT: single-photon emission computed tomography.
Toxicology: the branch of pharmacology studying the
adverse effects of chemicals on living organisms.
Preclinical Pharmacology, Toxicology,
and Concepts in Development of Novel
Therapeutic Agents
This section outlines some general pharmacodynamic,
pharmacokinetic, and safety aspects that are important for
the development of new drugs for FGIDs.
The Pharmacodynamic Target
Drug selectivity. Selectivity refers to the ability of a
compound to interact with only one receptor subtype,
leaving other receptors unaffected at concentrations ach-
ieved at clinically used doses, thereby avoiding side effects.
Considerations of drug selectivity should appraise all
biological effects of a drug, not just in the digestive tract. For
example, cisapride was a partial 5-HT4 receptor agonist,243 a
5-HT3 receptor antagonist (both of which convey potentially
beneficial GI effects), and a fairly potent hERG (human
ether-a-go-go related gene) Kþ channel blocker.244
Due to the multifactorial pathophysiology of FGIDs, sin-
gle receptor modulating drugs might be less efficacious than
balanced modulation of multiple targets, which may provide
a superior therapeutic effect and side-effect profile
compared with the action of a selective ligand.245 A key
challenge in the design of a ligand with multiple actions is to
achieve a balanced potency and activity at each target of
interest and a suitable pharmacokinetic profile. The less
selective a ligand is, the harder it is to predict toxicity or its
mechanistic explanation. This may jeopardize the develop-
ment and regulatory approval of less-selective ligands.
Because more than one mechanism may be responsible
for the same symptom in FGIDs, the selective approach to
May 2016
relieving symptoms or groups of symptoms (eg, pain and
constipation or diarrhea) was efficacious in approximately
60% of patients with tegaserod or alosetron or linaclotide
or lubiprostone.30,31,145,154,245 Diversity in underlying
mechanisms rather than inadequate dosing is more likely
the reason for lack of efficacy in approximately 40% of
patients. Hence, there is the need to consider using multiple
therapies or “designed” multiple ligands to enhance the
benefit/risk ratio.
Pharmacodynamic vs Pathophysiologic Target
Theoretically, ideal new drugs should target the entire
pathophysiologic mechanism(s) contributing to the func-
tional disorder rather than only an individual part or a
specific receptor. Thus, nonselective agents designed to
modulate multiple targets contributing to the whole path-
ophysiologic process (eg, dysmotility, sensory disorder, and
inflammation) would potentially be advantageous over
highly selective medications addressing a single mechanism.
Should appropriate patient subgroups be recruited to test
the therapeutic properties of a medication, even if this might
reduce the generalizability of the trial results? At the pre-
sent time, there is no drug that addresses all the mecha-
nisms underlying patients’ symptoms. In the future, the
selection of patients based on valid biomarkers (see section
Pharmacogenetics in IBS) rather than symptoms would
usher in an era of greater personalization of treatment
based on the affected mechanism.
Concepts for developing functional gastrointes-
tinal disorder drugs. There are at least 3 key aspects that
deserve rethinking in FGID drug development. First, func-
tional gut disorders have multifactorial pathophysiology,
which should be addressed by designed multiple ligands.246
Second, by restricting the drug to the intraluminal
compartment, systemic adverse effects are avoided. Pe-
ripheral restriction of the effects of the medication can be
achieved by excluding penetration of the blood
brain bar-
rier (eg, peripherally acting m-opioid receptor antagonists or
eluxadoline, a locally active m-opioid receptor agonist and d-
opioid receptor antagonist). A third approach is to develop
drugs acting exclusively in the GI tract and liver (eg, far-
nesoid X receptor agonists, such as obeticholic acid).
The gut microbiome is a target for therapeutic inter-
vention247,248; the microbiome may itself affect the actions
of the drug, and drugs may alter the microbiome. Insight
into the actions of lubiprostone143 provides an example of
possible interaction with the microbiome. In an ex vivo
model, lubiprostone decreased the thickness of the inner
mucus layer in both proximal and distal colon and, more
importantly, caused qualitative changes of stool microbiome
by increasing abundance of Lactobacillus and Alistipes,
which theoretically reflect a more “protective” microbiome
with anti-inflammatory properties.249 These findings are
consistent with previous in vitro and in vivo data250 and
suggest that active mucosal hydration functions as a prim-
itive innate epithelial defense mechanism; and that intesti-
nal microbiome could be a potential target in IBS.
Reverse pharmacokinetics (Figure 3) and reverse phar-
macodynamics are innovative ways to develop new drugs,
Pharmacology in FGID 1331.e2
especially those from natural sources.251 Classical pharma-
cokinetics were designed to determine the desirable phar-
macokinetic features of a new chemical entity to be
developed for clinical use. However, for most natural com-
pounds already used in traditional medicine, the molecular
targets are unknown and, without exact knowledge, it is
difficult to optimize the pharmacokinetic profile of drug
candidates and fulfill current regulatory standards. The
concept of “reverse pharmacokinetics” is based on the
thorough pharmacokinetic assessment of natural medicines,
for which purported clinical benefits are documented by
historical use, while target tissues and mechanisms remain
unclear.251 Examples would be curcumin in inflammatory
conditions or STW5 (Iberogast) in FD.252 Thus, the purpose
of reverse pharmacokinetics is to provide clues for target
identification and mechanistic understanding of agents
tested.
After oral administration, the drug’s pharmacokinetics
depend on intestinal and hepatic metabolism, as well as
drug delivery to intestinal epithelia or specialized intestinal
cells, such as M cells, goblet cells, and dendritic cells.253,254
Safety Aspects
Apart from the standard safety evaluations of every new
drug, 2 new concerns deserve special attention because of
recent experience. Cisapride resulted in tachyarrhythmia
associated with prolongation of the QT interval of the
electrocardiogram due to blockade of the hERG Kþ chan-
nels.255 Alosetron and cilansetron were associated with
ischemic colitis in about 1 in 1000 patients.185 Although
these are very rare events, even a low risk may not be
acceptable from a regulatory perspective for drugs that
provide relief of nonfatal diseases, such as FGIDs. The drug
development process should identify such undesired effects
as early as possible.256 Finally, the potential for drug in-
teractions is relevant, given the polypharmacy and frequent
use of psychotropic agents (which often depend on CYP2D6
metabolism).
Pharmacogenetics in Irritable
Bowel Syndrome
In addition to understanding the pathophysiology of IBS,
insight into pharmacogenetics and, specifically, the manner
in which genetic abnormalities influence drug activity,
binding, and metabolism has become central to proposing
control mechanisms in IBS and may impact the management
of individual IBS patients.
Drug Metabolism and Pharmacogenetics
The enzymatic metabolism of drugs involves modifica-
tions of functional groups (phase I reactions, such as
oxidation, dehydrogenation, and esterification) or conjuga-
tion with endogenous substituents (phase II reactions).257
The most common and most relevant drug modifications
in IBS result from CYP2D6 metabolism, which is an example
of phase I drug metabolism. There are distinct geographic
variations of the CYP genes, suggesting that population
1331.e3 Camilleri et al
substructure can strongly affect the variation in pharma-
cogenetic loci60 (Supplementary Table 7).
The number of functional alleles (3, 2, 1, and 0)
determines whether CYP2D6 metabolism is ultrarapid,
extensive, intermediate, or poor. About 1% of Asians and
5%
10% of Caucasians (Figure 2) are poor metabo-
lizers.258 Gene multiplication may result in 3 or more
functional alleles, and ethnic groups with 10 functional
alleles64 are infrequent among northern Europeans, rarer in
Chinese,259 but frequent (as high as 29%) in East African
populations.260 The most common nonfunctional alleles are
CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6, which
constitute approximately 98% of nonfunctional alleles in
Caucasians.261
CYP2D6 metabolism impacts the extensively used tri-
cyclic antidepressants and selective serotonin reuptake in-
hibitors in FGIDs and visceral hypersensitivity.262 Although
not yet fully appreciated in IBS practice, a multitude of
drugs are metabolized by CYP2D6, and there are many
drugs that inhibit or activate CYP2D6, thus creating the
possibility of significant drug interactions. In some ethnic
groups, CYP2D6 testing may be warranted if antidepres-
sants will be prescribed.263
The second category of pharmacogenetic modulation of
drug effects in IBS reflects variations in receptors, trans-
porters, or function of rate-limiting enzymes.
Serotonergic Pharmacogenetics
The most informative studies of pharmacogenetics in IBS
revolve around 5-HTTLPR genetics and the efficacy of alo-
setron in normalizing colonic transit in IBS-D242 and the
efficacy of tegaserod in the treatment of bowel dysfunction
in IBS-C.66 Thus, the 5-HT3 antagonist alosetron is more
effective when the 5-HTTLPR LL genotype results in
increased SERT expression and greater 5-HT clearance.
Alosetron competes more effectively for the 5-HT3 receptor
when extracellular 5-HT is lower. There is also evidence,
from a study of the 5-HT3 receptor antagonist ondansetron,
that the SL genotype is associated with a trend (P ¼ .07) to
effects on change in stool consistency and on the increase in
whole-gut transit time in an analysis of 87 patients in a
randomized, double-blind, placebo-controlled, crossover
study of 5 weeks of ondansetron, 4 mg, vs placebo with dose
titration allowed.264 Differences in the latter study with the
results reported with alosetron may reflect the different
medications, the dose titration of ondansetron, and the
greater sensitivity of scintigraphy to measure colonic transit
compared with radiopaque marker whole-gut transit time.
Conversely, the 5-HT4 receptor agonist tegaserod results in
lower efficacy in carriers of the SS genotype,186 because
there is more endogenous 5-HT to complement the effects of
the exogenous tegaserod in activating the 5-HT4 receptor.
Bile Acids and Pharmacogenetics in
Constipation-Predominant and Diarrhea-
Predominant Irritable Bowel Syndrome
In addition to the observations that genetic variations in
Klotho-b (KLB) and, possibly, fibroblast growth factor
Gastroenterology Vol. 150, No. 6
receptor 4 (FGFR4) are associated with accelerated colonic
transit in patients with IBS-D,265 variations in the same
genes influence the colonic transit response to chenodeox-
ycholic acid in IBS-C266 and to colesevelam in IBS-D
patients.267
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1331.e11 Camilleri et al Gastroenterology Vol. 150, No. 6

Development of new chemical entity

Compound Library: Lead Discovery: Preclinical Research Clinical Study
Target-based Structural/activity PK suitability Druggability
Drug design optimization

Classical PK

Existing natural medicines

Clinical Evidence: Preclinical Research Drug Candidates
Effective and safe ADME “dissection” Compatibility and
Natural medicine and mechanism optimization
of action study

Reverse PK with
“back to basics” approach

Hao H, et al. Trends Pharmacol Sci. 2014; 35:168 JM 1

Supplementary Figure 1. Drug discovery from natural medicines. In contrast to the traditional or classical approach, where
new chemical entities are identified by screening a compound library for target-based activity followed by validation and drug
development, an alternative approach is to build on the clinical evidence that a medicine derived from natural materials is
efficacious and safe, and to identify the active compound, its mechanism of action and pharmacokinetics to optimize the
efficacy of the natural remedy. ADME, absorption, distribution, metabolism, and excretion; PK, pharmacokinetics. This
concept and figure are adapted from Hao et al,251 with permission.
Supplementary Table 1.Agents Directed to Amines/Receptors and Peptides to Affect Functions of the Upper and Lower Gastrointestinal Tract
Target system/
receptor Type of ligand
5-HT 5-HT3-receptor antagonists (eg,
alosetron, ondansetron, ramosetron)
5-HT4 receptor agonists (eg,
prucalopride, velusetrag, mosapride,
naronapride, YKP10811)
5-HT1A receptor agonists (eg, buspirone)
ACh (Muscarinic) M3 receptor antagonists
M1 and M2 receptor antagonists
Acetylcholinesterase inhibitors (eg,
acotiamide, itopride)
Adrenoceptors b3-Adrenoceptor agonists
a2-Adrenoceptor agonists
Dopamine D2-receptor antagonists (eg,
domperidone, levosulpiride,
metoclopramide, itopride)
Motilin Motilides
Ghrelin Ghrelin agonists
Cannabinoid d-9-Tetrahydrocannabinol
Opioid m-Receptor agonists (eg, loperamide)
m-Receptor antagonists (eg, naloxone,
methylnaltrexone, alvimopan,
naloxegol)
k-Receptor agonists (eg, fedotozine,
asimadoline)
Somatostatin SSR-2 receptor agonists (eg, octreotide,
lanreotide)
Tachykinin NK1-receptor antagonists (eg,
aprepitant)
NK2-receptor antagonists (eg, ibodutant)
NK3-receptor antagonists (eg, talnetant)
Distribution of receptors
Intrinsic and extrinsic neurons
Enteric neurons, smooth muscle cells
Enteric neurons, extrinsic afferent
neurons
Smooth muscle
Enteric neurons and smooth muscle
Enteric neurons and smooth muscle
Smooth muscle
Enteric neurons and enterocytes
Area postrema, smooth muscle, enteric
neurons
Smooth muscle, enteric neurons
Hypothalamus, ?a
Enteric neurons
Nucleus tractus solitarius neurons
Enterocyte, enteric neurons, afferent
neurons, and inflammation
Enteric neurons, afferent neurons, and
inflammation
Enteric neurons and afferent neurons
Enterocytes, submucosal neurons,
myenteric neurons
Enteric neurons, interstitial cells of Cajal,
smooth muscle, immune cells
Enteric neurons, smooth muscle,
extrinsic afferents
Enteric neurons, extrinsic afferents
Pharmacologic action in animals
Inhibits visceral sensitivity, absorption/
secretion, motility
Enhances secretion and motility, reduces
visceral sensitivity
Inhibits motility and enhances
compliance
Increases smooth muscle relaxation,
compliance
Increases gastric emptying
Increases gastric emptying
Inhibits motility
Reduces secretion, enhances
compliance, and reduces motility and
tone
Contracts muscle
Stimulates motility
Stimulates appetite
Slows gastrointestinal transit
Reduces intestinal secretion and transit
Reverses opioid effects on motility
Reduces sensation, variable effect on
motility
Retards transit, reduces afferent firing
and sensation
Inhibits motility, fluid secretion, vagal
afferent sensation, and inflammation
Inhibits motility, H2O secretion,
sensation, inflammation
Inhibits motility and sensation
May 2016
Pharmacologic action in humans
Slows transit, increases colonic
compliance
Accelerates transit, increases colonic
HAPC and gastric accommodation,
reduces inhibition of RIII reflex during
rectal distension
Increases accommodation; central
actions anxiolytic agent and
tranquilizer
No published data
May enhance accommodation
Increases gastric emptying and
accommodation
No published data
Reduces secretion, enhances
compliance, and reduces motility,
tone, and sensation
Antiemetic, prokinetic, reduces
sensation?
Stimulates motility and transit
Accelerates gastric emptying, reduces
gastric accommodation
Delays gastric emptying; antiemetic
properties
Slows colonic transit, antidiarrheal,
increases resting anal tone
Accelerates colonic transit, reverses
OIC, reduces duration of PO ileus
Reduces sensation
Pharmacology in FGID 1331.e12
Slows transit, reduces sensitivity,
enhances absorption
Antiemetic
Inhibits NKA-induced motility
No published data
Supplementary Table 1. Continued

1331.e13 Camilleri et al
Target system/
receptor Type of ligand Distribution of receptors Pharmacologic action in animals Pharmacologic action in humans

Guanylate GC-C agonists (eg, linaclotide, Luminal side of the enteric mucosa Induces secretion of HCO3
,

Cl , H2O Looser stool consistency, accelerates
cyclase-C plecanatide) and inhibits visceral nociceptors via colonic transit, decreases visceral
cGMP pain
Chloride ClC2 activators (eg, lubiprostone) Enteric mucosa Induces secretion of bicarbonate, Looser stool consistency, accelerates
channels chloride, H2O colonic transit
NHE3 NHE3 inhibitor (eg, tenapanor) Enteric mucosa Inhibits absorption of Naþ Improves stool consistency
transporter

ACh, acetylcholine; ClC, chloride channel; HAPC, high-amplitude propagated contraction; NHE, sodium-hydrogen exchange; NK, tachykinin; OBD, opioid bowel
dysfunction; PO, postoperative; SSR, somatostatin receptor.
a
The question mark (?) refers to a hypothetical action or site of action that is not proven.

Gastroenterology Vol. 150, No. 6

May 2016 Pharmacology in FGID 1331.e14

Supplementary Table 2.Pharmacologic Actions of Psychotropic Drugs on Monoamine Reuptake and Receptorsa

Neurotransmitter reuptake blockade Receptor blockade

Drug 5-HT Norepinephrine Dopamine a1 a2 H1 ACh 5-HT1A Other 5-HTR D2

Tricyclic agents
Amitriptyline þþþþþ þþþ
b þþþ þ þþþþ þþþ þ þþþ

Imipramine þþþþ þþþþþ
þþ þ þþþþ þþ þþ þþ

Desipramine þþþ þþþþþ
þþ þ þþ þþ



Clomipramine þþþþþ þþþ
þþ þþþ þþ



SSRIs
Fluoxetine þþþþþ þþ






0
Paroxetine þþþþþ þþþ þ

0c þþ

0
Sertraline þþþþþ þ þþþ þþ þ 0 þ

0
Citalopram þþþþþ
0 þ þ þ 0

0
SNRIs
Venlafaxine þþþþ þ
0 0 0 0 0 0 0
Duloxetine þþþþþ þþþþ þ





0
Atypical agents
Bupropion 0 þ þ


0

0
Nefazodone þþ þþ þþ þþþ
þþ
þ þþ 0
Mirtazapine
0 0 þ þþþþ þþþþ þ
þþd 0
Quetiapine 0 0 0 þ þ þ þ þ þþþ þþ
Azapirones
Buspirone 0 0 0 0 0 0 0 þþ 0 þþ

a, a-adrenoceptor; ACh, muscarinic acetylcholine receptor; D, dopamine; H, histamine; SNRIs, serotonin-norepinephrine

reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.
a
Symbols þ to þþþþþ indicate increasing levels of potency.
b

indicated weak.
c
0 indicates no effect.
d
Mirtazapine also blocks 5-HT3 receptors (þþþ), which reduces nausea, and it has acute anxiolytic effects in humans.
Supplementary Table 3.Comparison of Novel 5-HT4 Agonists

1331.e15 Camilleri et al
Prucalopride Mosapride Velusetrag Naronapride YKP10811

Chemistry Benzofuran-carboxamide Benzamide Quinolinone-carboxamide Benzamide Benzamide

Selectivity and affinity Highly selective, high affinity; High selectivity and affinity for 5- High affinity and selectivity for h5- Specific 5-HT4 full High binding affinity to
for 5-HT4 receptor weak affinity for human D4 and HT4, But major metabolite HT4c over other biogenic agonist activity in the 5-HT4 receptor;
s1, and mouse 5-HT3 (M1) with 5-HT3-antagonistic amine receptors; >500-fold the GI tract, but a 120-fold and 6-fold
receptors at concentrations activity selectivity over other 5-HT partial agonist lower affinity,
exceeding the Ki for 5-HT4 receptors (including h5-HT2B, activity in the heart respectively, for 5-
receptors by 290-fold h5-HT3A) HT2A and 5-HT2B
receptors than for 5-
HT4; antagonist
activity at 5-HT2B
receptor
Hepatic metabolism Limited, not CYP 3A4 CYP 3A4 CYP 3A4 Hydrolytic esterase, not Oxidation of aromatic
CYP 3A4 rings and N-
dealkylation may
involve CYP 3A4
Pharmacodynamic Accelerated colonic transit in Accelerated esophageal motility, Accelerated colonic transit in Accelerated colonic Accelerated colon filling
efficacy in humans health and in chronic gastric emptying and small health in dose-related fashion transit in health at 6 hours, t1/2 of
constipation bowel transit in health ascending colon
emptying, and
colonic transit in
functional
constipation
Clinical trial efficacy Phase 2 and 3 portfolio in chronic Clinical trials in dyspepsia, GERD, Phase 2b Phase 1b Phase 2a study:
constipation IBS-C, capsule endoscopy increased stool
consistency over 8
days (ITT analysis) in
functional
constipation
Open label Open label experience of w1000 Several years of market — — —
effectiveness cumulative patient-years experience in Asian and South
American countries
Arrhythmogenicity No arrhythmic activity in human Low potency to inhibit hERG At 3 mM, no effect on hERG At 100 mM, no effect on Inhibited hERG channel
atrial cells; inhibited hERG channels, no arrhythmic channel current; safety ratio vs hERG channel; only at mM
channel only at mM activity in clinical trials, no cisapride >1000-fold; no affinity ratio concentration
concentration (IC50w4.9 clinically relevant effects on effect on QT in health or in 400 between IKr and

Gastroenterology Vol. 150, No. 6

10
6M); no clinically relevant
cardiac AEs in clinical trials of
>4000 humans
Cardiovascular safety Healthy subjects “thorough” QTc
including elderly study; safety in elderly cohort
80% on CV drugs
QT-intervals patients with constipation 5-HT4 receptors of
>1000-fold
Healthy subjects, no effects of Healthy subjects “thorough” QTc Healthy subjects QTc prolonged at
mosapride on heart rate, blood study; transient increase in “thorough” QTc doses of 100 to 600
pressure variabilities, heart rate not different from study mg (target dose
autonomic nervous activity placebo likely 10
20 mg)
parameters, QT intervals, or
QT dispersions
Supplementary Table 3. Continued

May 2016
Prucalopride Mosapride Velusetrag Naronapride YKP10811

Most common adverse Diarrhea, headache Diarrhea, abdominal pain, Diarrhea, nausea, headache Diarrhea, headache Diarrhea, headache,
events headache borborygmi
Approval status EMA, Canada, Mexico A variety of Asian and South NA NA NA
American countries
Approved dose 2 mg/d in adults; 1 mg/d in >65 5 mg tid in adults NA NA NA
years

NOTE. Adapted from Camilleri,140 with permission.

AE, adverse event; CV, cardiovascular; EMA, European Agency for Evaluation of Medicinal Products; GERD, gastroesophageal reflux disease; hERG, human ether-à-go-
go
related gene; IC50, half maximal inhibitory concentration; ITT, intention to treat; Ki, dissociation constant; NA, not available (drug not approved).

Pharmacology in FGID 1331.e16

Supplementary Table 4.Comparison of Secretagogues
Lubiprostone
Chemistry Bicyclic fatty acid called a
prostone
Target receptor Chloride channel (ClC2); CFTR
involved
Pharmacodynamics in humans Accelerated small bowel and
colonic transit in health
Clinical trial efficacy Phase II and III portfolio in chronic
constipation and IBS-C
Open label effectiveness Clinical practice experience
Arrhythmogenicity No arrhythmic activity
Cardiovascular safety Healthy subjects “thorough” QTc
study
Most common adverse events Nausea, diarrhea
Potential other actions Mucosal protection
Approval status FDA, some other countries
Approved doses 24 mg bid for constipation
8 mg bid for IBS-C
NOTE. Adapted from Camilleri,140 with permission.
ECG, electrocardiogram; ND, not done; NHE3, sodium-hydrogen exchanger 3.
1331.e17 Camilleri et al
Linaclotide Plecanatide Tenapanor
14 amino acid peptide, analog of 16 amino acid peptide, analog of Tetrahydroisoquinoline dimer
guanylin and uroguanylin uroguanylin
Guanylate cyclase-C activation with Guanylate cyclase-C activation with Inhibitor of the intestinal sodium
CFTR-mediated secretion CFTR-mediated secretion transporter NHE3
Accelerated colonic transit in IBS-C ND ND
in dose-related fashion
Phase 2b and 3 in chronic Phase 2a in chronic constipation and 2b Phase 2b in IBS-C
constipation and IBS-C study in IBS-C
— — —
Low bioavailability Low bioavailability Low bioavailability
No arrhythmic activity No expected arrhythmic activity No expected arrhythmic activity
Healthy subjects “thorough” QTc Phase I safety Safe on ECG studies
study
Diarrhea Diarrhea Diarrhea
Anti-nociceptive effects on afferent Anti-inflammatory, anti-apoptotic —
nerves
FDA, EMA, Canada, Mexico — —
145 mg qd for constipation — —
290 mg qd for IBS-C
Gastroenterology Vol. 150, No. 6
Supplementary Table 5.Opioid Antagonists Used to Treat Opioid-Induced Constipation

May 2016
Drug name Drug class Pharmacodynamic efficacy in humans Clinical trial optimal efficacy and safety Approval specific to OIC

Oral naloxone Nonselective opioid receptor Reverses opioid-induced delay in orocecal and Naloxone PR formulation prevents OIC in patients —
antagonist colonic transit receiving PR oxycodone
Methyl- PAMORA Reverses effects of opioid in health and of chronic Subcutaneous MNTX 0.15 mg/kg on alternate days FDA, Canada, and EMA
naltrexone methadone treatment on orocecal transit; no effective in inducing laxation in patients with (for OIC in palliative
effect on small intestinal or colonic transit advanced illness and chronic noncancer pain care)
delayed by codeine 30 mg qid in opioid-naïve (12 mg daily or alternate days); side effect:
healthy subjects diarrhea
Naltrexone ER m-opioid antagonist as ND Open-label 12-month safety of combination ER —
sequestered core: ratio pellets of morphine (median 59 mg/d) with a
naltrexone to morphine 4% sequestered naltrexone core (qd or bid): OIC
31.8%, nausea 25.2%; opioid withdrawal <5%
Alvimopan PAMORA 8-mg oral dose accelerates colonic transit and 0.5 mg bid dose efficacious in treating OIC; rare Approved for
reverses effects of codeine in opioid-naïve instances of ischemic heart disease postoperative ileus
healthy volunteers receiving codeine 30 mg qid
Naloxegol PAMORA; PEGylated Normalized morphine-induced delay in orocecal In two phase 3, twelve-week trials in adult patients FDA, EMA
naloxone conjugate transit with OIC and chronic noncancer pain, naloxegol
25 mg showed significant improvement in
response rate vs placebo; adverse events in
>9% abdominal pain and diarrhea
TD-1211 PAMORA ND 5 mg and 10 mg/d TD-1211 increased average —
SBM/wk over 2 wk in OIC patients

NOTE. Adapted from Camilleri,269 with permission.

ER, extended release; ND, not done; PAMORA, peripherally acting m-opioid receptor antagonist; PR, prolonged release; SBM, spontaneous bowel movement.

Pharmacology in FGID 1331.e18

Supplementary Table 6.Examples of Potential Medications Targeting Motility and Secretion in Other Treatment Classes

1331.e19 Camilleri et al
Pharmacodynamic (intestinal or Clinical efficacy: phase 2b or 3 Safety issues/
Drug class Examples Rationale and putative action colon) primary endpoints comments

TPH1 blocker LX-1031 Inhibits synthesis of 5-HT by Inhibits urinary 5-HIAA excretion; no Phase 2b trial in 155 non-IBS-C patients;
blocking TPH1 in studies of PD efficacy 1000-mg dose improved global
enterochromaffin cells assessment of adequate relief and
stool consistency
Oral carbon adsorbent AST-120 Adsorbs luminal factors that may No data Phase 2b study in nonconstipated IBS;
be causing colonic reduced pain and bloating, improved
dysfunction stool consistency
a2d ligand Pregabalin Reduced visceral afferent firing by Increases rectal sensation thresholds in None
blocking Ca2þ channels IBS; reduces colonic sensation
ratings in healthy subjects
NK2 receptor Ibodutant Inhibits visceral hypersensitivity Phase 2b study: significant effect of the
10 mg/d dose in females in a
prespecified analysis
GLP-1 analog Rose-010 Inhibits intestinal contractility Reduces intestinal contractility and Phase 2b study: reduced abdominal pain Nausea,
MMCs severity and increased number of vomiting
responders in IBS
ASBT (IBAT) inhibitor Elobixibat Inhibits transport of bile acids Accelerates colonic transit Phase 2b study: increased SBMs and
CSBMs in CIC
FXR agonist Obeticholic acid Inhibits hepatic BA synthesis Increases FGF-19 production in ileum Improved stool frequency and form in
open-label study in BA diarrhea
Mast cell stabilizers Disodium Reduces tryptase and mediators Reduces jejunal biopsy mast cell Enhanced benefit from food restriction
cromoglycate that mediate immune mediators in IBS patients diet in IBS-D patients with food
activation, visceral “allergies”
hypersensitivity
Ketotifen Reduces tryptase and mediators Increases rectal sensation threshold in Phase 2a study suggested benefit in Somnolence
that mediate immune patients with baseline visceral relief of symptoms and pain in subset
activation, visceral hypersensitivity; rectal mucosal with baseline visceral hypersensitivity
hypersensitivity biopsy histamine and tryptase release
not affected
Mesalamine Mesalamine or Reduces mucosal inflammation Reduces cytokines in rectal mucosal Phase 2a small study with PD
mesalazine biopsies in IBS; effects on proteases measurements showed improved
of mesalamine compounds not overall well-being, but no significant
consistently shown (positive results in effect on specific IBS symptoms;
n ¼ 10 study not confirmed in n ¼ 44 ineffective in 2 phase 2b larger trials

Gastroenterology Vol. 150, No. 6

study)

NOTE. Adapted from Camilleri,140 with permission.

ASBT, apical sodium dependent bile acid transporter; BA, bile acid; CIC, chronic idiopathic constipation; CSBM, complete spontaneous bowel movement; FGF-19,
fibroblast growth factor 19; FXR, farnesoid X receptor; GLP, glucagon-like peptide; 5-HIAA, 5-hydroxyindoleacetic acid; IBAT, ileal bile acid transporter; MMC,
migrating motor complex; NK, neurokinin; PD, pharmacodynamic; SBM, spontaneous bowel movement; TPH, tryptophan hydroxylase.
Supplementary Table 7.Gastrointestinal Conditions, Drugs, Genes, and Polymorphisms

May 2016
Condition Drug Protein (gene) Alleles or polymorphisms Clinical effects

GERD PPIs Cytochrome P450 CYP2C19*2, CYP2C19*3, CYP2C19*4, Wild-type predicts slower healing of esophagitis and lower
Helicobacter pylori 2C19 (CYP2C19) CYP2C19*5 cure rates of H pylori infection.
infection CYP2C19*5 results in decreased metabolism of drug.
FD, IBS Tricyclic CYP2D6 CYP2D6*3 The extensively used TCAs and SSRIs are metabolized by
antidepressants, Serotonin CYP2D6*4 CYP2D6; it causes drug interaction.
SSRIs transporter CYP2D6*5 In Caucasians, 5-HTTLPR may be a predictor of
Clonidine a2-adrenoceptor CYP2D6*6 antidepressant response and remission, while in Asians it
5HTT-LPR does not appear to play a major role.
a2A (C-1291G) SNPs Post-clonidine responses were associated with a2A (C-
1291G) SNPs for gastric accommodation and rectal
sensations of gas and urgency.
IBS-D Alosetron Serotonin 5HTT-LPR Patients with diarrhea and 5-HTTLPR *LL homozygotes may
Colesevelam transporter rs351855 predict better response and slowing of colonic transit.
(SLC6A4) rs497501 Differential colesevelam effects on ascending colon half-
FGFR4 emptying time and on overall colonic transit at 24 hours.
KLb
IBS-C Tegaserod Serotonin 5HTT-LPR Patients with constipation and 5-HTTLPR *LL homozygotes
CDC transporter rs376618 may predict worse clinical response.
(SLC6A4) KLB Arg728 or rs17618244 (G allele) Genetic variation in negative feedback inhibition of bile acid
FGFR4 synthesis may affect CDC-mediated acceleration of
KLB colonic transit; rs376618 in FGFR4 was associated with
differences in the effects of CDC on colonic transit; effect
of rs17618244 genotype on dose response in patients
with IBS-C.

CDC, chenodeoxycholic acid; FGFR4, fibroblast growth factor receptor 4; GERD, gastroesophageal reflux disease; 5-HTTLPR, serotonin transporter linked polymorphic
region.
PPI, proton pump inhibitors; SLC, solute carrier; SNP, single nucleotide polymorphisms.

Pharmacology in FGID 1331.e20


Age, Gender, and Women’s Health and the Patient
Lesley A. Houghton,1,2 Margaret Heitkemper,3 Michael D. Crowell,4 Anton Emmanuel,5
Albena Halpert,6 James A. McRoberts,7 and Brenda Toner8
1
Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida; 2Centre for Gastrointestinal Sciences,
University of Manchester, Manchester, United Kingdom; 3University of Washington, Seattle, Washington; 4Division of
Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona; 5University College London, London, United Kingdom;
6
Boston Medical Center, Boston, Massachusetts; 7University of California, Los Angeles, California; 8University of Toronto,
Toronto, Ontario, Canada
Patients with functional gastrointestinal disorders (FGIDs)
often experience distress, reduced quality of life, a
perceived lack of validation, and an unsatisfactory expe-
rience with health care providers. A health care provider
can provide the patient with a framework in which to un-
derstand and legitimize their symptoms, remove self-doubt
or blame, and identify factors that contribute to symptoms
that the patient can influence or control. This framework is
implemented with the consideration of important factors
that impact FGIDs, such as gender, age, society, and the
AGE, GENDER, AND
WOMEN’S HEALTH
patient’s perspective. Although the majority of FGIDs,
including globus, rumination syndrome, irritable bowel
syndrome, bloating, constipation, functional abdominal
pain, sphincter of Oddi dyskinesia, pelvic floor dysfunction,
and extraintestinal manifestations, are more prevalent in
women than in men, functional chest pain, dyspepsia,
vomiting, and anorectal pain do not appear to vary by
gender. Studies have suggested sex differences in somatic,
but not visceral, pain perception, motility, and central
processing of visceral pain; although further research is
required in autonomic nervous system dysfunction, ge-
netics, and immunologic/microbiome. Gender differences
in response to psychological treatments, antidepressants,
fiber, probiotics, and anticholinergics have not been
studied adequately. However, a greater clinical response to
5-HT3 antagonists but not 5-HT4 agonists has been re-
ported in women compared with men.
Keywords: Sex; Development; Society; Symptoms.
T
his review discusses the patient’s perspective and
biological basis for sex and gender differences in
functional gastrointestinal disorders (FGIDs). Attention is
given to the lived experience of irritable bowel syndrome (IBS)
as well as the importance of patient interaction with the health
care provider. In addition, the review highlights the current
literature related to gender- and sex-based differences in
visceral and somatic sensitivity, pain, motility, and the overlap
of FGIDs, in particular IBS, with other chronic conditions.
The Patient Perspective
The Patient Experience of FGIDs
“IBS is very frustrating: it dominates life style and daily
activities mostly through its unpredictability. You must
Gastroenterology 2016;150:1332–1343
always plan for the ‘what if’ ‘what if I eat more’ ‘what if
toilet facilities are not available’ ‘what if I cannot break
away.’ It leaves you feeling ‘dirty or unclean’ and inhibits
social mixing and sexual activity. IBS is frustrating. And
that’s the bottom line.” IBS study participant.
For patients with chronic symptoms, the psychological
and social ramifications of their illness are often more
important than the physical impairment. Three over-riding
themes seem to dominate the experience of living with
moderate to severe FGID: (1) a sense of frustration, (2) a
sense of isolation, and (3) search for a niche in the health/sick
role continuum/dissatisfaction with the medical system.1–4
The effects of IBS on quality of life (QoL) often are under-
estimated. Patients with mild to moderate disease severity
report that IBS restricts daily activities on average 73 days
per year (20%); resulting in loss of work (13% of patients).5
There is often a disconnect between patients’ and
physicians’ views of the IBS experience, regarding percep-
tions of etiology, severity, treatment approaches, and
efficacy.6–8 When 1014 patients and 508 physicians used
identical scales to rate IBS-related pain and discomfort, re-
sponses showed that physicians rated discomfort as signif-
icantly less severe than patients.9 Conversely, 35% of more
than a 1000 IBS patients in an international survey, re-
ported their symptoms as severe. In the same survey, to
receive a treatment that would make them symptom free,
patients would give up 25% of their remaining life (average,
15 y) and 14% would risk a 1 in 1000 chance of death.5
Many patients are reluctant to accept the functional diag-
nosis and many misconceptions, for example, that anxiety,
depression, and diet cause IBS, and fear that IBS leads to
cancer.7,8 Such misconceptions likely affect clinical out-
comes and health care utilization.
The Patient–Health Care Provider Encounter
“The biggest problem is that no one (in the medical field)
treats the whole person. I feel more like I’m going to a drug
Abbreviations used in this paper: EAL, early adverse life event; FGID,
functional gastrointestinal disorders; HRT, hormone replacement therapy;
5-HT, serotonin; IBS, irritable bowel syndrome; QoL, quality of life.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.017
May 2016
dealer than someone that looks at the problem in its totality.
As a result I have turned my attention to helping myself, and
have had some degree of success. I wish doctors would
listen to patients more when we talk about the symptoms
and how they affect our daily lives,” IBS study participant.
Only a small proportion (z25%) of IBS sufferers consult
physicians.10 However, those who do, have high health care
utilization.11 The nature of the patient–physician relation-
ship is complex. Factors within and outside the health care
system are constantly molding patient and physician
behavior. Patients feel frustrated with unsatisfactory
explanations of FGIDs, which may be experienced as a denial
of the legitimacy of their symptoms and perceive lack of
empathy.2 Conversely, physician frustration and dissatis-
faction related to treating patients with FGIDs stem from a
lack of understanding of the disease, limited treatment
options, limited training in communication skills, increased
workload, and the perception of personality characteristics
of patients with IBS with psychiatric comorbidities.12 Gas-
troenterologists perceive that patients with IBS require
longer visits despite not being as sick as patients with other
disorders that they manage9 and can show gender bias.13
Negative attitudes toward patients with IBS may form a
barrier to objective patient assessment and effective
physician–patient relationship building, and ultimately
negatively impact clinical outcome.14 Effective communica-
tion skills can be learned and practiced and, importantly, do
not increase the encounter time. Rather, effective commu-
nication skills make the process of assessment and diag-
nosis more efficient, improve clinical outcomes, and
increase physician job satisfaction.15–17
IBS can be challenging for both the physician and the
patient. Patients must learn to self-manage a condition that
can have a profound impact on everyday life. Health care
providers can help by eliciting and addressing patient con-
cerns; by offering a positive diagnosis and clear, under-
standable, and legitimizing explanations of the disorder;
show empathy; and enter into a meaningful partnership that
helps individuals replace feelings of helplessness with
means of empowerment.
Gender
Sex refers to the biological make-up of the individual’s
reproductive anatomy whereas gender refers to an in-
dividual’s lifestyle or personal identity. Often, these terms
are used interchangeably. In this article we use sex to
describe what is known about biological differences
between males and females and gender to refer to what is
known about behavior between men and women.
The literature on gender and health has discussed the
detrimental impact of adherence to some traditional femi-
nine gender roles on women’s health and well-being.18
These include gender-related expectations, such as societal
standards for attractiveness; social norms regarding
women’s caretaking role in relationships; and sanctions
against anger expression by women. The messages women
receive about gender-related expectations and the societal
consequences of not measuring up to these expectations can
Gender and the Patient 1333
have health consequences.19 There are several common
gender role concerns among women with IBS including
shame and bodily functions, bloating and physical appear-
ance, and pleasing others, assertion, and anger.19
One central theme that women with IBS commonly
report is feelings of shame associated with losing control of
bodily functions. Women are taught that bodily functions
are something to be kept private and secret. One important
implication of such teachings is that bowel functioning
becomes a source of shame and embarrassment more so
than it does for men.
The finding that women often score higher on indices of
bloating and constipation also can be discussed as a gender-
related theme. Society’s focus on how women look (eg,
thinness as a necessary standard of attractiveness)20 can
lead women to experience bloating not only as a source of
physical discomfort, but of psychological distress as well.
The physical and psychological distress that women may
experience with abdominal discomfort, coupled with the
perception that their pain is being minimized or trivialized
by health care professionals, may lead women to respond by
becoming more hypervigilant to any sign of pain or
discomfort.
Women as compared with men are socialized to please
AGE, GENDER, AND
others, often at the expense of their own needs. Women who
WOMEN’S HEALTH
express anger, make demands, or question authority are
often given the label of being hysterical, have their com-
plaints dismissed, or have their femininity called into
question. Potential repercussions for women who express
their own wants and needs often are sufficient to keep
women silent. These social expectations of women can lead
to the silencing of certain thoughts, feelings, and behaviors
rather than jeopardize relationships that are in place.21 A
study that compared women with IBS with women with
inflammatory bowel disease found that women with IBS
score higher on measures of self-silencing than inflamma-
tory bowel disease patients.21 In another study, women
reported shame in not living up to gender norm expecta-
tions for women in domains of relationships (taking care of
others at the expense of their own needs), attractiveness
(caused by bloating), and lack of desire to engage in sex
(caused by IBS symptoms).22 Men in this study focused
more on IBS symptoms impacting their paid employment
and sense of control. They also found that in interactions
with health care providers, women risked being trivialized
and men risked being overlooked because IBS may be
labeled as a women’s health concern.
Gender and Social Factors
It is important to acknowledge that health and illness
occur within a larger social context. The meaning and
expression of illness occur against a complex backdrop of a
multitude of social determinants of health. The social de-
terminants that have been investigated in FGIDs include life
stressors; history of sexual, physical, and emotional abuse;
and early life experiences including gender role socializ-
ation, social support, and social factors as assessed by QoL
scales.
 1334 Houghton et al Gastroenterology Vol. 150, No. 6

There have been limited studies to date that have
assessed gender differences in life stress related to FGIDs.23
Although the data support a significant role for life stress in
IBS, future studies will need to determine whether there are
differences in the relationship between stress and FGIDs in
women and men. Although stress affects the gut in most
people, patients with IBS appear to experience greater
reactivity to a variety of stressors.
One form of social stress that has received attention in
the study of FGIDs is sexual, physical, or emotional abuse.24
Table 1 shows the summary of studies focused on gender
differences in history of sexual, physical and emotional
abuse.24–28 However, most work in this area has included
only women or a female-predominate sample. Because of
conflicts in the literature, more research is needed to
determine whether there are gender differences in history
of abuse in FGIDs.
Studies also have investigated whether women and men
with FGIDs differ on health-related QoL measures.29 For
example, in a study of referral center and primary care
patients, Simren et al30 found that women with IBS reported
a lower QoL compared with men with IBS. Similar results
were found in a Chinese outpatient population.29 Dancey
et al31 found that men and women with IBS reported similar
AGE, GENDER, AND
section focuses on population-based research, which is used
to fully evaluate the epidemiology and clinical symptoms in
these individuals. The proposal that FGIDs may be more
prevalent in women stems from a variety of sources
reviewed elsewhere: studies documenting a greater preva-
lence of FGIDs with other chronic pain conditions that are
more common in women (fibromyalgia, chronic pelvic pain),
studies proposing an effect of the menstrual cycle on
symptom severity, and studies suggesting that particular
agents are more effective in women.
Functional Esophageal Disorders
Functional esophageal disorders are common.32 Globus
sensation and rumination syndrome are reported by
approximately 1 in 10 of the population,32–35 and are more
common in women. Men with globus tend to have greater
levels of somatization and depression.33 The prevalence
estimates of functional chest pain, based on self-report, vary
between 12.5% and 25%,32,36 with an equal gender preva-
lence in the general population.32 There is a higher female-
to-male ratio in tertiary care referral centers,37 and women
tend to use terms such as “burning” and “frightening” more
than men.38 The challenge in research studies of functional
esophageal disorders is identifying those individuals who

QoL scores, as well as similar levels of symptom severity,

WOMEN’S HEALTH

perceived stigma, and illness intrusiveness. However, these
investigators also found gender differences in the relation-
ship among these variables. For example, among women, IBS
symptom severity exerted a significant impact on QoL,
whereas for men, the psychosocial impact of illness intru-
siveness was greater in every domain except sexual relations.
The authors suggest that these results have implications for
how socialization shapes IBS-related gender differences.
Gender and Epidemiology
Most individuals with FGIDs do not seek health care and
the decision to seek care introduces bias in research. This
predominantly have a functional esophageal disorder rather
than gastroesophageal reflux disease, which is not associ-
ated with gender difference in rates or reflux symptoms.
Functional Gastroduodenal Disorders
Functional dyspepsia affects 15%–20% of the general
population39 and does not vary with gender.39–41 Being a
women was a significant predictor of functional dyspepsia
when compared with organic causes of dyspepsia.42
Although females have physiological evidence of delayed
gastric emptying, there is little relationship between these
measures and symptom severity or hormonal status.43,44
Adolescent girls are twice as likely to report aerophagia as

Table 1.Gender Differences of History of Sexual, Physical, and Emotional Abuse in Persons With and Without IBS

Gender differences
within group
Reference Early life events Findings comparisons
25
Childhood abuse, sexual abuse A history of sexual abuse was more common in women Not addressed
than in men, but the investigators did not differentiate
between patients with or without IBS
26
Severe lifetime sexual trauma, All of the IBS patients studied who reported a history of Women > men
severe childhood sexual abuse, sexual abuse were female
lifetime sexual victimization
24
General trauma, physical Significant differences were observed mainly in women with IBS; Women > men
punishment, emotional abuse, various types of early adverse life events were associated
and sexual events with the development of IBS, particularly among women
27
Childhood abuse No significant association of childhood adversity with the No differences
likelihood of developing IBS in either men or women
28
Childhood abuse A history of child abuse was similar in case and control groups, Not addressed
but the investigators did not differentiate between patients
with or without IBS
May 2016
Figure 1. Odds ratio for
IBS in women vs men
according to geographic
location. Data are grouped
according to geographic
region. Numerically higher
ratios are reported from
the Western world.48
adolescent boys.45 The overall prevalence of functional
vomiting is 2.3%, and there is no association with gender.46
Functional Bowel Disorders
Female-to-male ratios of IBS vary widely geographically,
from 3:1 in urbanized Western populations to 1:1 in
Nigeria47 (Figure 1 and Table 225,29,30,32,34–37,39,40,45–75), but
overall the prevalence of IBS internationally is 67% higher
in women than in men (odds ratio, 1.67; confidence interval,
1.53–1.82).47
In terms of symptom severity, among patients with mild
symptoms (<3 Manning criteria), 65% were women,
increasing to 80% in those with more severe symptoms
(
3 criteria).25 Women have a more impaired QoL with IBS,
with the somatic symptoms correlated to a gender-related
increased prevalence of anxiety and depression.25
There is a greater women-to-men predominance in
non–pain-associated symptoms of constipation, bloating,
and extraintestinal manifestations.48 Women are twice as
likely as men to report bloating or abdominal disten-
tion.66,67 Abdominal pain scores for men and women with
IBS are similar; however, men report more diarrhea and
women report more constipation.30,48,60,65 In addition,
women with IBS were more likely to report bloating and
nausea as well as extraintestinal symptoms compared with
men.48 There is an amplification of GI symptoms during the
late luteal and early menses phases.76
The female-to-male ratio for constipation is increased for
both the outlet-type (poor pelvic muscle tone) and the
combined IBS þ outlet–type of functional constipation.77
Women with functional constipation were 2 times more
likely to seek medical care compared with men.61,62,78 As
with most FGIDs, the prevalence of functional constipation
and IBS constipation is lower in Asian populations, but the
female preponderance is similar to Western populations.79
Gender and the Patient 1335
Functional abdominal pain is much more common in
children and adolescents than adults, and the rate of diag-
AGE, GENDER, AND
WOMEN’S HEALTH
nosis is higher in girls than in boys.68
Functional Disorders of the Biliary
Tract and Pancreas
The prevalence of sphincter of Oddi dyskinesia is 0.8%,
and is 4–5 times more common in women.32,55
Functional Anorectal Disorders
Prevalence rates of fecal incontinence vary from 2% to
11%.64,70 Among nursing home residents, incontinence is
more common in men,71 in contrast to older people living at
home.69 There is no difference in gender in functional
anorectal pain.32 Pelvic floor failure is common and
increases with age, and is more common in women.32
Gender and Overlapping
Functional Disorders
Patients with FGIDs often report other physical and
mental comorbidities (ie, extraintestinal conditions).80 Co-
morbid conditions reported by IBS patients include fibro-
myalgia, migraine headache, joint hypermobility syndrome,
temporomandibular joint disorder, bladder pain syndrome/
interstitial cystitis, anxiety, and depression.81–83 All of these
conditions have a female predominance in the general
population and many have a pain component.
Among women with FGIDs a number of female-specific
conditions are more common when compared with non-
FGID groups. These include dysmenorrhea, endometriosis,
adenomyosis, leiomyomas, pelvic floor myalgia, vulvodynia,
chronic cyclic pelvic pain, dyspareunia, dysmenorrhea, and
polycystic ovary syndrome. Dyspareunia and sexual func-
tioning in women with IBS remain understudied problems.
 1336 Houghton et al Gastroenterology Vol. 150, No. 6

Table 2.The Effect of Sex and Age on the Prevalence of FGID

FGID Effect of sex References for sex Change with age References for age

Esophageal
Globus F>M 32
Y 32,49
49

Rumination F¼M 32
Y 32

F>M 34
35

Functional chest pain F¼M 49

Y 32,49
36
50

F > M (at tertiary care) 37

Functional heartburn F¼M 49

¼ 32
51

Dysphagia F>M 32
[ 32
49

Gastroduodenal
Dyspepsia F¼M 32
Y 52
39 46
40 53

Aerophagia M>F 32
Y 32

F>M 54
45

Functional vomiting F¼M 46

Y 46

Biliary tract F>M 32

[ 32
55
AGE, GENDER, AND
WOMEN’S HEALTH

Lower GI tract
IBS F>M 56
Y 32
32 58
25 59
47
29
57

Functional constipation F>M 56

[ 63
32
46 64
60
30
61
62

Functional diarrhea M>F 32

Y 46
46
60
30
48
65
32 32
Functional bloating Discordant Discordant
F>M 66
67
48

FAPS F>M 32
Y 32
68

Fecal incontinence F > M (at home) 69

[ 70

M > F (nursing homes) 71 64

Functional anorectal pain F>M 32

Y 32

Outlet delay F>M 72

¼ 72
73
74
75

FAPS, functional abdominal pain syndrome.

May 2016
Hysterectomy is 3-fold higher in women with IBS,84 sug-
gesting that the overlap with gynecologic conditions may
contribute to greater health care seeking and subsequent
surgical intervention.
Several mechanisms may account for the comorbidity in
women with FGIDs, particularly IBS. These include brain
activation patterns, dysregulation of the hypothalamic–
pituitary–adrenal axis, immune dysfunction, visceral and
somatic pain sensitivity alterations, autonomic nervous
system dysregulation, and genetic susceptibility. Because
the etiology and pathophysiology of each of these conditions
likely are complex and multifactorial, a single common
pathogenesis has remained elusive. Other factors, including
access to health care and health care–seeking behavior, also
may contribute to gender differences in the diagnosis of
comorbid conditions. The type, number, and duration of
comorbid conditions may contribute to the toll of inter-
personal stress.
Gender and Pathophysiology
Preclinical
Visceral pain perception. Under basal conditions,
most studies have found that normal cycling females have a
greater response than males to visceral pain stimuli.85,86
Genetic background clearly has a role because the strain
of rodent determines which sex is more sensitive to noxious
visceral stimuli.87 Visceral pain can be enhanced by chemi-
cal irritation, inflammation, and stress. Generally, all of these
insults either show no sex difference or greater pain re-
sponses in female animals than males.85 Stress, particularly
repeated stress and early life stress, also produces
visceral hyperalgesia days or even months after the stress
period, with female rodents being significantly more
susceptible.88,89
The role of sex hormones in visceral pain has received
considerable attention and produced much controversy.
Studying natural variations in sex hormones in female ro-
dents is complicated by a much shorter (4–6 days) estrus
cycle, with smaller changes in the plasma estrogen and
progesterone levels than in women.90 Because studies
evaluating the effect of the estrus cycle in rodents have
produced conflicting results,85,91,92 many investigators have
resorted to ovariectomizing female rodents and comparing
the effect of estrogen and progesterone replacement. This
strategy also has resulted in conflicting observations that
probably result from the time between ovariectomy and
pain testing, the dose of estrogen/progesterone, and
whether it was administered abruptly with a single dose or
at a slow constant rate.85,93 The fact that estrogens can act
rapidly by binding to estrogen receptors located in the
plasma membrane, in addition to their slow effects medi-
ated by gene expression,94 may explain some of these
differences.
Somatic pain perception. A great deal more pre-
clinical work has been performed on sex differences in so-
matic pain in animals, with more equivocal results than
visceral pain. Sex differences, if found at all, depend on the
specific modality being tested (thermal, mechanical,
Gender and the Patient 1337
chemical, electrical), the location or dermatome involved,
and the experimental model (acute, neuropathic, ischemic,
inflammatory pain).95 Again genetic background seems to
play an important role in determining which sex is more
sensitive because different strains of mice and rats can
produce opposite effects using the same pain test.95 The role
of specific receptors and gene polymorphisms in sex-specific
visceral and somatic pain responses is accumulating.86,92
Motility and permeability. Both estrogen and to a
lesser extent progesterone affect GI motility and colonic
permeability.92 Treatment of ovariectomized rats with a
combination of estrogen and progesterone results in slower
colonic transit,96 possibly mediated by effects on nitric
oxide–containing neurons in the myenteric plexus97 and the
number and function of mast cells in GI mucosa.98 In
addition, stress has a greater effect on decreasing upper GI
motility and increasing lower GI motility in female
compared with male animals.99,100 This effect likely is
mediated by corticotropin-releasing factor receptor-1,
which is potentiated by estrogen and expressed by colonic
myenteric neurons.101 Estrogen also contributes to the
maintenance of the intestinal barrier that serves an impor-
tant role in the body’s defense against pathogens. The pos-
itive role of estrogen in maintaining intestinal barrier
AGE, GENDER, AND
function may be through maintenance of tight junctions
WOMEN’S HEALTH
and/or influence on inflammatory response.102
Clinical
Abdominal symptoms. In the general population,
women are more likely to report abdominal pain and pain-
related IBS diagnostic symptoms (eg, pain relieved by
defecation), whereas in the IBS population, the prevalence
of pain-related symptoms does not vary by gender. In
addition, women with IBS report more constipation,
straining, bloating, and abdominal distention, and men with
IBS report more diarrhea-related symptoms, including
increased stool frequency.103
Visceral pain perception. There are no conclusive
data to suggest that gender influences visceral pain
perception or the referral of pain to GI stimulation in
healthy and FGID subjects.104–108 Women, however, are
more likely to show increased sensitivity after repetitive
sigmoid distention than men with IBS.107,109 Reasons for
inconsistencies across studies may include study design,
small subject numbers and techniques, ovarian hormone
and receptor levels, and/or stress levels, mood, vigilance,
and early life and social factors.
Somatic pain perception. Studies suggest that
healthy women tend to show greater somatic pain sensi-
tivity than men.86 In FGIDs, studies are scarce, with only one
study in IBS suggesting that thermal sensitivity does not
differ between sexes.110 Variability between studies is
probably for similar reasons discussed for visceral pain
perception.
Motility. Esophageal anatomy and innervation do not
appear to differ significantly by gender, and only minor
gender-specific differences have been reported in esopha-
geal motor function.111 Slower gastric emptying rates of
both solids and liquids have been shown in females
 1338 Houghton et al
compared with males.112–116 Postprandial proximal gastric
relaxation was prolonged and perception scores increased
in women compared with men.117 Studies have found colon
transit times to be shorter in men than women, particularly
in the right colon.118–120 Rao et al,121 using ambulatory
24-hour colonic manometry, found pressure activity in the
colon of healthy women to be reduced compared with age-
matched men. The phase of menstrual cycle was not
controlled in these studies. There are no published nondrug
studies comparing colonic motility in women and men with
IBS. Anal sphincter pressures, anal pressures during
maximum sphincter contraction, and volumes required to
induce a desire to defecate have been reported to be lower
in women.122,123
Cardioautonomic tone. Autonomic nervous system
dysfunction has been reported in patients with IBS.124
However, few studies have evaluated gender differences in
measures of autonomic function other than GI motility in
persons with IBS. Cheng et al125 reported significant
blunting of the autonomic nervous system response to
flexible sigmoidoscopy (a visceral stressor) in patients with
IBS compared with controls, and that, overall, women had
higher cardiovagal tone and lower cardiosympathetic bal-
ance compared with men.
AGE, GENDER, AND
Central processing of visceral stimuli. Healthy
WOMEN’S HEALTH
subjects. By using functional magnetic resonance imaging,
Kern et al126 showed greater response to rectal distension
in sensory and affective regions (dorsal anterior cingulate
cortex, prefrontal cortex, and insula cortex) in females
compared with males. In contrast, Berman et al127 found a
trend for greater activation of the insula and anterior and
midcingulate cortex to rectal distension in men compared
with women. A more recent functional magnetic resonance
imaging study reported greater activity in the dorsolateral
prefrontal cortex and middle temporal gyrus during antici-
pation of rectal pain, and in the cerebellum and medial
frontal gyrus during painful rectal stimulation in women
compared with men.128 Although a study using magneto-
encephalography while recording cortical evoked potential
to painful esophageal stimulation reported no sex differ-
ence,129 sex differences in brain response to esophageal
pain have been observed.130 Despite no significant differ-
ences in psychophysiological factors known to influence
brain processing, such as anxiety, personality type, auto-
nomic response to pain, and pain perception levels and
thresholds, women compared with men showed a greater
decrease in amygdala activity during anticipation of
esophageal pain and a greater increase in midcingulate
cortex and anterior insula activity during esophageal
pain.130 These observations were interpreted as women
having greater engagement of cognitive coping strategies to
the anticipation of visceral pain, and greater emotional
response during actual esophageal pain.129
FGID subjects. Initial brain imaging studies using rectal
balloon distension in IBS patients found that male patients
showed greater activation of the insula compared with fe-
male patients,131,132 as well as dorsolateral prefrontal cor-
tex and dorsal pons/periaqueductal gray.132 In contrast,
female IBS patients showed greater activation of the
Gastroenterology Vol. 150, No. 6
ventromedial prefrontal cortex, right anterior cingulate
cortex, and left amygdala compared with male patients.132
These data suggest that female patients have greater acti-
vation of affective and autonomic regions, whereas male
patients show a greater activation of regions in the corti-
colimbic pain inhibition system. A follow-up study using
connectivity modeling of the same data suggested that the
differences between men and women mainly are owing to
differences in the effective connectivity of emotional arousal
circuitry rather than visceral afferent processing circuitry
(Figure 2).133
More recent neuroimaging studies have shown brain
activity/connectivity differences between men and women,
even in the absence of a noxious stimulus (eg, rectal
distension). Female IBS patients have shown higher fre-
quency power of the insula compared with male patients.134
Although sex differences were seen in healthy controls in
the resting state, oscillatory dynamics of emotional arousal
regions (amygdala and hippocampus) were exaggerated in
IBS patients, mainly owing to an increased high-frequency
power in female patients.134 Furthermore, sex differences
in the resting state oscillatory dynamics of sensorimotor
regions seen in healthy subjects (greater low-frequency
power in men) were reversed in IBS patients, with greater
low-frequency power in women.134 A second resting state
study showed sex differences in the functional connectivity
between the dorsal anterior insula and medial prefrontal
cortex and precuneus in patients with IBS are similar to
healthy subjects, but more enhanced.135 These findings may
relate to females dedicating more resource allocation to
interoceptive awareness, whereas males rely more on
cognitive processes, with IBS placing further stress on this
bias. Finally, sex differences in the impact of early adverse
life events (EALs) on resting state brain connectivity has
been shown in IBS patients.136 EAL scores were associated
with greater connectivity of thalamus, insula, anterior
cingulate cortex, and middle temoral gyrus with the cere-
bellar network in men only. The cerebellar network is
involved in fear perception, motor function, and visual-
motor learning, as well as physical and psychological pain.
The functional consequences of these sex-specific alter-
ations in cerebellar network alterations remain unknown.
Sex differences in structural changes of the brain in
patients with IBS also have been shown. Female patients
have shown significantly less cortical thickness in the right
subgenual anterior cingulate cortex than male patients.137
Moreover, using diffusion tensor imaging, reduced integ-
rity of sensorimotor and descending pain modulation
pathways has been shown in female compared with male
IBS patients. Such differences were not seen in healthy
subjects.138
Genetics and immunologic/microbiome. Multiple
factors including genetics, the environment, sex hormones,
and the gut microbiota may modulate the immunologic
response to inflammation and infection.88 Our understand-
ing of the role of inflammatory factors in FGIDs and genetics,
especially IBS, is increasing rapidly. The use of new-
omics approaches will need to consider sex as a potential
factor in terms of understanding new metabolomics and
May 2016 Gender and the Patient 1339

AGE, GENDER, AND

WOMEN’S HEALTH
Figure 2. Estimated effective conductivity differences between men and women in proposed network comprising the
homeostatic-afferent, emotional-arousal, and cortical-modulatory circuits. The operation of the proposed network (as esti-
mated by the completely unconstrained model) during baseline, inflation, and expectation (columns) is presented for females
(top rows) and males (bottom rows). The b coefficients (effective connectivity) are shown by the thickness and color of the
arrows. Solid arrows represent a parameter estimate that was considered significantly different from zero, whereas dashed
lines represent nonsignificant coefficients. Amyg, amygdala; INS, insula; mOFC, medial orbital frontal cortex; sACC, supra-
genual anterior cingulate cortex.

transcrioptomics findings. Further research is needed to
clarify the potential relevance of these factors in immune
system dysregulation and FGIDs.
Emerging evidence suggests that interactions between
gut microbiota and altered immune function may play a role
in the pathogenesis of IBS, and several studies have sup-
ported the importance of immune activation in the patho-
physiology of postinfectious IBS.139 Female gender in both
adults and children has been reported as a risk factor for
developing IBS symptoms after infectious gastroenter-
itis.140,141 The gut bacteria are modulated by sex steroid
hormones, in particular estrogen. In addition, gut bacteria
can influence the metabolism of estrogen (Figure 3).142 Flak
et al143 proposed the concept of “microgenderome,” the
bidirectional interaction between sex hormones and the
microbiota.
Gender and Treatment Response
Clinical Assessment
The clinical implications of gender are relevant in both
the diagnosis and clinical management of FGIDs. Beginning
with the history, IBS-like symptoms often are present in
gynecologic conditions, the most serious of which are
ovarian and endometrial cancer, and should be included
in the initial differential diagnosis. Asking the patient
when symptoms started may provide important informa-
tion about etiology and subsequent approaches to man-
agement. There are history and examination features
unique to women: menstrual history, gynecologic surgery,
and bimanual pelvic examination. The comorbidity of IBS
with gynecologic pain conditions and pelvic floor
dysfunction warrants careful examination. In the differ-
ential diagnosis, clinicians should avoid mistakenly using
the gender prevalence to influence a premature diagnosis
of a FGID.
Psychological Treatment
Whether gender makes a difference to outcomes with
psychological therapy is unclear because women outnumber
men in most FGID treatment trials.144 These trials have not
been powered sufficiently or included subanalyses to
determine whether or not there is a differential response to
treatment between genders.145,146
There is no gender bias in outcomes with cognitive
behavioral therapy, psychological therapy, or emotional
awareness training for IBS,147 and gender was not selected
into a predictive model of treatment response. By contrast,
 1340 Houghton et al
Guthrie et al148 reported minor advantages for women in
response to therapy compared with men, but gender was
not selected in their final analysis model. For individual
psychotherapy in patients with functional dyspepsia and
severe IBS,149 efficacy is similar to selective serotonin re-
AGE, GENDER, AND
WOMEN’S HEALTH
uptake inhibitor therapy with no gender difference in
outcome with either treatment.
Two evaluations of hypnotherapy150,151 provided con-
trasting results with respect to gender. An audit of 1000 IBS
patients who met Rome II criteria (80% female) for IBS and
underwent hypnotherapy for 3 months found that 80% of
women improved compared with 62% of men.151 A study of
250 participants noted a poor response in men with IBS
with diarrhea.150 By contrast, a randomized controlled
trial,151 albeit in a smaller population, showed that gender,
age, disease duration, and IBS type had no influence on the
long-term success of hypnotherapy.
Pharmacologic Treatment
Psychotropic agents. A recent systematic review of
antidepressant therapy identified that most studies did not
conduct separate analyses by gender.146
Gut-directed agents. A number of small, variable-
quality studies have been subject to meta-analysis152 and
shown modest benefits over placebo for fiber, anticholin-
ergics, and peppermint oil, but no separate analysis of
gender difference was undertaken.
Therapies targeted at serotonin/5-hydroxytryptamine
(5-HT) receptors in the gut seem to have a differential effect
in men and women. Alosetron, a 5-HT3 antagonist, provided
more robust efficacy in women than men at the same
dose.153 The basis for this gender difference is not clearly
established. Alosetron is more effective in slowing colonic
transit,154 attenuating the gastrocolonic response, and
increasing rectal compliance155 in women than men.
Three large series156 of prucalopride, a highly selective
5HT4 agonist, recruited 85% female patients and showed
equal efficacy in both sexes. For other drugs commonly used
to treat motility disturbance (domperidone, opioid-based
Gastroenterology Vol. 150, No. 6
Figure 3. Sex hormones in
the mutual brain–gut–
microbiota interactions.
Sex hormones influence
peripheral and central
regulatory mechanisms
involved in the patho-
physiology of IBS,
contributing to the alter-
ations in stress response,
visceral sensitivity and
motility, intestinal barrier
function, and immune
activation of intestinal
mucosa. Sex hormones
also have a direct effect on
the gut microbiota. ENS,
enteric nervous system.
constipating agents, laxatives, probiotics), there is no evi-
dence of a gender-related difference in efficacy.157
Most medications for FGIDs are cleared through the
cytochrome P450 pathway, which can be affected by female
sex hormones. Although women clear drugs more quickly
than men through this pathway, this is balanced by the
difference in body size and adiposity of women. There have
been no clinically significant differences in the pharmaco-
kinetics of FGID drugs, and, hence, dosages need not be
adapted by gender.
Life Stages and Aging
The FGIDs affect people across the spectrum of age.
Some FGIDs increase with age whereas others decrease.
Some begin in childhood whereas others start after devel-
opmental stages including puberty and menopause. The
trajectory of many FGIDs are unknown owing to lack of
long-term follow-up evaluation. Cohort studies with pre-
identified clinical and biological markers may yield impor-
tant information about the normal GI tract aging in concert
with the evolution and progression of FGIDs.
Extensive epidemiologic data exist for IBS, dyspepsia,
heartburn, constipation, and fecal incontinence, but less is
known about the other FGIDs. The presence of FGIDs in
children is well recognized. The exact age of onset of FGIDs
remains to be determined. A link between childhood IBS and
adult IBS remains to be established.
Both laboratory animal and human data indicate that
EALs may contribute to either increased visceral sensitivity
later in life and/or potentially visceral and somatic condi-
tions.24 Although EALs result in higher rates of IBS in both
genders, women appear to be more susceptible to the
development of pathologies after exposure to EALs.89
Approximately 70%–95% of women report heartburn,
nausea, or vomiting during their pregnancies. Most episodes
of heartburn occur during the first and second trimesters.
Perimenopause is defined as the period of transition to
menopause. In a cross-sectional study of premenopausal
and postmenopausal women with IBS, there were more GI
May 2016
symptoms in early postmenopausal women compared with
premenopausal women.158 Menopause is the cessation of a
woman’s reproductive ability. Understanding the effects of
menopause on FGIDs is confounded by the effects of aging,
the presence of comorbid conditions, and medication use
(ie, hormone-replacement use [HRT]). In one study using
the General Practice Research Database in the United
Kingdom, investigators found that current and past users of
HRT had an increased risk (incidence, 1.7 in nonusers and
3.8 among users) of IBS compared with nonusers.159
Overall, the prevalence of IBS decreases with age in both
men and women.160 The existing literature is discordant
with regard to the changes in the estimates of bloating by
age.32 Most studies have found that the prevalence of con-
stipation increases with advancing age.63,64,161 Less is
known regarding functional diarrhea, although one study
identified decreasing rates of diarrhea with age.46
There is some evidence to suggest that with aging there
is reduced biodiversity. However, it is difficult to separate
out changes that are related to aging, per se, or lifestyle,
history of antibiotic treatment, hospitalization, and frailty.
Reductions in fiber intake caused by poor dentition,
decreased saliva production, and reduced economic re-
sources also may contribute to age-related changes in
microbiota composition.
Fecal incontinence has been studied extensively and in-
creases with age. Data from the Nurse’s Health Study show
that 4% of women age 62–87 have fecal incontinence and
7% have both urinary and bowel incontinence.162
Methodologic Issues in FGIDs
As a result of methodologic issues limiting interpreta-
tion of studies, there remain many unanswered questions
concerning gender, age, and patient perspectives in FGIDs.
Because of the female predominance and greater likelihood
of women to participate in research studies, there are
insufficient numbers of male participants to make mean-
ingful interpretations and adequately assess gender and
sex differences in psychological, physiological, and treat-
ment studies. Given the intersection of gender and socio-
economic factors in women’s health, the environment,
relationships, and resources (eg, socioeconomic status)
need to be considered when assessing gender differences.
Another major methodologic concern is that most studies
use a cross-sectional design, which limits the more
comprehensive understanding of the pathogenesis, devel-
opment, course, and impact of these disorders in men and
women.
Many physiologic studies use relatively small sample
sizes and do not account for psychosocial variables, over-
lapping FGID or comorbidities, abuse history, or EALs, and,
therefore, may not apply to the general patient population.
These studies may be influenced by the selection bias of
participants who are willing to undergo invasive research
protocols.
Translating the various mechanisms of pain and GI
function from animal studies to human beings is chal-
lenging. Differences in the type and strain of the animal
Gender and the Patient 1341
model and type of stressor, if used, need to be taken into
account when interpreting these studies.
Similarly for women, the menstrual cycle needs to be
considered in studies. In most studies, menstrual phase is
frequently not determined, or is assessed by the count
forward/backward method and not by measuring the
luteinizing hormone surge or ovarian hormone levels to
assess the follicular and luteal phases more accurately.
Other confounding methodologic issues include the use of
oral contraceptive agents, HRT, and premenopausal vs
postmenopausal status in women. The impact of the tran-
sition from a premenopausal to perimenopausal state to
menopause remains unknown.
Most studies examining psychological factors have
focused on anxiety and depression and, to a lesser extent,
personality traits. Other aspects of psychological functioning
such as quality of relationships, social support, health per-
ceptions, traumatic and stressful events, and effects of
childhood experience other than abuse largely have been
ignored in studies comparing men and women.
Adequate sample sizes of each gender, particularly men,
and comparable treatment doses must be obtained to
determine if men and women respond similarly to treat-
ment. There may be gender bias in the placebo response.
AGE, GENDER, AND
Patients for clinical trials generally are recruited from spe-
WOMEN’S HEALTH
cialty practices where women are more likely to be referred
than men, thus compounding problems of selection bias.
Future studies will need to have adequate numbers of
men with gender-related variables such as history of EALs,
abuse, anxiety, or depression.19 At the same time, greater
attention needs to be given to transgender men and women.
In summary, this review emphasizes: (1) the importance
of the patient’s experience and perspective, (2) the influence
of society, culture, gender, and age on all aspect of the in-
dividual’s experience, (3) the influential role of an in-
dividual’s sex on the biologic and physiologic processes of
brain–gut interactions, and (4) the potential of the health
care provider in influencing patient outcomes.
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. To access the supplementary
material accompanying this article, visit the online version
of Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.017.
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Reprint requests
Address requests for reprints to: Lesley A. Houghton, PhD, FRSB, RFF,
AGE, GENDER, AND
WOMEN’S HEALTH
FACG, AGAF, Division of Gastroenterology and Hepatology, Mayo
Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224. e-mail:
Houghton.Lesley@mayo.edu; fax: (904) 953-7366.
Conflicts of interest
These authors disclose the following: Lesley Houghton has consulted over the
past 12 months for GSK and Pfizer; Michael Crowell has consulted over the
past 12 months for EndoStim, Inc, Medtronic, Inc, and Salix; and Albena
Halpert has consulted over the past 12 months for Allergan.
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 Gastroenterology 2016;150:1344–1354

Multicultural Aspects in Functional Gastrointestinal

Disorders (FGIDs)
Carlos F. Francisconi,1,* Ami D. Sperber,7,* Xiucai Fang,2 Shin Fukudo,3 Mary-Joan Gerson,4
Jin-Yong Kang,5 and Max Schmulson6
1
Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Gastroenterology Division, Hospital de Clínicas
de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; 2Department of Gastroenterology, Peking Union Medical College
Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; 3Department of Behavioral
Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 4Advanced Specialization Program in Couple and
Family Therapy, New York University Postdoctoral Program in Psychotherapy and Psychoanalysis, Division of
Gastroenterology, Mount Sinai School of Medicine, New York, New York; 5Parkside Hospital, London, United Kingdom;
6
Laboratorio de Hígado, Páncreas y Motilidad–Unit of Research in Experimental Medicine, Faculty of Medicine–Universidad
Nacional Autónoma de México, Hospital General de Mexico, Mexico City, Mexico; and 7Faculty of Health Sciences, Ben-Gurion
University of the Negev, Beer-Sheva, Israel

Cross-cultural factors are important in functional gastro-
intestinal disorders (FGIDs). In the setting of FGIDs, the
aims of this review were as follows: (1) to engender in-
terest in global aspects; (2) to gain a clearer understanding
of culture, race, and ethnicity, and their effect on patient
care and research; (3) to facilitate cross-cultural clinical
and research competency; and (4) to improve and foster
the quality and conduct of cross-cultural, multinational
research. Cultural variables inevitably are present in the
MULTICULTURAL ASPECTS
knowledge on and appreciation of the relevance of FGIDs at
a global level (Figure 1).
The aims of this review were as follows: (1) to engender
greater interest in the global aspects of FGIDs; (2) to gain a
clearer understanding of culture, race, and ethnicity, and
their effect on patient care and research in FGIDs; (3) to
facilitate cross-cultural clinical and research competency in
FGIDs; and (4) to improve the quality of multinational

research in FGIDs and foster collaborative international

physician–patient context. Food and diets, which differ
among cultural groups, are perceived globally as related to
or blamed for symptoms. From an individual perspective,
biological aspects, such as genetics, the microbiome, envi-
ronmental hygiene, cytokines, and the nervous system,
which are affected by cultural differences, all are relevant.
Of equal importance are issues related to sex, symptom
reporting and interpretation, and family systems. From the
physician’s viewpoint, understanding the patient’s
explanatory model of illness, especially in a cultural
context, affects patient care and patient education in a
multicultural environment. Differences in the definition
and use of complementary and alternative medicine and
other issues related to health care services for FGIDs are
also a relevant cross-cultural issue. This article highlights
the importance of cross-cultural competence in clinical
medicine and research.
research networks for the conduct of cross-cultural, multi-
national research in this area.
Figure 2 presents a conceptual model of the interaction of
factors that have been identified as central to understanding
the influence of multicultural factors on FGIDs. Obviously,
reality entails greater complexity than any model can capture,
but Figure 2 attempts to incorporate salient factors and the
interactions between them, as discussed in text later. The
model highlights the following: (1) the centrality of the patient,
the physician, food and eating, and culture in symptom
interpretation and clinical manifestations; and (2) the other
factors that feed into these central aspects. These other factors
are shown in association with the central items to which they
would seem most linked, although in reality there are multiple
avenues of interaction and mutual influence. This article fo-
cuses on individual factors and the interactions between them.

Keywords: Culture; Explanatory Model; Cross-Cultural Compe- Definitions

tence; Cross-Cultural Research. Culture has been defined as the values, beliefs, norms,
and practices of a particular group that are learned and

T he inclusion of a new chapter in the Rome IV book

devoted to multicultural aspects in functional
gastrointestinal disorders (FGIDs) attests to the growing
*Authors share co-first authorship.

Abbreviations used in this paper: CAM, complementary and alternative

recognition of the importance and value of a global
perspective in addressing these disorders. The Rome
Foundation has expanded its scope and global outreach
greatly in the past decade. Various initiatives undertaken in
recent years, collectively called the Rome Foundation Global
Initiative, show this concern for the dissemination of
medicine; FD, functional dyspepsia; FGID, functional gastrointestinal dis-
orders; 5-HTT, hydroxytryptamine transporter; IL, interleukin; IBS, irritable
bowel syndrome; PI-IBS, postinfection irritable bowel syndrome; TCM,
traditional Chinese medicine; TNF, tumor necrosis factor.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.013
May 2016
Figure 1. The Rome Foundation’s global initiative began with the Rome Translation Project and the Global Perspective
conference held in Milwaukee in 2011. Since then, it has branched out in many directions, encompassing outreach educational
programs, Rome-sponsored symposia at international meetings around the world, fostering of cross-cultural research net-
works, and a planned global epidemiology study.
shared, and that guide thinking, decisions, and actions in a
patterned way.1 Individuals within social networks share
ideas and values, which create order and further adaptation
to local surroundings.
The terms culture, ethnicity, and race often are used
interchangeably, although each has a specific definition and
reference. Ethnicity can be thought of as a measure of cul-
tural heritage, in contrast to race, which is based more on
phenotype (eg, skin color).2,3 The term race is considered
controversial and may not reflect biologic difference owing
to the complexity of the human genome. Although there is
some recognized overlap between ethnicity and race in this
article, the term race will refer to the conventional pheno-
type definition, and in all other category designations,
ethnicity is intended.
Ethnocentrism is defined as judging another culture
solely by the values and standards of one’s own culture,4
which can be an impediment to effective clinical practice
and research. Beliefs and definitions may have an impact on
symptom interpretation. For example, a doctor may ask a
patient if they suffer from bloating, but the patient may
think the doctor is asking about abdominal pain.
Ethnic identity can be defined as that part of an in-
dividual’s self-concept that is derived from his or her
knowledge of membership in a social group, together with
the value and emotional significance attached to that
membership.5,6
A patient’s culture is related closely to religious princi-
ples, language (implicit expression of symptoms and
Multicultural Aspects in FGIDs 1345
MULTICULTURAL ASPECTS
feelings), and explanatory models of illness. The effect of
culture on health and health care can manifest itself in
illness beliefs,7 symptom expression, and learned coping
patterns. Cultural and ethnic factors also may affect patho-
physiology, the patient–physician relationship, the diag-
nostic process,8 openness to treatment modalities such as
complementary and alternative medicine (CAM) and psy-
chotherapy,8,9 and health outcomes.10
Gender generally is used to refer to the nonbiological
aspects of being a woman or man, such as the social or
cultural expectations associated with femininity or mascu-
linity.11 The term sex generally is used to refer to a person’s
biological femaleness or maleness. However, most differ-
ences between men and women are known to be a function
of the interaction between biology and the environment.11 In
this review, the term sex will be used as a more inclusive
term. The term sex will be used for the classification of in-
dividuals based on their reproductive organs and function,
as assigned by their chromosomal complement. Gender roles
are based on sex stereotypes, which are socially shared be-
liefs that biological sex determines certain qualities.
Symptom Interpretation and Reporting
The manner in which symptoms manifest and are re-
ported varies between groups. Evidence exists that African
Americans have lower pain tolerance and higher ratings
of suprathreshold stimuli than non-Hispanic whites,
with greater symptom severity and increased functional
 1346 Francisconi and Sperber Gastroenterology Vol. 150, No. 6

Figure 2. A conceptual model of the interactions between culture and FGIDs. The focus is on patients, physicians, food and
eating, and culture in symptom interpretation and clinical manifestations. Although no figure can do justice to all the in-
teractions among factors, the other factors are shown in association with the central factor with which they are most
significantly linked. CNS, central nervous system; SIBO, small intestine bacterial overgrowth.
MULTICULTURAL ASPECTS

disability related to somatic pain. Similarly, Hispanic in-
dividuals have increased sensitivity to pain compared
with non-Hispanic whites.12,13 Sociocultural, psychological,
biological,12 and ethnic variables can indicate coping
styles, which can influence experimental and acute pain
response.14
Some ethnic groups readily describe sensations as
painful, whereas others do not complain about pain at all.15
In much the same way, the sensation of pain may be local-
ized differently in non-Western compared with Western
populations (ie, Chinese patients often report pain as
occurring in the upper abdominal region, but because it is
relieved by a bowel movement, it meets the Rome diagnostic
criteria for irritable bowel syndrome [IBS]).
Even if the patient and the physician speak the same
language, misunderstandings can take place concerning
symptom interpretation and reporting, especially if the
symptoms are of a somewhat embarrassing nature. This is
particularly the case in FGIDs, in which symptoms are vague
and multiple, and in which there are no robust ways of
objectively capturing or quantifying them. Furthermore,
there are many colloquial ways of describing various
symptoms. These can vary greatly from region to region
within the same country and may not necessarily be un-
derstood by people living outside a particular region.16 This
whole issue becomes even more complex when considering
how a word used to describe a symptom is translated into
another language, particularly if the exact equivalent does
not exist in that language.
For example, “bloating” is a word that is particularly
difficult to understand and translate into other languages
and adapt into other cultures. Bloating as an English term
refers to any abnormal general swelling or any increase in
abdominal girth. The most common symptom associated
with bloating is a sensation that the abdomen is full or
distended. According to Stedman’s Medical Dictionary, bloat
or bloating refers to abdominal distension from swallowed
air or intestinal gas.17
Whorwell18 proposed that bloating is a sensation of
increased pressure within the abdomen, whereas distension
is a demonstrable increase in abdominal girth. However,
putting this distinction into practice is a major challenge
because the term bloating is confined primarily to English-
speaking cultures. The Latin language holds no equivalent
word for bloating and the word distension usually is used.
In Spain and Latin America, physicians use the term
distension (a technical medical term) to describe what
patients and the public refer to as bloating, often using the
words “swelling” and “inflammation.”
Important related issues are whether postprandial full-
ness is different from bloating and whether bloating and
abdominal pain are part of a severity continuum. For
example, in China postprandial fullness is limited to the
epigastrium, whereas bloating refers to a sensation of gas in
most of the abdomen and can reflect abdominal discomfort,
another term that does not translate well into other
languages. Thus, bloating also may be a component of
discomfort in some cultures.
May 2016
In many languages, including English, Spanish, and Farsi,
postprandial fullness is different from bloating. In Chinese,
in contrast, patients and physicians may not be able to
distinguish between the source of fullness (gastric) and
bloating/distension (intestinal).
Bloating, however defined and perceived, is a key
symptom among IBS patients in Asia, occurring almost as
commonly as abdominal pain, and is an important motive
for patient consultation.19 In this region, phrases such as
“feeling blown up like a balloon” are regarded as important
features of IBS.20,21
Americans may consider pain and discomfort on a con-
tinuum of severity, whereas Europeans perceive them as
different types of nociceptive input.22,23 Spiegel et al24
conducted a study designed to develop a framework for
measuring patient symptoms and inform patient reported
outcomes for clinical trials. They concluded that discomfort
encompasses a range of symptoms such as bloating, gas,
fullness, flatulence, sensation of incomplete evacuation, and
urgency, with wide variations in patient understanding.
Thus, asking patients about discomfort alone can be
nonproductive because the term is nonspecific and covers
many symptoms and concepts. It should be noted that this
study was conducted in one country and one language
alone, and does not necessarily reflect similar symptom
experiences in other countries, languages, and cultures.
A multinational study involving the United States, Mexico,
Canada, England, Italy, Israel, India, and China showed sig-
nificant positive correlations between pain and bloating in
the 6 Western-culture countries and India.25 The only
exception was China, where this relationship was signifi-
cantly negative. One possible explanation is that the 2
symptoms in China may be conceptualized as being on a
continuum, where bloating may be considered a milder form
of pain. Investigators also found differences in symptom
expression in different parts of Europe. Pain, discomfort, and
bloating scores were consistently higher in Italy than in
England, so the relative influence of sociocultural norms,
language, and symptom interpretation may be significant.25
The observation that Chinese physicians and patients
may attribute the origin of abdominal symptoms to a
problem in the upper abdomen rather than to bowel
dysfunction might lead to diagnostic confusion in some
cases and even to misdiagnosis in others, such as IBS being
diagnosed as functional dyspepsia (FD).20,21 This may
explain the lower rates of IBS in these populations, with a
concomitant higher prevalence of FD.20 In a study from
Taipei, Taiwan, 50% of patients initially diagnosed with FD
actually had pure IBS, based on the Rome I criteria, because
their upper abdominal pain or discomfort was relieved with
defecation.26 A study from Guangzhou, China, observed that
postprandial fullness was the only independent predictor of
FD in patients with overlapping IBS according to the Rome
III criteria.26 Thus, postprandial fullness is defined as orig-
inating from the gastroduodenal region, whereas abdominal
discomfort, possibly including bloating (but not pain)
relieved by defecation, is considered a symptom of IBS.
In summary, there is no consistent understanding of the
term bloating across cultures and languages. It is interesting
Multicultural Aspects in FGIDs 1347
to note that although the term bloating presents no lin-
guistic problems to English-language authors or the general
English-speaking public, non-English scholars have had to
adapt words, or groups of words, from their own language
to describe this term.
Pictograms have been developed in an attempt to over-
come difficulties in clinical research and improve under-
standing of what is reported by patients. The pictorial
version of the Bristol Stool Form Scale27 is a good example
of how patients easily can communicate the appearance of
their stools, without having to choose from verbal response
options that may be difficult to understand or translate from
one language to another and between cultures. The success
of this scale is underlined by the fact that it is now used
widely in both clinical and research settings. However, a
picture-only version has not, to our knowledge, been vali-
dated in any formal study.
Carruthers et al28 asked patients to describe the images
they had of their condition and a medical artist then painted
these in watercolor. The images subsequently were verified
or modified according to the wishes of the patient to ensure
they represented the perspective of the patient, not the
artist. The investigators reported that 90% of the patients in
the study who had bloating as their principal symptom
chose 1 of 3 images representative of bloating as the image
that most reflected their worst symptom. Thus, the use of
symptom images might be an ideal way of crossing the
language and cultural barriers that currently prevent accu-
MULTICULTURAL ASPECTS
rate comparison of symptoms from different parts of the
world.
However, the use of pictograms does entail potential
problems that should be weighed in terms of benefit vs
possible harm: (1) overly realistic images may be offensive
in some cultures; (2) colors have significance in some cul-
tures, so one should use caution in the choice of colors; (3)
should the body be depicted in full anatomic detail or
covered by clothes, (4) should pictograms be accompanied
by text, and (5) pictograms should be adapted and validated
for specific cultures.
Food and Food Taboos
Food in most cultures plays a prominent role in FGID
patient symptom attribution and reporting. This is espe-
cially true of IBS and FD, clinical entities for which there is a
large body of research concerning the association of eating
and food with gastrointestinal symptoms.
The act of eating involves 3 elements: the person, the
circumstances under which food intake occurs, and the
nature of the ingested food. These 3 elements are all subject
to culture-related influences. Other relevant regional issues
related to food can be linked to its scarcity (hunger stem-
ming from low socioeconomic status), overabundance,
intolerance, and cultural taboos. Food is reported to be
associated with symptom onset or exacerbation in a signif-
icant proportion of patients with FGIDs.
Cultural factors can impart positive or negative mean-
ings to food (placebo or nocebo properties, respectively).
There are several cultural aspects to food and eating, and
 1348 Francisconi and Sperber
potential internal conflicts related to food ingestion that can
lead to functional symptoms based on activation of neural
circuits in the central nervous system.29
Certain food types have religious connotations in some
cultures and their consumption may be seen as sacrilegious,
such as the eating of pork in Islam and Judaism.
Ethical issues related to food are relevant to some
groups of patients. For example, there are strong advocates
for the avoidance of meat consumption because of the
cruelty of animal slaughter or procurement of food in ways
that can damage the ecosystem.30 Vegans avoid the use of
animal or animal-derived products for nourishment,
clothing, or any other purpose. Physicians should respect
the ethical and religious beliefs of their patients when
providing counsel on food and diet, and understand how
potential breaches of these ethical and religious values may
lead to the development of functional abdominal symptoms.
The Rome Foundation Working Group on the Role of
Food in FGIDs recently published a series of evidence-based
comprehensive reviews on the physiological changes asso-
ciated with nutrient intake related to carbohydrates,31
fiber,32 protein,33 and fats,34 but information relating to
cultural, ethnic and geographic differences still is lacking.
Food can be classified according to how it is perceived
within culture groups, so physicians should be aware of the
significance of different food types to individual patients.
Often patients provide information on perceived associa-
tions between types of food and their digestive symptoms,
MULTICULTURAL ASPECTS
leading physicians to prescribe a particular diet as part of
the treatment.
Chinese, Hispanic, and Iranian populations35 believe that
diseases can be caused by an imbalance between hot and cold
principles and, as such, classify diseases and foods in terms of
their hot and cold characteristics. These classifications bear
no relation to the actual temperature, but rather to related
properties. For example, Puerto Ricans in New York attribute
cold diseases to cold foods, such as avocados, bananas,
coconut, and white beans, believing them to provoke a cooling
of the stomach. Consequently, doctors should not prescribe
cold remedies, such as sodium bicarbonate, milk of magnesia,
and belladonna, for these diseases.36,37
Traditional Chinese medicine (TCM) is completely
different from Western medicine as we know it. Illnesses in
TCM are categorized into 4 main syndromes (ie, cold syn-
drome, heat syndrome, deficiency syndrome, and excess
syndrome). They then are differentiated further along the
lines of yin and yang, qi and blood, and the viscera where
the symptoms originate. Viscera, for example, the spleen or
spleen-qi, is not the anatomic spleen, but rather an indica-
tion of digestive function. This is the case for the terms liver
and blood, as well. TCM emphasizes diagnosis and treatment
based on an overall analysis of the illness and the patient’s
condition, mostly based on the practitioner’s experience
over a long time in practice, so the diagnosis for one disease
in TCM might be more than 10 syndromes.38,39 For example,
the common distinguishing pattern for IBS with diarrhea
is liver–qi stagnation and spleen–qi deficiency, which is
considered a cold and deficiency syndrome. Ginger, one of
the common subsidiary foods in Asian countries, is
Gastroenterology Vol. 150, No. 6
considered to have a warm efficacy in TCM and usually is
used to supplement prescription medicine. One survey
found that 28% of Chinese IBS patients drink ginger soup
(cooked with brown sugar and red dates) when their bowel
symptoms get worse and 43.5% of them reported this to be
effective in reducing symptoms.40
Indeed, diet plays a crucial role in any treatment pro-
gram in Chinese medicine. The Chinese verbs for “to eat”
and “to take” (medicine) are the same. All food is believed to
have medicinal value, and in ancient times court chefs were
considered physicians. This primacy of nutrition in Chinese
society may create a preferential labeling of adverse sen-
sations as arising through meals rather than caused by
bowel dysfunction.
Dietary habits in Asia vary widely between the different
countries and analyses of possible associations between
specific foods and IBS symptoms are lacking. There would
appear to be a trend in Asian countries to Westernization,
with increasing consumption of milk and dairy products.
These may give rise to symptoms often associated with
lactose intolerance, which ranges from 12.6% in Bangladesh
to 70%–100% in other countries.41,42 IBS patients in the
Middle East often are convinced that their abdominal symp-
toms are related to food and eating, whereas diet in Israel is
associated with a prevalence of bloating and flatulence.
Italian patients with FGIDs often report food avoidance.
Many patients avoid lactose or gluten in the belief they are
intolerant of these food components.43 This conduct is
reinforced by the fact that General Practitioners also
consider food allergies and/or food intolerance to be a
probable cause of IBS.44
In Eastern Europe, diarrhea and constipation in FGIDs
are attributed to the type of food consumed, food in-
tolerances and allergies, as well as nonfunctional conditions
such as lactose intolerance and celiac disease, but epide-
miologic data exist only for FD.45
Recently, a blood test for food intolerance has become
very popular in many South American countries. Patients
are furnished with a list of foods to which they are intol-
erant, based on antibodies, and follow very strict elimina-
tion diets in accordance with the results, but without a
documented reduction in gastrointestinal symptoms.
Physicians should be aware of the importance of cultural
associations with food and eating because these play a
central role in the patient’s explanatory model of illness
from the patient perspective. Cultural competency in the
clinical setting should include recognition of the role of food
and eating, including cultural aspects, and nutritional
counseling should consider these factors.
Explanatory Models of Illness
Patients
Patients have symptom- or disease-related beliefs that
affect their concerns, anxieties, and expectations of the
health care process. This set of beliefs has been called the
“explanatory model.”46 Cultural background, socioeconomic
status, educational level, and sex are major factors that
May 2016
contribute to the development of explanatory models.47
These models provide a way of understanding patient per-
spectives in a health care setting. FGIDs, which have unclear
etiologies, are more likely to be influenced by cultural fac-
tors than disorders that have a defined biological basis with
clear-cut diagnostic criteria.48 To achieve effective commu-
nication with patients, the physician should be cognizant of
and adjust to the cultural background and perspective
through which the patient views their illness. Elicitation of
the patient’s explanatory model can facilitate the compli-
cated and often frustrating communication process between
physicians and patients who have unexplained symptoms
and chronic conditions.
Because the physician–patient relationship is a critical
part of therapy in FGIDs it is important to understand the
cultural background in which the patient’s explanatory
model developed and to negotiate a treatment partnership
that will be effective within the context of patient and
medical team beliefs and attitudes.49
Barriers to the physician–patient relationship often are
created by patient beliefs that may make the consulting
process difficult. The inherent intricacy and multifaceted
nature of the physician–patient encounter in this clinical
setting may make it difficult for patients to convey their
concerns during the consultation.50 Some relevant questions
from the patient’s perspective are important to address: (1)
What caused my sickness? (2) Why did I become sick at this
time? (3) How does the illness work inside me? (4) What
will happen to me? What will it do to me? and (5) How
should it be treated?
Physicians
Physicians also develop explanatory models, primarily
based on pathophysiology and the need to expedite the
diagnostic process and provide effective therapy, as taught
in medical school. These models also include several
important elements: (1) etiology, (2) time and mode of
onset, (3) pathophysiology, (4) course (including symptom
severity and trajectory, ie, acute, chronic, impaired), and (5)
recommended treatment.
There is an almost inevitable discrepancy or disconnect
between the explanatory models of the physician and the
patient. The physician is driven by the therapeutic impera-
tive, that is, something has to be performed (tests, treatment,
education, and reassurance), and the sooner the better.
An important culture-related skill for physicians is cul-
tural competency, which is gaining in importance owing to
the multicultural backgrounds of patients in clinical prac-
tices. Cultural competency includes overcoming any lan-
guage barrier (linguistic competency) and an understanding
of the cultural background from which the patient comes
and within which he/she develops explanatory models of
illness. All physician–patient encounters have the potential
for cross-cultural misunderstanding. Issues that may lead to
these misunderstandings and their unwanted consequences
include differing or even conflicting attitudes relating to
authority, physical contact, communication style, sex, sexu-
ality, and family.49 Important cultural issues related to the
Multicultural Aspects in FGIDs 1349
religious significance involved in the contact and context of
clinical encounters between doctors and patients must be
considered. For example, male physicians should act with
caution when examining Muslim female patients and, like-
wise, non-Muslim female physicians must be careful when
examining Muslim men.
Clinicians should ask themselves whether cultural fac-
tors are liable to lead them to misunderstand a patient’s
history? By eliciting a patient’s explanatory model, physi-
cians have a better chance of understanding where the pa-
tient is coming from and how to foster and therapeutic
relationship.
Practical Approaches to Cultural
Issues Related to the
Physician–Patient Relationship
Two scenarios can be presented in which cultural issues
may become important in the physician–patient relation-
ship: the physician represents the prevailing culture and the
patient represents a distinct different culture, or the
physician represents a minority culture and the patient
represents the prevailing one. Physicians who are unaware
of these issues or lack cultural competency might try to
impose their values on patients, severely impairing the
provider–patient relationship.
Recommendations that can lead to improved cultural
competency in the clinical setting include the following: (1) be
MULTICULTURAL ASPECTS
aware of cultural differences at the onset of the consultation
(eg, is the patient from a different culture?), (2) assess whether
the patient has or has not assimilated into the prevailing cul-
ture, (3) be aware of the patient’s cultural beliefs and attitudes
relating to physical contact (handshake, hug, touching of the
head),51 (4) have respect for elderly patients and avoid making
the consultation too informal at an early stage, and (5) respect
cultural principles regarding eye contact.
Family Systems
Family relationships can have a significant effect on the
illness experience of the patient. Family structures differ
widely among geographic regions and cultural groups, from
the extended family structure in developing countries, espe-
cially in rural areas, to the more typical nuclear family in
developed countries. These differences can have an impact on
how patients are supported and how relationships with
health care providers are negotiated. Cultural belief systems
regarding illness, which can affect the patient with FGIDs, are
most clearly enacted and transacted within the family.
The family setting is particularly relevant to multicul-
tural issues because family dynamics are the major site for
transmission of cultural values, and family structure may
vary considerably in different cultures. As stated by
McGoldrick et al,52 “It is almost impossible to understand
the meaning of behavior unless one knows something of the
cultural values of a family.” Even the definition of family
differs greatly from group to group. The dominant American
(Anglo) definition focuses on the intact nuclear family,
whereas for Italians, family means a strong, tightly knit,
 1350 Francisconi and Sperber
3- or 4-generational family that also includes godparents
and old friends. African American families focus on even
wider networks of kin and community and Asian families
include all ancestors, going all the way back to the beginning
of time, and all descendants, or at least male ancestors and
descendants, reflecting a sense of time that is almost
inconceivable to others.52
Research has shown the relevance of conflict in intra-
family relationships, with it being among the most impor-
tant risk factors for a variety of health outcomes and
seeming to affect women more than men.53
An international cross-cultural study of patients with IBS
encompassing 8 geographic sites examined the relationship
of symptom severity with family support or conflict.54
Support and conflict were related significantly to symptom
severity and the results indicated a global pattern rather
than cultural differences in different locations. They also
verified that the perception of family support was correlated
with lower levels of symptom distress, whereas intrafamily
conflict correlated with higher levels.
Within the family setting there are culturally based dif-
ferences in health care and health care outcomes. For
example, evidence from India suggests that men use the
health care system more than women and that female
subservience in rural areas can result in them being unable
to access the health care system as much as the men.55 This
same form of male dominance also is observed in
Pakistan.56 In IBS epidemiology studies in Israel involving
MULTICULTURAL ASPECTS
subpopulations,57–59 an attempt to survey the adult Israeli
Arab population by telephone was unsuccessful because the
women were not permitted to answer telephone calls and,
therefore, could not respond to survey questions.
Parental, in particular maternal, attitudes regarding
physical distress are likely to vary with culture. Research in
Japan showed that Japanese mothers are more attentive to
their children’s complaints compared with mothers in the
United States, so solicitous behavior in Japan would be
considered normative and not problematic, while it might
be considered contributive to the development of IBS in the
United States.60
Gerson and Gerson61 showed that family inclusion in IBS
patient treatment programs varied considerably between
different cultures, depending on factors such as gender
norms, nuclear or extended family structure, and openness
to exploration of relationship difficulties. Based on these
observations, they incorporated a family systems perspec-
tive in a group treatment program for IBS patients.
Physicians should be open to diverse narratives. Patients
and families who believe that their doctor attends to and
respects their symptoms and complaints are more likely to
be open to medical recommendations.
Local Biologics
Complex environmental and biological factors interact
with patients’ explanatory models of illness, sex, and family
systems. These also can affect the way in which patients
interpret and report symptoms and adhere to treatment
recommendations.
Gastroenterology Vol. 150, No. 6
In recent years, biological factors such as low-grade
inflammation, immune activation, the gut microbiota, and
genetic differences have gained importance in relation to
FGIDs and theories as to their pathophysiology. These fac-
tors also may be affected by culture, ethnicity, and
geographic region. In addition, environmental aspects such
as climate, water composition, and psychosocial stressors
may affect sociocultural issues in FGIDs.
Genetics
Genes and culture often are thought of as being at
opposite ends of the nature–nurture spectrum but there are
relevant interactions.62 Different genes associated with
FGIDs have been studied. Those linked to serotonin meta-
bolism, such as the hydroxytryptamine transporter (5-HTT)
gene, provide interesting indications for sociocultural issues
and gene–environment interactions.
Polymorphisms in the 5-HTT linked promoter region
and their effects on the expression and function of 5-HTT
have been linked to patient emotional behavior and vary in
frequency in different races and ethnicities. These poly-
morphisms also are reflected in the effectiveness of selective
serotonin reuptake inhibitors. A high response rate to
selective serotonin reuptake inhibitors has been reported in
Caucasian and Japanese populations,63,64 whereas a higher
percentage of nonresponders has been seen in African
American people.65
Microbiota, Postinfection IBS, and
Small Intestine Bacterial Overgrowth
The Rome Foundation Working Team on Intestinal
Microbiota reviewed associations between FGIDs and the
intestinal microbiome.66 The importance ascribed recently
to intestinal microbiota comes from a growing recognition
of its association with alterations in digestive system func-
tion and brain–gut interactions. However, little is known
worldwide about variations in the composition and function
of the human gut microbiome, and even less in relation to
IBS and other FGIDs. Arumugam et al67 identified 3 robust
clusters of bacteria in individuals from 4 countries, called
enterotypes. They showed that these enterotypes are neither
nation- or continent-specific, nor dependent on individual
host properties such as body mass index, age, or sex.
Nonetheless, the enteric microbiota may be related to
phenotypic manifestations of FGIDs, as well as to the psy-
chological reactions of patients.68
De Filippo et al69 compared the fecal microbiota
composition of children from urban Florence, Italy, and
from a rural area of Burkina-Faso in Africa. The in-
vestigators detected a significant difference in intestinal
microbiota composition for these 2 populations, which was
attributed to the marked difference in eating habits, among
other factors. These differences can have a significant effect
on gut function and brain–gut interaction.
Postinfection IBS (PI-IBS) is a typical example of how
one episode of intestinal infection, with its alteration of in-
testinal microbiota, can bring about lasting changes in both
May 2016
intestinal function and central mechanisms of pain percep-
tion. Nevertheless, no evidence exists to indicate that
developing countries with higher rates of intestinal infection
have a higher incidence of PI-IBS. For instance, the
population-based prevalence of IBS in Mexico is 16%,
whereas the prevalence of PI-IBS is 5%, which is low
compared with other parts of the world.70
Environmental Hygiene
The hygiene hypothesis contends that the high preva-
lence of IBS in the West may be related, at least in part, to a
lack of exposure to enteric pathogens in early life, whereas
early exposure in underdeveloped countries may protect in
adulthood against the development of this disease.21 This
does not explain the high prevalence of IBS in countries
where infections remain common.21 Hygienic conditions
across regions, often associated with socioeconomic status,
may have a differential impact on the risk of developing
PI-IBS.71
Immunologic Factors: Cytokines
Recent evidence has supported abnormalities in immune
regulation and/or immune activation in IBS.72 Proin-
flammatory (tumor necrosis factor [TNF]-a, interleukin [IL]
1b, IL6, and IL8) and anti-inflammatory (IL10) cytokines are
among those most studied, but findings on their association
with IBS are inconsistent.73 Serum/plasma levels of TNF-a
tended to be higher in IBS vs controls and reached signifi-
cance in IBS subtypes vs controls and in female IBS patients
in different countries, such as Sweden, Turkey, China,
India, Mexico, and the United States. However, studies
from Ireland reported either no difference or even a
decrease in TNF-a circulating levels in IBS patients, result-
ing in considerable heterogeneity in the meta-analysis of
TNF-a levels.74
Cytokines are determined genetically. A recent system-
atic review and meta-analysis assessing TNF-a (-308 G/A)
polymorphisms, IL10 (-1082 G/A), and transforming growth
factor-b1 (þ869 T/C and þ915 G/C) in IBS patients and
controls in 5 studies from Holland, Turkey, Iran, India, and
Korea,74 found no overall associations between TNF-a (-308
G/A) genotypes in IBS. Conversely, a study in Asia showed
an association between TNF-a genotypes (-308 G/A and
G/G) and IBS, whereas results from a Mexican study were
negative.75 However, low producers of IL10 were more
frequent in diarrhea-predominant IBS vs constipation-
predominant IBS and IBS-mixed in this population.75
These results from around the world suggest once again
that biological factors, such as genetic characteristics, may
influence differences in cytokine levels between IBS patients
and controls in different populations. At the moment these
impressions should be qualified by 2 other possible expla-
nations for the conflicting results: (1) most studies are not
large scale and may be relatively small to determine geno-
type differences, and (2) genetic allele frequency for some
genes show that the major allele in one race (eg, Caucasians)
is the minor allele in another race (eg, Asian).
Multicultural Aspects in FGIDs 1351
Treatment
Some treatment modalities are affected significantly by
region and culture. One example is CAM. The National
Center for Complementary and Alternative Medicine76 in
the United States defines CAM as health care approaches
developed outside of mainstream Western or conventional
medicine. CAM use is widespread throughout the world and
possibly increasing over time. The type and prevalence of
CAM use varies greatly from country to country. In Western
countries, CAM use is generally more common among
females, young and middle-aged adults, and patients with a
higher educational attainment and larger household
income.77–79 In urban Nigeria, by contrast, males and
patients with lower income are more likely to use CAM.80
Patients generally use CAM in conjunction with conven-
tional medicines, but many people fail to inform their con-
ventional health care providers about this use.
Intercountry comparisons are hindered by definitions.
What is defined as CAM in one country may be considered
relatively mainstream in another. Most studies on CAM
relate to its use in holistic medical care. Only a few specif-
ically addressed gastroenterologic conditions, and even
fewer considered FGIDs.
Research in the United States showed that the most
commonly used CAM methods include the consumption of
ginger, and use of massage therapy and yoga. CAM use was
associated with female sex, younger age, college education,
anxiety, depression, somatization, and impaired quality of
MULTICULTURAL ASPECTS
life. Satisfaction with physician care was not a predictive
factor for its use, and patient willingness to use conven-
tional medical care was not reduced.81
Recommendations for CAM by health care providers
reflect their belief in the efficacy of this treatment modality
and its place in the social environment in which they live.
Physicians in Western societies should become more
familiar with the various types of CAM, their effectiveness,
and side effects. It should be noted that different cultures
and countries have different perspectives as to what com-
prises CAM treatment. For example, probiotics and pre-
biotics may be considered a component of conventional care
in one country or culture, and a CAM treatment in another.
Culture, Ethnicity, and Health
Care Outcomes
Belief refers to the attitude we have whenever we take
something to be the case or regard it as true. The interaction
between culture, beliefs, and health affects the quality of
health care and health outcomes. Often the importance of
cultural factors goes unrecognized, and in clinical practice
this can result in poor health outcomes. Culture and
ethnicity may affect the diagnostic process and health out-
comes. Patient ethnicity exerts an enormous effect on both
diagnostic studies and medications prescribed by doctors.8
The social circumstances of the doctor and patient cast a
large shadow on treatment. Notions about the patient’s
needs for medication may be tied more to ethnicity than to
illness per se.8,9
 1352 Francisconi and Sperber
Some population subgroups, including ethnic groups, are
more likely to receive suboptimal health care than others.10
The concept of health literacy has been coined to describe
the skills required to function in the health care environ-
ment.82 Many individuals from some cultural subgroups
do not have these skills and function with a handicap
within the health care system. Limited literacy ability,
MULTICULTURAL ASPECTS
particularly in a second language, may lead to difficulty in
understanding diagnoses, discharge instructions, and treat-
ment recommendations.
Differences in Health Care Services
and Their Impact on FGIDs
Variations in health care provision around the world
may affect how patients with FGIDs are investigated, diag-
nosed, and managed. Prompted by the lack of global infor-
mation, the Rome Foundation’s Working Team on
multinational, cross-cultural research in FGIDs recently
addressed this issue. It identified 7 key elements in this
regard: (1) coverage afforded by the different health care
systems/providers; (2) level of the health care system
where patients with FGIDs are treated; (3) extent and types
of diagnostic procedures typically undertaken to diagnose
FGIDs; (4) physician familiarity with implementation of the
Rome diagnostic criteria in clinical practice; (5) range of
medications approved for use in FGIDs and the approval
process for new agents; (6) costs involved in treating FGIDs;
and (7) prevalence and role of CAM in FGIDs. The study was
conducted in 4 countries (Italy, India, Mexico, and South
Korea), and resulted in the following findings: (1) large
variations exist between different countries in access to
good quality medical care; (2) it would appear that although
the Rome diagnostic criteria are well accepted in Italy,
Mexico, and South Korea, a substantial number of physi-
cians, especially general practitioners, do not use them in
clinical practice; (3) antispasmodics, osmotic agents, and
Gastroenterology Vol. 150, No. 6
Figure 3. Cross-cultural,
multinational research has
tremendous potential and
can be applied to almost
all aspects of FGIDs from
basic research to epide-
miology to psychosocial
comorbidity to drug trials.
In all cases, cross-cultural
research competence is
of the essence.
laxatives are universally available and regularly prescribed
in the 4 countries; (4) CAM is used in many places for
FGIDs—in some regions it is part of the accepted health care
system (eg, India); and (5) there are differences in the
health care burden of FGIDs because medications for FGIDs
are not covered by public health care services.83
The Conduct of Cross-Cultural,
Multinational Research on FGIDs
Cross-cultural, multinational research has the potential
to advance the field of FGIDs at many levels. In addition to
FGID prevalence studies, cross-cultural comparative
research can make a significant contribution in genetics,
psychosocial modulators, symptom reporting, symptom
interpretation and symptom presentation, extraintestinal
comorbidity, diagnosis and treatment, determinants of dis-
ease severity, health care infrastructures, health care utili-
zation, and health-related quality of life, all issues that can
be affected by culture, ethnicity, and race.
Establishing Cross-Cultural Research
Networks and Fostering Cross-Cultural
Research
Appropriate strategies should be established that allow
researchers from different nations and cultures to work
together on common projects. A recent publication of the
Rome Foundation Working Team discussed ways of
fostering multinational research networks.84
Conclusions and Suggestions
for Future Directions
Cross-cultural factors in FGIDs are of great importance,
but remain mostly under-recognized in clinical practice and
research. The development of cross-cultural competency in
May 2016
clinical practice is of particular importance in the treatment
of disorders such as FGIDs because they are poorly under-
stood and have an unclear etiology, prognosis, and clinical
course. The development of cross-cultural competency in
basic, clinical, and translational research and the conduct of
fruitful multinational, cross-cultural research can make a
major contribution to our understanding of biological and
psychosocial factors that underlie these disorders, and can
facilitate their effective management (Figure 3).
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. To access the supplementary
material accompanying this article, visit the online version
of Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.013.
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Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350 CEP 90035-003, Porto
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 Gastroenterology 2016;150:1355–1367

Biopsychosocial Aspects of Functional Gastrointestinal

Disorders: How Central and Environmental Processes Contribute
to the Development and Expression of Functional
Gastrointestinal Disorders
Lukas Van Oudenhove,1 Rona L. Levy,7 Michael D. Crowell,2 Douglas A. Drossman,3
Albena D. Halpert,4 Laurie Keefer,5 Jeffrey M. Lackner,6 Tasha B. Murphy,7 and Bruce D. Naliboff8
1
Laboratory for Brain-Gut Axis Studies, Translational Research Center for Gastrointestinal Disorders, University of Leuven,
Leuven, Belgium; 2Department of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona; 3Center for Education
and Practice of Biopsychosocial Care LLC, Drossman Gastroenterology PLLC, Chapel Hill, North Carolina; 4Center for
Digestive Disorders, Boston Medical Center, Pentucket Medical Associates, Haverhill, Massachusetts; 5Division of
Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; 6Behavioral Medicine Clinic, Department of
Medicine, University at Buffalo School of Medicine and Biomedical Sciences, State University of New York, New York;
7
Behavioral Medicine Research Group, School of Social Work, University of Washington, Seattle, Washington; and
8
Center for Neurobiology of Stress, Departments of Medicine and Psychiatry and Biobehavioral Sciences, David Geffen School
of Medicine at University of California, Los Angeles, California

We provide a general framework for understanding func-
tional gastrointestinal disorders (FGIDs) from a bio-
psychosocial perspective. More specifically, we provide an
overview of the recent research on how the complex in-
teractions of environmental, psychological, and biological
factors contribute to the development and maintenance of
FGIDs. We emphasize that considering and addressing all
these factors is a conditio sine qua non for appropriate
treatment of these conditions. First, we provide an over-
view of what is currently known about how each of these
understanding FGID from a biopsychosocial perspective.
Further, we emphasize why and how knowledge of this
biopsychosocial framework is critical for assessment and
treatment of these difficult-to-treat disorders that often
induce uncertainty and frustration in caregivers and pa-
tients alike. The many processes that are part of these
complex interactions of the individual’s physiology, psy-
chology, and environment are illustrated in an overview of
the biopsychosocial model of FGID (Figure 1) and described

factors—the environment, including the influence of those
in an individual’s family, the individual’s own psychological
states and traits, and the individual’s (neuro)physiological
make-up—interact to ultimately result in the generation of
FGID symptoms. Second, we provide an overview of
commonly used assessment tools that can assist clinicians
in obtaining a more comprehensive assessment of these
factors in their patients. Finally, the broader perspective
outlined earlier is applied to provide an overview of cen-
trally acting treatment strategies, both psychological and
pharmacological, which have been shown to be efficacious
to treat FGIDs.
Keywords: Adverse Life Events; Anxiety; Depression;
Psychological Treatments.
Biopsychosocial Basis of the Functional
Gastrointestinal Disorders
It is generally accepted that functional gastrointestinal
disorders (FGIDs) result from complex and reciprocal in-
teractions between biological, psychological, and social
factors, rather than from linear monocausal etiopathoge-
netic processes. This consensus report, based on an
extensive critical literature review by a multidisciplinary
expert committee, aims to provide a framework for
BIOPSYCHOSOCIAL ASPECTS
further.
Environmental Influences
Childhood environmental factors: parental beliefs
and behaviors. There is familial aggregation of childhood
FGID.1 Children of adult irritable bowel syndrome (IBS)
patients make more health care visits than the children of
non-IBS parents. This pattern is not confined to gastroin-
testinal (GI) symptoms2 and holds for maternal and
paternal symptoms.3,4 Although there is ongoing research
into a genetic explanation for these familial patterns, what
children learn from parents can make an even greater
contribution to the risk for developing an FGID than
genetics.5 The basic learning principle of positive rein-
forcement or reward, defined as an event following some
behavior that increases the likelihood of that behavior
occurring in the future, is a likely contributor to how this
can occur. Children whose mothers reinforce illness
Abbreviations used in this paper: ANS, autonomic nervous system; CBT,
cognitive-behavioral treatment; FD, functional dyspepsia; FGID, functional
gastrointestinal disorder; FSS, functional somatic syndromes; GI,
gastrointestinal; HPA, hypothalamoLpituitaryLadrenal; IBS, irritable
bowel syndrome; SNRI, serotonin noradrenalin reuptake inhibitor; TCA,
tricyclic antidepressant.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.027
 1356 Van Oudenhove et al Gastroenterology Vol. 150, No. 6

Figure 1. Biopsychosocial Model of IBS. Genetic and environmental factors, such as early life experiences, trauma, and social
learning, influence both the brain and the gut, which in turn interact bidirectionally via the autonomic nervous system and the
HPA axis. The integrated effects of altered physiology and the person’s psychosocial status will determine the illness
experience and ultimately the clinical outcome. Furthermore, the outcomes will in turn affect the severity of the disorder. The
implication is that psychosocial factors are essential to the understanding of IBS pathophysiology and the formulation of an
effective treatment plan. Figure adapted from Drossman et al,109 with permission.
BIOPSYCHOSOCIAL ASPECTS

behavior experience more severe stomachaches and more Parents’ catastrophizing cognitions about their own pain
school absences than other children6 (Figure 2). In predicted responses to their children’s abdominal pain that
addition, when parents were asked to show positive or encouraged illness behavior, which in turn predicted child
sympathetic responses to their children’s pain in a functional disability.12
laboratory, the frequency of pain complaints was higher
than when parents are instructed to ignore them.7 Finally, a
large randomized clinical trial of children with functional
abdominal pain found that cognitive-behavioral treatment
(CBT) targeting coping strategies, as well as parents’ and
children’s beliefs about, and responses to, children’s pain
complaints, induced greater baseline to follow-up
decreases in pain and GI symptoms compared with an
educational intervention controlling for time and
attention,8 and that this effect was mediated by changes in
parents’ cognitions about their child’s pain.9
There is also a strong association between parental
psychological status, particularly anxiety, depression, and
somatization, and children’s abdominal symptoms.4,10,11
This association could be occurring through modeling—
children observing and learning to display the behaviors
they observe, in this case, possibly heightened attention to,
or catastrophizing about, somatic sensations. However, the Figure 2. Associations between maternal reinforcement and
parental IBS, and illness behavior. In addition to increased
effect of parental traits on children’s symptoms could also reported severity, children whose mothers strongly reinforce
occur through reinforcement. Parents with certain traits or illness behavior also experience more school absences than
beliefs, such as excessive worry about pain, might pay other children. Figure adapted from Levy et al,6 with
more attention to, and thereby reward, somatic complaints. permission.
May 2016
Environmental stressors in childhood and adult
life. Adverse life events (including sexual, physical, and
emotional abuse). Compared with controls, IBS patients
report a higher prevalence of adverse life events in general,
and physical punishment, emotional abuse, and sexual
abuse in particular13; such history is related to FGID
severity and clinical outcomes, such as psychological
distress, and daily functioning.14 This in turn leads to
increased health care seeking, which could explain the
higher association of abuse histories with GI illness in
referral centers compared with primary care.14 Population-
based studies have led to more conflicting results with re-
gard to the association between self-reported FGIDs and
abuse history.15,16 Further, it should be noted that high
frequencies of childhood abuse (approaching 50%) are not
unique to patients with FGID, as similar figures are found in
patients with non-GI functional somatic syndromes (FSS, eg,
pelvic pain, headaches, and fibromyalgia).17
The onset of FGIDs has been associated with the expe-
rience of severely threatening events, such as the breakup of
an intimate relationship. In one study, two-thirds of patients
had experienced such an event compared with one-quarter
of healthy controls.18
Prospective studies have demonstrated that the experi-
ence of stressful life events is associated with symptom
exacerbation and frequent health care seeking among adults
with IBS.19,20 Chronic life stress is the main predictor of IBS
symptom intensity over 16 months, even after controlling
for relevant confounders.21
Finally, stress can affect FGID treatment outcomes—one
study demonstrated that the presence of a single stressor
within 6 months before participation in an IBS treatment
program was directly associated with poor outcomes and
higher symptom intensity at 16-month follow-up when
compared with patients without exposure to such a
stressor.22
Social support. Quality or lack of social support is
related to many aspects of IBS.23 Patients report finding
social support as a way to help overcome IBS.24 Relatedly,
perceived adequacy of social support is associated with IBS
symptom severity, putatively through a reduction in stress
levels.25 However, negative social relationships marked by
conflict and adverse interactions are more consistently and
strongly related to IBS outcomes than social support.23
Illustrative of the role of social support and clinically
important, a supportive patient practitioner relationship
significantly improved symptomatology and quality of life in
patients with IBS.26
Culture. Cultural beliefs, norms, and behaviors affect
all aspects of what has been discussed in this section: in-
teractions within the family, with other support systems,
and the world at large. For more extensive discussion, see
the article in this issue regarding multicultural aspects of
FGIDs.
Psychological Distress
Psychological distress is an important risk factor for the
development of FGIDs and, when present, can perpetuate or
Biopsychosocial Aspects of Functional GI Disorders 1357
exacerbate symptoms. Further, it affects the doctor patient
relationship and negatively impacts treatment outcomes.
However, psychological distress can also be a consequence
rather than a cause of disease burden.
Comorbid anxiety and depression are independent pre-
dictors of post-infectious IBS and functional dyspepsia (FD)
but, at the same time, also occur as a consequence of bodily
symptoms and related quality of life impairment. The
absence of formal psychiatric comorbidity does not exclude
a role of dysfunctional cognitive and affective processes not
captured by the current psychiatric classification system(s)
(in the sense of not reaching the threshold for a psychiatric
disorder or not being included in the classification system,
eg, in the case of symptom-specific anxiety, which is relevant
in the context of FGID but does not constitute a psychiatric
disorder).
Mood disorders. Overlap between depression and
FGID is about 30% in primary care settings and slightly
higher in tertiary care.27 Depression can impact the number
of functional GI symptoms experienced or the number of
FGID diagnoses.28,29 Suicidal ideation is present in between
15% and 38% of patients with IBS, and has been linked to
hopelessness associated with symptom severity, interfer-
ence with life, and inadequacy of treatment.30 Comorbid
depression has been linked to poor outcomes, including high
health care utilization and cost, functional impairment, poor
quality of life, and poor treatment engagement and
outcomes.25,31
Anxiety disorders. Anxiety disorders are the most
common psychiatric comorbidity, occurring in 30% 50% of
FGID patients. They may initiate or perpetuate FGID symp-
toms through their associated heightened autonomic
arousal (in response to stress) or at the level of the brain,
BIOPSYCHOSOCIAL ASPECTS
which can interfere with GI sensitivity and motor function.
Vulnerability to anxiety disorders might share similar
pathways as vulnerability to FGIDs, particularly with
respect to anxiety sensitivity, body vigilance, and ability to
tolerate discomfort.
Somatization, somatic symptom disorder, and
functional somatic syndromes. The Diagnostic and
Statistical Manual of Mental Disorders, 5th edition dis-
carded the concept of somatization, originally defined as
“a tendency to experience and communicate somatic
symptoms unaccounted for by pathological findings in
response to psychosocial stress and seek medical help for
it,”32 but often operationalized in a descriptive way,
measuring somatization by simply quantifying the number
of (medically unexplained) symptoms, in favor of somatic
symptom disorder.33 In the new diagnostic category, so-
matic symptoms may or may not be medically unex-
plained, but are distressing and disabling and associated
with excessive and disproportionate thoughts, feelings,
and behaviors for more than 6 months.34 This approach
shifts the experience of medically unexplained symptoms
from (unconscious) manifestations of psychological
distress toward abnormal cognitive affective processes
(eg, excessive illness worry, body preoccupation, and hy-
pochondriasis), both as contributors to, and consequences
of, symptoms.35
 1358 Van Oudenhove et al
Somatization is associated with GI sensorimotor pro-
cesses, including gastric sensitivity and gastric emptying,
symptom severity,36 and impaired quality of life in FD.37
Further, somatization is associated with health care use
and predicts a poor response to treatment, including
increasing one’s likelihood of discontinuing medication due
to perceived adverse effects.38 Therefore, assessing soma-
tization by checking severity of multiple somatic symptoms
remains clinically useful.
Somatization has been thought to explain the frequent
extraintestinal symptoms of IBS, and the high co-occurrence
between FGID and other FSS,39 and is a term that is
commonly used in the medical literature to refer to medi-
cally unexplained syndromes (in parallel with the psychi-
atric terminology outlined here). There is extensive overlap
among FSS—two-thirds of FGID patients experience symp-
toms of other FSS, including interstitial cystitis, chronic
pelvic pain, headaches, and fibromyalgia,40 independent of
psychiatric comorbidity, but the question whether the
different FSS represent truly distinct disorders (“splitter”
view) or different manifestations of a common underlying
pathophysiological process (“lumper” view) remains unre-
solved at present and falls outside the scope of this article.
CognitiveLaffective processes. Overlapping psy-
chological constructs, including health anxiety (gastroin-
testinal) symptom-specific anxiety, attentional bias,
symptom hypervigilance, and catastrophizing, have been
linked to FGID independent of psychiatric comorbidity, and
are important treatment targets for CBT (see Psychological
Treatments section)41 (Figure 3). An overview of these
processes and their roles in FGID is provided in Table 1.
BIOPSYCHOSOCIAL ASPECTS
Mechanisms: The Neurophysiological Basis of
the Biopsychosocial Model
Here we give an overview of the neurophysiological
mechanisms that explain the link between psychological
processes, psychiatric comorbidity, and FGID symptoms
described in the previous sections. Specifically, the critical
role of bidirectional signaling mechanisms between the GI
tract and the central nervous system are discussed,
including the central processes involved in modulation of
visceral afferent signals and the influence of efferent output
of central stress and emotional arousal circuits on motor,
barrier, and immune functions of the GI tract. Finally, the
emerging evidence on bidirectional communication between
the gut microbiota and the (emotional) brain is outlined
briefly.
BrainLgut processing. The “brain gut axis” is the
bidirectional neurohumoral communication system be-
tween the brain and the gut that is continuously signaling
homeostatic information about the physiological condition
of the body to the brain through afferent neural (spinal and
vagal) and humoral “gut brain” pathways.42 Under normal
physiological conditions, most of these interoceptive gut
brain signals are not consciously perceived. However, the
subjective experience of visceral pain results from the
conscious perception of salient gut brain signals induced
by noxious stimuli, which indicate a potential threat to
Gastroenterology Vol. 150, No. 6
homeostasis, thereby requiring a behavioral response. In the
brain, [visceral afferent] interoceptive signals are processed
in a homeostatic afferent network (brainstem sensory
nuclei, thalamus, posterior insula) and integrated with and
modulated by emotional arousal (locus coeruleus, amyg-
dala, subgenual anterior cingulate cortex) and cortical
modulatory (prefrontal cortex and anterior insula, peri-
genual anterior cingulate cortex) neurocircuits. Key regions
in these emotional arousal and cortical modulatory cir-
cuits project in a “top-down” fashion to brainstem areas,
such as the periaqueductal gray and the rostral ventrolat-
eral medulla, which, in turn, send descending projections to
the dorsal horn of the spinal cord, where pain transmission
is modulated (descending modulatory system) (Figure 4).
Thus, [visceral] pain perception does not display a linear
relationship with the intensity of peripheral afferent input,
but rather emerges from a complex psychobiological pro-
cess whereby visceral afferent input is processed and
continuously modulated by cognitive and affective circuits
at the level of the brain and through descending modulatory
pathways. These mechanisms help understand the influence
of the cognitive and affective processes outlined in the
previous section on GI symptom perception in FGID pa-
tients, as well as the therapeutic effect of interventions
targeting these processes, and constitute the basis for a
model of FGID as disorders of gut brain signaling. More
specifically, dysfunction of these modulatory systems might
allow physiological (non-noxious) stimuli to be perceived as
painful or unpleasant (visceral hypersensitivity), which can
lead to chronic visceral pain and/or discomfort, hallmark
symptoms of FGID. The results of functional brain imaging
studies in FGID will be outlined and should be interpreted
within this framework.
Functional gastrointestinal disorders. Behavioral
studies on psychosocial influences on perception of
gastrointestinal distension. The exact nature of the visceral
hyperalgesia or hypersensitivity found in a substantial
subset of IBS and FD patients remains unclear. The concept
of “visceral hypersensitivity” is operationalized as lower
pain thresholds during visceral sensory testing, that is,
reporting pain at lower pressures or volumes during
repeated ascending inflations of a GI balloon catheter.
However, as we have outlined, it is becoming increasingly
clear that psychological processes and psychosocial factors
can influence visceral perceptual sensitivity.
Several studies suggest that an increased psychological
tendency to report pain, which can be driven by hypervig-
ilance, underlies the decreased pain thresholds in IBS pa-
tients, rather than increased neurosensory sensitivity.43
Studies on the effects of stressors on perception of colo-
rectal distention in healthy subjects and IBS patients have
produced somewhat inconsistent findings, due to variations
among the stressors used or potential confounders, such as
distraction. However, a study that controlled for distraction
demonstrated that IBS patients, but not healthy subjects,
rated rectal distension more intense and unpleasant during
dichotomous listening stress compared with relaxation.44
In addition, anxiety and depression levels are associated
with increased pain ratings but not increased rectal
May 2016 Biopsychosocial Aspects of Functional GI Disorders 1359

Figure 3. Gastrointestinal-symptom specific anxiety: when normal becomes threatening. Gastrointestinal symptom-specific
anxiety is an important perpetuating factor of FGID and is characterized by worry and hypervigilance around GI sensations
that can range from normal bodily functions (hunger, satiety, gas) to symptoms related to an existing GI condition (abdominal
pain, diarrhea, urgency). The worry and hypervigilance usually generalize into fear regarding the potential for sensations or
symptoms to occur and/or the contexts in which they may be most likely to present. Gastrointestinal symptom-specific anxiety
can result in avoidance and behaviors out of proportion to symptoms.

sensitivity in IBS.45 Further, several studies have demon-
strated a relationship between psychosocial status on the
one hand, and gastric discomfort thresholds or symptom
reporting in FD on the other.46 In the next section, we will
discuss the emerging evidence from functional brain imag-
ing studies clarifying the mechanisms underlying these
region involved in pain modulation, which is paralleled by
higher pain ratings during anticipation.48
Taken together, these results are consistent with the
model of FGID as disorders of gut brain signaling outlined
here: anxiety-related impairment of the descending modu-
latory system causes defective sensory filtering, dependent

psychological influences on rectal sensitivity in IBS.
Visceral stimulation studies. A recent meta-analysis of
rectal distension studies demonstrated that IBS patients
showed greater brain responses than healthy subjects in
homeostatic afferent brain regions. Further, IBS patients
showed engagement of emotional arousal regions that
lacked consistent activity in healthy subjects and less
involvement of key cortical modulatory regions.47 This
response pattern is consistent with the increased sympa-
thetic arousal, anxiety, and vigilance often associated with
IBS. Similarly, FD patients activate homeostatic afferent
and sensory brain regions at significantly lower intragastric
balloon pressures than healthy controls, with these lower-
intensity levels of gastric stimulation, inducing similar
levels of perception (gastric hypersensitivity). During pain-
ful gastric distension, FD patients did not activate the per-
igenual anterior cingulate cortex, a key region of the
descending modulatory system, and this lack of activation
was correlated with anxiety levels.48
A few studies have also examined the brain response to
anticipation of a visceral stimulus in both healthy subjects
and IBS patients. In IBS patients, the anticipatory response
in the locus coeruleus is predictive of both the subjective
and brain response to subsequent noxious rectal disten-
tion.49 In FD, during anticipated gastric distension, patients
fail to deactivate the amygdala, a key emotional arousal
BIOPSYCHOSOCIAL ASPECTS
on which physiological levels of gastric distension are
perceived as painful.
Brain networks. Compared with healthy subjects, IBS
patients show up-regulated connectivity within the
emotional arousal circuitry, and altered serotonergic
modulation of this circuitry appears to play a role in visceral
hypersensitivity in female IBS patients.50 Additionally, the
importance of descending pain modulatory circuitry has
been demonstrated in IBS patients and healthy controls.51
Structural imaging. IBS is associated with decreased
gray matter density in cortical modulatory prefrontal and
parietal regions, as well as in emotional circuits.52 Control-
ling for anxiety and depression, several of the affective re-
gions no longer differed between IBS patients and controls,
whereas the differences in prefrontal and posterior parietal
cortices remained. These findings are consistent with the
close relationship of IBS to mood disorders. In another
study, pain catastrophizing was negatively correlated with
degree of cortical thickness in the prefrontal cortex.53
Similarly, gray matter density in sensory and homeo-
static afferent regions, as well as cortical pain modulatory
areas is decreased in FD patients compared with healthy
controls, and most of these differences disappear when
controlling for anxiety and depression scores.54
It remains unknown whether these changes are pre-
existing risk factors for disease or whether they are
 BIOPSYCHOSOCIAL ASPECTS
Table 1.Cognitive Affective Processes Influencing the Symptom Experience in Functional Gastrointestinal Disorders
Term Definition
Illness anxiety Global tendency to worry about
current and future bodily
symptoms, formerly referred to as
hypochondriasis
Symptom-specific Worry/hypervigilance around the
anxiety likelihood/presence of specific
symptoms and the contexts in
which they occur
Hypervigilance/ Altered attention toward, and
attentional bias increased engagement with,
symptoms and reminder of
symptoms
Catastrophizing 2-pronged cognitive process in which
an individual magnifies the
seriousness of symptoms and
consequences while
simultaneously viewing
themselves as helpless
NCCP, noncardiac chest pain.
Association with FGID
Low insight
Extensive research into what is wrong
Not easily reassured,
Lack of acceptance
Risk factor for development of FGID
Belief that normal gut sensations are
harmful or will lead to negative
consequences
Promotes GI symptoms
IBS patients showed higher recall of
pain words and GI words
compared with healthy controls
NCCP patients hypervigilant toward
cardiopulmonary sensations
Results in symptom amplification
Increased pain
Inhibits pain inhibition
Negatively affects interpersonal
relationships
Leads to increased worry, suffering,
disability
1360 Van Oudenhove et al
Outcomes Management
Chronicity Responsive to CBT
Social dysfunction, occupational
difficulties,
High health costs,
Negative doctor patient relationship,
Poor treatment response
Drives health care use Aerophagia improved with distraction
Negatively impacts treatment May be differentially responsive to
response interoceptive exposure-based
behavior therapy
Dismiss signs of improvement Responsive to CBT
Ignore information suggesting that
their FGID is not serious
High symptom reporting Improves with CBT
Reduced quality of life Mediates outcome
Can impact patient self-report
Burdens provider
Gastroenterology Vol. 150, No. 6
May 2016 Biopsychosocial Aspects of Functional GI Disorders 1361

Figure 4. Overview of pathways through which psychological processes exert their role in functional gastrointestinal disorders.
The “emotional motor system” consists mainly of subcortical and brain stem areas (amygdala, hypothalamus, and peri-
aqueductal gray matter) that are crucial in relaying descending modulatory output from affective and cognitive cortical cir-
cuitry, as well as regulating autonomic and HPA axis output. CRF, corticotrophin-releasing factor. Figure adapted from Van
Oudenhove and Aziz46 and Naliboff and Rhudy,110 with permission.

secondary changes, and what the underlying biological
substrates are.
Resting state functional imaging. Female IBS subjects
have greater high-frequency power in the insula and low-
frequency power in the sensorimotor cortex than male IBS
subjects during task-free rest. Correlations were observed
between resting-state activity and IBS symptoms.55 It
should be emphasized, however, that these new findings,
although interesting, are preliminary. Specifically, it remains
to be determined whether these findings are specific to IBS,
or a feature of FSS in general, and to what extent these
changes are driven by comorbid psychiatric disorders.
In FD, using 18F-fluorodeoxyglucose positron-emission
tomography, increased activity was found in homeo-
static afferent and sensory regions, but also in the peri-
genual anterior cingulate cortex, a key pain modulatory
area. The activity in the homeostatic afferent regions
correlated with dyspepsia symptom levels.56 Further, FD
patients with comorbid anxiety and depression are charac-
terized by altered activity in homeostatic afferent and
sensory regions, as well as a number of other regions
compared with patients without such comorbidity.57 Using
radioligand positron-emission tomography, higher
cannabinoid-1 receptor availability was found in FD
compared with matched controls, in virtually all of these
regions, indicating that altered endocannabinoid function
BIOPSYCHOSOCIAL ASPECTS
can underlie the differences in resting state brain activity
found in FD.58 Several recent resting-state functional mag-
netic resonance imaging studies in FD demonstrated altered
functional connectivity at rest, including in the “default
mode network”59 (a set of coherent brain processes in
medial prefrontal, temporal, and parietal regions that is
active during self-referential and reflective activity at rest,
without attention being allocated to a particular intero- or
exteroceptive stimulus), pain modulatory networks, as well
as homeostatic afferent circuits. The dysfunctional con-
nectivity patterns correlate with dyspepsia symptom
severity, as well as comorbid anxiety and depression
levels.60
Taken together, these findings indicate that patients with
IBS and FD are not only characterized by abnormal brain
responses to visceral pain stimuli, but also by abnormal
brain activity and connectivity at rest. These abnormalities
seem to be at least partly related to comorbid anxiety and
depression.
White matter tract imaging. IBS patients have white
matter tract alterations in multiple areas, including thal-
amus basal ganglia and sensory/motor association/inte-
gration regions compared with healthy controls.61 Another
study showed that white matter changes in IBS are related
to symptom severity and psychological variables of trait
anxiety and catastrophizing.62 Zhou et al63 demonstrated
 1362 Van Oudenhove et al
abnormalities in a number of white matter tracts in FD
patients vs healthy controls, but again, most of these dif-
ferences were accounted for by comorbid anxiety and
depression.63
Psychosocial influences on gut function through
efferent output of central emotionalLarousal
circuits. Brain gut interfaces: the autonomic nervous
and stress-hormone systems. In addition to their modu-
latory influences on the processing of visceral afferent
input, psychological processes and distress can influence
various aspects of GI function through efferent brain gut
pathways. More specifically, emotional arousal brain
circuits control output of the efferent autonomic
nervous system (ANS) (ortho/parasympathetic
balance) as well as the stress hormone system
(hypothalamo pituitary adrenal [HPA] axis), both of
which can alter GI motor, immune, or barrier function,
which can in turn influence visceral afferent signaling.
The “emotional motor system,” consisting of key
subcortical nodes of the emotional arousal circuit
(hypothalamus, amygdala, and periaqueductal gray)
plays a key role in these processes64 (Figure 4). The
corticotrophin-releasing factor transmitter system, both
centrally (at the level of the dorsal motor nucleus of the
vagus, hypothalamus, and amygdala) and peripherally
(at the level of the GI tract/enteric nervous system), is of
major importance here as it influences autonomic
outflow as well as stimulates the HPA axis resulting in
adrenocorticotropic hormone and cortisol secretion.65
Studies of stress influences on motor, barrier,
and immune functions of the gastrointestinal
tract. Gastric motility. Evidence on the influence of stress
on gastric motility is mixed, although most older studies
BIOPSYCHOSOCIAL ASPECTS
point toward a stress-induced reduction in antral motility
and/or gastric emptying.46 More recent studies demon-
strated impairment of gastric accommodation during exper-
imentally induced anxiety in healthy subjects,66 as well as an
association between both state anxiety and comorbid anxiety
disorders and impaired accommodation in FD.58
Colonic motility. IBS patients show exaggerated motility
responses to physical and psychological stress, as well as
intravenous injection of corticotrophin-releasing factor.67 A
critical role for motility disturbances in producing symp-
toms, especially pain, in a majority of IBS patients has,
however, not been clearly demonstrated, except for stool
frequency and consistency,68 abdominal distension, and
dissatisfaction with bowel movements.69
Colonic mucosal permeability and low-grade mucosal
and systemic inflammation. A subset of IBS patients (not
limited to post-infectious IBS) are characterized by impaired
colonic mucosal integrity and low-grade mucosal and even
systemic inflammation. These alterations, although not
confirmed in all studies, may be related to rectal hyper-
sensitivity and pain symptom levels.70 Animal studies have
demonstrated the influence of stress on colonic perme-
ability, as well as mucosal and systemic inflammation,
mediated by the ANS (eg, the vagal efferent cholinergic anti-
inflammatory pathway) and HPA axis.71 In humans, indirect
evidence comes from studies in IBS linking HPA axis
Gastroenterology Vol. 150, No. 6
hyperactivity (cross-sectionally) to increased systemic
interleukin 6 levels.72 Anxiety and depression levels have
been linked to production of tumor necrosis factor a and
other pro-inflammatory cytokines,73,74 as well as to number
of mast cells in the mucosa.75 In addition, psychological
morbidity or stressful life events at the moment of acute
gastroenteritis predict the development of post-infectious
IBS, although this has not been confirmed in all studies.76
Finally, both public speech stress and intravenous injec-
tion of corticotrophin-releasing factor increase small intes-
tinal permeability through activating the HPA axis (and/or
influencing ANS outflow), in a mast cell-dependent
fashion.77
Autonomic nervous system and hypothalamoL
pituitaryLadrenal axis function in functional
gastrointestinal disorders. Autonomic nervous sys-
tem. There is only limited support for robust differences in
autonomic function measured using cardiovascular (eg,
heart rate variability) or circulating (eg, catecholamine)
indices of sympathetic and parasympathetic function, both
at rest and in response to stress, between patients with
FGID and healthy controls. The evidence suffers from limi-
tations, including small sample sizes not allowing conclu-
sions on subgroups or sex differences, inappropriate control
of confounders, and reliance on non-GI measures. However,
autonomic dysregulation does seem to occur in subgroups
of patients and might influence various processes relevant
to FGID pathophysiology.78–80
Hypothalamic-pituitary-adrenal axis. Similarly, there is
limited evidence for robust alterations in HPA-axis function
in FGID, but there are suggestions that some aspects of HPA
function might be compromised in some IBS subgroups,
especially under stressful conditions.81–85
Microbiome Gut Brain Axis
The microorganisms in the gut (gut microbiota) engage
in bidirectional communication with the brain via neural,
endocrine, and immune pathways with significant conse-
quences for behavioral disorders, including anxiety,
depression, and cognitive disorders, as well as chronic
visceral pain.86 Although much of what is known in this area
is based on animal studies, there is also a small, but growing
number of relevant human studies. For example, in initial
studies, IBS symptoms have been associated with alter-
ations in microbiota composition (although larger studies
allowing to control for more potential confounders are
clearly needed),87 probiotics have shown promise in treat-
ing symptoms in IBS,88 and deficiency in Bifidobacteria has
been associated with greater abdominal pain and bloating in
a healthy population.89 In addition, administration of a
probiotic alters central processing of emotional stimuli, as
well as resting brain connectivity in sensory and affective
brain circuits.90
Based on these findings, the hypothesis of a
microbiome gut brain axis is emerging, with the possi-
bility that modulation of the gut microbiota may be a target
for new therapeutics for stress and pain-related disorders,
including FGID.
May 2016
Psychosocial Assessment
Clinical Assessment
Psychosocial assessment is a critical part of patient care
in FGID. As a general rule, primary care clinicians and gas-
troenterologists should approach psychosocial assessment
from a screening perspective with the goal to identify pa-
tients at risk for refractory symptoms, poor treatment
response or low quality of life. In the absence of frank
psychopathology and moderate to severe symptoms, one
might also assess visceral-specific anxiety, catastrophizing,
somatization, and quality of life to determine whether a
comprehensive evaluation by a health psychologist or psy-
chiatrist would be indicated.
We suggest that clinicians include a brief psychosocial
assessment of each FGID patient, in addition to a full
clinical assessment of the presenting symptoms. This re-
quires a satisfactory patient doctor relationship, estab-
lished during the early part of the consultation, and a few
specific questions about key psychosocial processes inte-
grated into routine history taking. If the patient queries
the relevance of these questions, the clinician can truth-
fully respond, “I always ask my patients these questions as
part of my initial assessment—it helps me determine the
best way to help. The items may or may not apply to you.”
This psychosocial assessment will only be satisfactory if
the patient is able to speak freely, which requires privacy,
a lack of judgment or stigma, and sufficient time. Sensitive
areas of discussion include abuse history, depressed
mood, possible suicidal thoughts, and the nature of close
relationships. Sometime these require a second appoint-
ment directed toward this area of assessment. In addition,
the clinician should provide feedback about the results of
the entire evaluation and to discuss treatment plans,
which can involve both medical and psychosocial treat-
ment strategies.
A more detailed psychosocial assessment, preferably by
a [health] psychologist, [consultation-liaison] psychiatrist,
or specially trained gastroenterologist or other clinician is
particularly useful for severe symptoms, previous treatment
failure, poor adherence to a treatment regimen, and marked
disability. Our recommended assessment and treatment
flowchart is also included as Supplementary Table 1A
(overview) and 1B (detailed steps) and guidelines and flags
for mental health professional involvement are shown in
Supplementary Table 2.
Questionnaires can enhance the information obtained
at the clinical interview, but not replace it. Further,
questionnaires only provide meaningful information if
they are reliable (consistent), valid (measure what they
are supposed to measure), and free of potential
response biases. However, although these psychometric
properties have been established in many populations
for a given questionnaire, they might not have been
tested in specific FGID populations. The clinician should
be acquainted with the results and interpretation of
such questionnaires and a close working relationship
with a mental health professional is helpful in this
respect.
Biopsychosocial Aspects of Functional GI Disorders 1363
Assessment Tools in Adult Patients
An overview of key areas for psychosocial assessment
in adult patients is given in Supplementary Table 3. Addi-
tional standardized self-report questionnaires are listed in
Supplementary Table 4.
Assessment Tools in Children and Their Parents
An overview of key areas for psychosocial assessment in
children and their parents is given in Supplementary
Table 3. Additional standardized self-report questionnaires
are listed in Supplementary Table 4.
Structured Interviews
Details on recommended tools for assessment of the
different psychosocial domains outlined earlier are provided
in the Supplementary Material.
Treatment
Psychological Treatments
Rooted in the biopsychosocial model of FGID and its
biological basis outlined earlier, psychological treatments
hold that biological factors work in concert with psycho-
logical and social variables to influence the expression of
symptoms and their impact on other health outcomes (eg,
quality of life and health care use). As such, psychological
treatments aim to tackle the environmental and psycho-
logical processes that aggravate symptoms. The most
commonly studied psychological treatments for FGID are
CBT, psychodynamic psychotherapy, and hypnosis. A brief
overview is given in Supplementary Table 4.
Cognitive-behavior therapy. CBT refers to a family of
BIOPSYCHOSOCIAL ASPECTS
psychological treatments rather than a specific or uniform
set of techniques. The rationale and techniques of CBT draw
from behavior theories that emphasize learning processes
and cognitive theory that emphasizes faulty cognitions or
thinking processes. These same learning processes can be
used to help patients gain control and reduce symptoms of
FGID.91 Cognitive theory views external events, cognitions,
and behavior as interactive and reciprocally related. As
such, each component is capable of affecting the others, but
the primary emphasis is the way patients process informa-
tion about their environment. Cognitive factors, especially
the way people interpret or think about stressful events, can
intensify the impact of events on responses beyond the
impact of events themselves (Figure 3). To the extent that
thinking processes are faulty, exaggerated, and biased, pa-
tients’ emotional, physiological, and behavioral responses to
life events will be problematic. Clinically, this means that
modifying their thinking styles can change the way patients
behave and feel both emotionally and physically. These
cognitive changes can occur by teaching patients to sys-
tematically identify cognitive errors or faulty logic brought
about by automatic thinking or providing experiential
learning opportunities that systematically exposes patients
to the situations that cause discomfort.
Rather than focusing on the root causes of a problem,
like traditional “talk therapy,” CBT focuses on teaching
 1364 Van Oudenhove et al
people how to control their current difficulties and what is
maintaining them. Further, because CBT is a more directive
therapy, the therapist plays a more active role. CBT re-
quires active participation of the patient both during and
between sessions, as well as responsibility for learning
symptom self-management skills. In addition, CBT is more
problem-focused, goal-directed, and time-limited (3 12
hourly sessions). In the case of FGID, CBT includes a com-
bination of techniques including self-monitoring, cognitive
restructuring, problem solving, exposure, and relaxation
methods.
Self-monitoring. Self-monitoring is the ongoing, real-
time recording of problem behaviors. In CBT for IBS, self-
monitoring focuses on internal and external triggers, as
well as thoughts, somatic sensations, and feelings that
typically accompany flareups. In addition to providing a rich
source of clinically relevant information to structure treat-
ment, self-monitoring comprises a useful therapeutic strat-
egy because it increases awareness of the determinants of a
patient’s problem.
Cognitive strategies. Cognitive strategies are designed
to modify thinking errors that bias information processing.
Examples include a tendency to overestimate risk and the
magnitude of threat, or underestimate one’s own ability to
cope with adversity if it were to occur.40 These self-
defeating beliefs are clinically important because they are
believed to moderate excessive stress experiences. Once
these negative beliefs are identified, the patient works with
the therapist to challenge and dispute them by examining
their accuracy in light of available evidence for and against
them, and replacing these beliefs with those that are more
logical and constructive.
Problem-solving. Problem-solving refers to an ability to
BIOPSYCHOSOCIAL ASPECTS
define problems, identify solutions, and verify their effec-
tiveness once implemented.92 As an intervention, it is rooted
in a problem-solving model of stress93 that emphasizes the
causal relationship between how people problem solve
around stressors and their health. Therapists teach patients
how to effectively apply the steps of problem solving,
including identifying problems, generating multiple alter-
native solutions (“brainstorming”), selecting the best solu-
tion from the alternatives, developing and implementing a
plan, and evaluating the efficacy.
Relaxation procedures. Relaxation procedures have
long been a staple of psychological treatments for FGID94
and are designed to directly modify the biological pro-
cesses (eg, autonomic arousal) that are believed to aggra-
vate GI symptoms.
Progressive muscle relaxation training consists of sys-
tematic tensing and relaxing selected muscle groups of the
whole body; it presumably helps patients dampen physio-
logical arousal and achieve a sense of mastery of physio-
logical self-control over previously uncontrollable and
unpredictable symptoms.95
In breathing retraining, the patient is taught to take slow
deep breaths and attend to relaxing sensations during
exhalation. This relaxation procedure is based on the
assumption96 that patients with stress-related physical ail-
ments develop inefficient respiratory patterns (eg, shallow
Gastroenterology Vol. 150, No. 6
chest breathing) which, if chronic, can intensify physiolog-
ical arousal that aggravates somatic complaints.
Meditation is a self-directed practice that emphasizes
focused breathing, selective attention to a specially chosen
word, set of words, or object, and detachment from thought
processes to achieve a state of calmness, physical relaxation,
and psychological balance. One type of meditation featured
in the FGID literature is mindfulness meditation,97 where an
individual disengages him/herself from ruminative
thoughts, which are regarded as core aspects of pain and
suffering, by developing a nonreactive, objective, present-
focused approach to internal experiences and external
events as they occur.98
Hypnosis. In hypnosis,99 a therapist typically induces a
trance-like state of deep relaxation and/or concentration
using strategically worded verbal cues suggestive of
changes in sensations, perceptions, thoughts, or behavior.
Most hypnotic suggestions are designed to elicit feelings of
improved relaxation, calmness, and well-being. In the
context of IBS, hypnotic suggestions are “gut directed,” that
is, the therapists convey suggestions for imaginative expe-
riences incompatible with aversive visceral sensation. Hyp-
nosis for a patient with IBS might include a suggestion that
the patient feel a sense of warmth and comfort spreading
around the abdominal area.
Exposure. Exposure treatments are designed to
reduce catastrophic beliefs about IBS symptoms, hyper-
vigilance to IBS symptoms, fear of IBS symptoms, and
excessive avoidance of unpleasant visceral sensations or
situations100 by helping patients confront them in a sys-
tematic manner. Exposure can include interoceptive cue
exposure in which the patient repeatedly provokes un-
pleasant sensations, or situational or in vivo exposure in
which feared situations or activities are confronted. The
basic idea behind exposure interventions is that the most
effective way to overcome a fear is by facing it head on so
that the natural conditioning (learning) processes
involved in fear reduction (habituation and extinction) can
occur. Without therapeutic assistance, the individual
withdraws from fear-inducing situations, thereby inad-
vertently reinforcing avoidance. Through exposure treat-
ments, patients learn that the stimuli that are a source of
fear and avoidance are neither dangerous nor intolerable
and that fear will subside without resorting to avoidance,
a behavior that reinforces fear and hypervigilance in the
long-term.101
Efficacy of psychological treatments. Two meta-
analyses102,103 have concluded that psychological therapies,
as a class of treatments, are at least moderately effective for
relieving symptoms of IBS when compared with a pooled
group of control conditions. One measure of clinical efficacy
is the numbers needed to treat, referring to the number of
patients needed to be treated to achieve a specific outcome,
such as a 50% reduction in GI symptoms. Numbers needed
to treat of 2 and 4 were found in both meta-analyses.
Ljótsson and colleagues104 have used the Internet as a
platform for delivering treatment to a larger proportion of
FGID patients than would have had access to clinic-based
treatments.
May 2016
Is the Patient a Good Candidate for
Psychological Treatments?
Characteristics to guide decision making about which
patients are likely to benefit from psychological treatments
are provided in the Supplementary Material.
Pharmacological Treatment. We recognize and have
acknowledged that there is limited evidence from random-
ized controlled trials in gastroenterology for some of the
agents discussed here. However, we have relied on
evidence-based data from other related pain disorders, as
well as on the consensus of experts in this field to provide
their best current recommendations for practice.
Mechanism of action of centrally acting agents in
functional gastrointestinal disorder. There are several
(not mutually exclusive) putative mechanisms of action
explaining the therapeutic effects of antidepressants and
other centrally acting agents in the treatment of FGID in
adults, including effects on gut and/or ANS physiology, and
central analgesic effects, which may or may not be inde-
pendent of anxiolytic and antidepressant effects.
Further details on the mechanisms of action of psycho-
tropic drugs in FGID are also described elsewhere in this issue.
Clinical considerations for the use of psychotro-
pic medications in functional gastrointestinal dis-
orders. Although antidepressants are used extensively,
they are still considered “off label” for their use in FGID. The
accumulated clinical experience, lack of other effective
treatment options, and evidence from other FSS, such as
fibromyalgia, make them viable options for treating pain
and improving quality of life in FGID. In general, they should
be reserved for patients with moderate to severe disease
severity, with significant impairment of quality of life, and
where other first-line treatments have not been sufficiently
effective.
Choice of agent. Choice of agent is determined by the
patient’s predominant symptoms, disease severity, presence
of comorbid anxiety or depression, prior experience with
medications in the same class, and patient and prescriber
preference.
In general, tricyclic antidepressants (TCAs) are the first
choice for pain in nonconstipated IBS patients due to their
dual mechanism of action (serotonin and noradrenalin
reuptake inhibition). Nortriptyline or desipramine is
generally better tolerated than amitriptyline or imipramine
due to less anti-histaminergic and anti-cholinergic effects.
The usual starting dose is 25 50 mg at night and can be
titrated up as needed up to about 150 mg/d, while care-
fully monitoring side effects and/or blood levels, although
typically lower doses than the full antidepressant dose are
effective for visceral pain if no psychiatric comorbidity is
present. Because selective serotonin reuptake inhibitors
are less effective for pain, they are not commonly used as
monotherapy. Rather, selective serotonin reuptake in-
hibitors are a useful augmentation agent in combination
with other drugs, such as serotonin noradrenalin reuptake
inhibitors (SNRIs) or TCAs, or when the patient has a high
level of anxiety that is contributing directly to their clinical
presentation. The selective serotonin reuptake inhibitors
and SNRIs have a more narrow therapeutic range and
Biopsychosocial Aspects of Functional GI Disorders 1365
therefore the doses used for the treatment of pain are
closer to the doses used to treat mood and anxiety disor-
ders.105 Starting doses are usually within the lower range
of the psychiatric dose (eg, citalopram 20 mg or duloxetine
30 mg) and titrated up as needed. For SNRIs, especially
venlafaxine, the analgesic effect usually requires higher
doses (225 mg) because the noradrenergic mechanism of
action only kicks in at these doses. If nausea and weight
loss are of concern, the addition of a low dose (15 30 mg)
of mirtazapine can be helpful. Atypical antipsychotics, such
as quetiapine, are only recommended for patients with
severe, refractory IBS, especially if severe anxiety and
sleep disturbances are also present and patients have
failed to respond to other centrally acting agents. A low
starting dose of 25 50 mg is recommended and can be
titrated up as required.106,107
Augmentation. Augmentation, that is, the use of a
combination of drugs from different classes in submaximal
doses instead of one drug at a maximal dose, is common in
psychiatry and increasingly used in FGID. Examples of
augmentation include adding buspirone to an selective se-
rotonin reuptake inhibitor, TCA, or SNRI to enhance their
therapeutic effect, or adding a low-dose antipsychotic (eg,
quetiapine) to a TCA or SNRI to reduce pain and anxiety and
improve sleep.106 If there is a component of abdominal wall
pain associated with the GI pain, pregabalin or gabapentin
can be added to a TCA or SNRI.106
Adherence. Careful patient selection, initiation at a low
dose with gradual escalation, monitoring for side effects,
and a good patient doctor relationship are important for
medication adherence and, therefore, therapeutic response.
In particular, eliciting and addressing any potential con-
cerns/barriers to taking psychotropic medications for FGID,
BIOPSYCHOSOCIAL ASPECTS
discussing potential side effects, setting realistic expecta-
tions, and involving the patient in decision making result in
improved adherence.107
Centrally acting agents and psychological treat-
ments. Centrally acting agents and psychological treat-
ments are often used together for their complementary and
synergistic effects; such combination is recommended when
the FGID is severe and associated with anxiety or depres-
sion comorbidity.106
Although drugs work faster and are readily available,
psychological treatments have several advantages: they are
safe, effective, their effects persist beyond the duration of
the treatment, and they may be more cost-effective.108
Limitations of using psychological treatments are longer
treatment duration and need for patient motivation, as well
as availability and access to a mental health professional
trained in FGID treatment.
Conclusions
In this article, we provided a comprehensive overview of
recent research to improve understanding of the complex
interactive biopsychosocial processes that constitute the
pathophysiology of FGID. In addition, we outlined the clin-
ical tools and practices health care practitioners can utilize
to improve assessment and treatment of these disorders.
 1366 Van Oudenhove et al
Further research is needed to expand this knowledge base,
which will foster the development of novel, more efficacious
treatments that are more efficiently delivered as well as
better tailored to individual patients.
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. To access the supplementary
material accompanying this article, visit the online version
of Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.027.
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Reprint requests
Address requests for reprints to: Rona L. Levy, MSW, PhD, MPH, Behavioral
Medicine Research Group, University of Washington, Mailstop 354900, 4101
15th Ave NE, Seattle, Washington 98195. e-mail: rlevy@u.washington.edu;
fax: (425) 488-3616.
Acknowledgments
The authors would like to thank Jerry Schoendorf for his help with making and
adapting the figures.
Conflicts of interest
These authors disclose the following: Albena Halpert is on the advisory board
of Allergan; Michael Crowell is a consultant for Medtronic-Covidien and Salix.
The remaining authors disclose no conflicts.
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 Gastroenterology 2016;150:1368–1379

SECTION II: FGIDs: DIAGNOSTIC GROUPS

ESOPHAGEAL

Esophageal Disorders
Qasim Aziz,1 Ronnie Fass,2 C. Prakash Gyawali,3 Hiroto Miwa,4 John E. Pandolfino,5 and
Frank Zerbib6
1
Barts and The London School of Medicine and Dentistry, Wingate Institute of Neurogastroneterology, Centre for Neuroscience
and Trauma, Blizard Institute Queen Mary University of London UK, London, United Kingdom; 2MetroHalth Medical Center, The
Esophageal and Swallowing Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio; 3Division of
Gastroenterology, Washington University School of Medicine, St. Louis, Missouri; 4Division of Upper Gastroenterology,
Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan; 5Division of Medicine-Gastroenterology and
Hepatology, Feinberg School of Medicine Center, Northwestern University, Chicago, Illinois; 6CHU de Bordeaux,
Gastroenterology Department, Université de Bordeaux, Bordeaux, France

Functional esophageal disorders consist of a disease cate-
gory that presents with esophageal symptoms (heartburn,
chest pain, dysphagia, globus) that are not explained by
mechanical obstruction (stricture, tumor, eosinophilic
esophagitis), major motor disorders (achalasia, esoph-
agogastric junction outflow obstruction, absent contrac-
tility, distal esophageal spasm, jackhammer esophagus), or
gastroesophageal reflux disease. Although mechanisms
responsible are unclear, it is theorized that visceral hy-
persensitivity and hypervigilance play an important role in
symptom generation, in the context of normal or border-
line function. Treatments directed at improving borderline
motor dysfunction or reducing reflux burden to subnormal
levels have limited success in symptom improvement. In
contrast, strategies focused on modulating peripheral
triggering and central perception are mechanistically
viable and clinically meaningful. However, outcome data
from these treatment options are limited. Future research
needs to focus on understanding mechanisms underlying
visceral hypersensitivity and hypervigilance so that
appropriate targets and therapies can be developed.
Keywords: Heartburn; Chest Pain; Dysphagia; Globus;
Esophageal Motility Disorders; Gastroesophageal Reflux
Disease; Rome IV.
least 3 months of symptoms with an onset at least 6 months
before diagnosis is applied to each diagnosis to establish
chronicity.
Recent advances in our understanding of esophageal mo-
tor disorders,2 and the appreciation that EoE may be associ-
ated with diverse esophageal symptoms3 (Figure 1) have led
to more specific revisions of exclusionary criteria for func-
tional esophageal disorders. Similar to ROME III, achalasia and
absent contractility remain exclusion criteria.1 However, the
term histopathology-based esophageal motor disorder used in
previous definitions (Rome III) is no longer accurate because
these motor disorders are not diagnosed based on histology,
but instead are defined by motor patterns. Furthermore,
recent descriptions of spastic and hypercontractile motor
phenotypes have expanded the exclusion criteria.4 In contrast,
borderline motor abnormalities, such as ineffective esopha-
geal motility and fragmented peristalsis, are not exclusionary
because these motor patterns can be seen in asymptomatic
controls, and likely generate symptoms in the context of a
secondary process, such as gastroesophageal reflux disease
(GERD), visceral hypersensitivity, and hypervigilance.2
The current ROME IV criteria place a strong emphasis on
ruling out mechanical obstruction as a mechanism of
symptom generation. For instance, evidence of EGJ outflow
obstruction would rule out a functional diagnosis because
this can represent achalasia in evolution or a subtle me-
chanical obstruction. Further evaluation targeting structural

F unctional esophageal disorders present with typical

esophageal symptoms that are not associated with
structural, inflammatory, or a major motor abnormality1
(Table 1). Thus, these patients typically present in the
context of a normal endoscopy, and no evidence of me-
chanical obstruction or biopsy-confirmed eosinophilic
esophagitis (EoE). In addition, there is no evidence of a
major motor disorder (achalasia, esophagogastric junction
[EGJ] outflow obstruction, absent contractility, distal
esophageal spasm, jackhammer esophagus) and no patho-
logic esophageal acid exposure. The pathophysiology of
these disorders focuses on alterations in neural processing
between peripheral triggering and central perception of
esophageal symptoms. These disorders do not progress
along a tangible organic natural history, and, accordingly, a
chronicity exists that reflects the underlying pathogenesis
and disease burden. Thus, an arbitrary requirement of at
EGJ processes (eg, endoscopic ultrasound, contrast radiog-
raphy) should be considered once an EGJ outflow obstruc-
tion pattern is recognized.2 Similarly, evidence of EoE on
endoscopy or on mucosal biopsy also excludes a functional
diagnosis because esophageal symptoms (heartburn, chest
pain, dysphagia) can be related to the underlying inflam-
mation and mechanical effects on the esophageal wall.3
Abbreviations used in this paper: EGJ, esophagogastric junction; EoE,
eosinophilic esophagitis; GERD, gastroesophageal reflux disease; NCCP,
noncardiac chest pain; NERD, nonerosive reflux disease; PPI, proton
pump inhibitor; SSRI, serotonin reuptake inhibitor; TCA, tricyclic
antidepressant.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.012
May 2016 Functional Esophageal Disorders 1369

Table 1.Functional Esophageal Disorders perception in the context of heartburn and chest pain
(Figure 2).

Functional chest pain
Functional heartburn
Reflux hypersensitivity
Globus
Functional dysphagia
Another major change in the ROME IV classification is
the more restrictive definition of GERD, accepting that
sensitivity to a physiologic reflux burden may sit more
firmly within the functional realm than true GERD, albeit
within a spectrum allowing for overlap with GERD
(Figure 2). The previous exclusion of patients with symp-
tom–reflux correlation (based on response to proton pump
inhibitor [PPI] therapy and symptom–reflux association
with physiologic esophageal acid exposure) from func-
tional esophageal disorders places undue emphasis on the
strength of the PPI trial, and negates the underlying
pathogenesis of visceral sensitivity in the reflux-
hypersensitive esophagus. Thus, response to PPI as a cri-
terion for defining GERD has been tempered by the high
placebo response, low specificity, and limited predictive
value.5 Although patients with symptom–reflux correlation
to physiologic reflux events may respond to PPI therapy,
the most logical pathophysiologic explanation is consistent
with the current understanding of visceral hypersensitivity
and mechanisms of peripheral or central sensitization;
thus, these should be included within the functional
paradigm. However, care should be exercised in inter-
preting these designations because heavy emphasis is
placed on the accuracy of ambulatory reflux monitoring,
which can be falsely negative and subject to day-to-day
variation in reflux burden.6 The role of weakly acidic
reflux events (reflux events with pH values between 4 and
7) in generating symptoms and end-organ damage remains
controversial; one could argue that this, too, would be
more consistent with hypersensitivity and abnormal
ESOPHAGEAL
A1. Functional Chest Pain
Definition
Functional chest pain is defined as recurring, unex-
plained, retrosternal chest pain of presumed esophageal
origin, not explained on the basis of reflux disease, other
mucosal or motor processes, and representing pain different
from heartburn. Functional chest pain is a subset within the
broad umbrella of noncardiac chest pain (NCCP). History
and physical examination do not reliably segregate esoph-
ageal from cardiac chest pain, stressing the need for an
initial cardiac evaluation in appropriate clinical settings.
Epidemiology
The prevalence of functional chest pain is unknown and
is based largely on inferential data from studies assessing
NCCP. Population-based surveys assess the prevalence of
NCCP at 19%–33%.7,8 However, this includes chest pain
from other esophageal processes including GERD, EoE, and
esophageal motor disorders, and therefore likely over-
estimates the prevalence of true functional chest pain. For
instance, Fass et al9 estimated that within NCCP cohorts,
50%–60% have GERD, 15%–18% have esophageal dysmo-
tility, and approximately 32%–35% have true functional
chest pain. Within these limitations, the prevalence appears
to be gender-equal, higher in patients younger than 45–55
years of age and lower in less-developed countries.
Clinical Evaluation
Initial exclusion of cardiac disease is a key step, and
esophageal work-up should proceed only after confirmation
(typically from the patient’s cardiologist or primary care
physician) that symptoms are unrelated to concurrent cor-
onary artery disease. After exclusion of a cardiac cause,
further work-up is guided by the prevalence of the under-
lying causes of NCCP, and potential clues from clinical

Table 2.Pain Modulators for the Treatment of Functional Esophageal Disorders

Class of drug Dose Disorder RCT Side effects Response

TCAs
Imipramine 50 mg/day NCCP þ þ/- 57%
Amitriptyline 10–20 mg/day NCCP, globus þ þ/- 52%
SSRIs
Sertraline 50–200 mg/day NCCP þ þ 57%
Paroxetine 50–75 mg/day NCCP þ þ/- Modest
Citalopram 20 mg/day ES þ þ/- Significant
Trazodone
Vs clomipramine 50/25 mg/day NCCP - þ Modest
Trazodone alone 100–150 mg/day dysmotility þ þ/- 29%–41%
SNRIs
Venlafaxine 75 mg/day NCCP þ þþ 52%
Other
Theophylline 200 mg twice/day NCCP þ þ/- 58%
Gabapentin 300 mg 3 times/day globus þ þ/- 66%

ES, esophageal hypersensitivity; RCT, randomized control trial; SNRI, serotonin norepinephrine reuptake inhibitor.
 1370 Aziz et al Gastroenterology Vol. 150, No. 6
ESOPHAGEAL

Figure 1. The role of the

brain–gut axis in mediating
esophageal symptoms.
Gut luminal and mucosal
injury can sensitize
visceral afferents causing
allodynia or hyperalgesia.
Psychological and cogni-
tive factors such as
hypervigilance partici-
pate in heightened pain
perception. Both centrally
and peripherally directed
treatments can be helpful
in management.

evaluation that may support one of these causes. Given the
high prevalence of GERD within NCCP, a short course of
high-dose PPI therapy is simple and cost effective in
determining whether GERD may be triggering chest pain.10
The role of upper endoscopy is unclear based on limited
data available, but this has exclusionary value. Therefore,
endoscopy is performed using indications similar to tradi-
tional GERD with the caveat that mucosal biopsies are
considered to rule out EoE. Patients not responding to the
PPI trial may be referred for ambulatory reflux testing if
clinical suspicion for GERD remains high; in this context, this
test should be performed off acid suppression.11 There are
insufficient data assessing the superiority of one reflux
monitoring method over the others; therefore, either pH
monitoring, combined pH–impedance monitoring, or
extended pH monitoring beyond 24 hours can be used,
reflecting availability and expertise of the center. Most pa-
tients with NCCP have normal motor function; esophageal
manometry should be considered once GERD has
been comfortably ruled out because the diagnosis of major
motor disorders represents another important exclusion
criteria.
Diagnostic criteria for functional chest pain. Criteria
must be fulfilled for the past 3 months with symptom onset
at least 6 months before diagnosis with a frequency of at
least once a week. The criteria must include all of the
following.
1. Retrosternal chest pain or discomfort; cardiac causes
should be ruled out.
2. Absence of associated esophageal symptoms, such as
heartburn and dysphagia.

Figure 2. The interplay between esophageal hypersensitivity and acid exposure in the reflux symptom spectrum. Symptoms in
erosive esophagitis are dominated by abnormal acid exposure whereas symptoms in functional heartburn are dominated by
hypersensitivity. Symptoms in NERD and reflux hypersensitivity are related to a combination of both acid exposure and hy-
persensitivity, with a shift reflecting a more pronounced effect of acid exposure along the NERD diagnostic spectrum and a
more pronounced effect of esophageal hypersensitivity along the reflux hypersensitivity diagnostic spectrum.
May 2016
3. Absence of evidence that gastroesophageal reflux or
eosinophilic esophagitis are the cause of the
symptom.
4. Absence of major esophageal motor disorders (acha-
lasia/EGJ outflow obstruction, diffuse esophageal
spasm, jackhammer esophagus, absent peristalsis).
Justification for Criteria Change
The criteria have been revised to ensure that the defi-
nition is consistent with the clinical description of NCCP.
Overt GERD and EoE overlaps are addressed with the
requirement that concurrent heartburn and dysphagia are
not present. The current recognition that EoE can present
with chest pain, and the new categorization of spastic and
hypercontractile disorders within the Chicago Classification,
warrant a more detailed description of exclusion criteria.
Physiological Features
The major physiologic mechanisms that underlie func-
tional chest pain focus on hypersensitivity from peripheral
and/or central sensitization, altered central processing of
visceral stimuli, and altered autonomic activity. Studies
consistently have shown altered pain perception and
heightened visceral sensitivity in functional chest pain.12
Esophageal tissue injury, inflammation, or repetitive me-
chanical stimuli all can sensitize peripheral afferent nerves,
and esophageal hypersensitivity can be shown long after the
original stimulus has resolved. However, it remains unclear
as to what factors determine persistence of such hyper-
sensitivity. In addition, a role for enhanced central pro-
cessing of visceral sensory input also has been suggested,
based on studies using cerebral evoked potentials, which
show unique latency patterns in NCCP patients.13 These
mechanisms are neither completely understood nor
consistently reported, and it is possible that variations in
mechanisms may exist within the functional chest pain
spectrum. Autonomic dysregulation could reflect another
subcategory within functional chest pain. The understand-
ing of the role of motor abnormalities remains incomplete
despite the association of spasm, hypercontractile disorders,
and achalasia with chest pain. However, there is little evi-
dence to support a causal relationship between minor motor
abnormalities and chest pain. Recent evidence suggests that
sustained longitudinal muscle contraction can be associated
with chest pain,14 and hypotheses regarding pathogenesis
focus on an ischemic model; however, further research
is needed to prove that this is causal and not an
epiphenomenon.
Psychological Features
Psychiatric diagnoses, particularly anxiety disorders,
depression, and somatization disorder, have been shown in
up to 75% of NCCP patients.15 Chest pain is an important
component of panic attacks; furthermore, there are higher
levels of neuroticism in patients with NCCP. These associa-
tions are important because NCCP patients with psycho-
logical comorbidity show diminished quality of life, more
Functional Esophageal Disorders 1371
frequent chest pain, and refractoriness to treatment when
compared with patients without psychological comorbid-
ESOPHAGEAL
ity.16 Regardless of cause or effect, treatment of underlying
psychological issues is paramount to successful therapy.
Treatment
The treatment of functional chest pain has focused pre-
dominantly on medications that target neuromodulation of
pain (Table 2).17 However, benefits of complementary
behavioral treatments, such as cognitive behavioral therapy
and hypnosis, increasingly are recognized, and these
modalities are being used often as acceptance of these
approaches in gastroenterology widens.18
Antidepressants modulate both peripheral and central
hyperalgesia independent of mood, and these agents should
be considered as first-line medical treatment. Different
categories of antidepressants have been used, including
tricyclic antidepressants (TCAs), serotonin reuptake in-
hibitors (SSRIs), serotonin noradrenergic reuptake in-
hibitors, and trazodone; effectiveness can be as high as 50%
greater than placebo in randomized trials (Table 1).17
However, their side-effect profile and social stigma limit
their utilization, prompting study of alternate agents, such
as gabapentin, pregabalin, and theophylline. In all instances,
clinical use of these neuromodulators should be weighed
against potential side effects.
Behavioral therapies are an important alternative and
sometimes complementary approach to neuromodulators
because these therapies can offer symptom improvement
with minimal side effects.18 Psychological intervention, us-
ing cognitive behavioral therapy, coping skills, and hypnosis,
has been shown to be effective and durable in both patients
with and without psychological comorbidity.
A2. Functional Heartburn
Definition
Functional heartburn is defined as retrosternal burning
discomfort or pain refractory to optimal antisecretory
therapy in the absence of GERD, histopathologic mucosal
abnormalities, major motor disorders, or structural expla-
nations. The definition of functional heartburn has evolved
over the years. The so-called acid sensitive esophagus
initially included in the functional heartburn group in ROME
II, was revised further by ROME III as a part of the non-
erosive reflux disease (NERD) spectrum.1 However, the
acid-sensitive esophagus in ROME IV has been defined as a
stand-alone functional esophageal diagnosis. The current
diagnosis of functional heartburn remains focused on a lack
of conclusive evidence for GERD, no evidence of a symptom
reflux correlation, and a negative response to acid-
suppressive therapy because this should alert the physi-
cian to the potential of a functional disorder.
Epidemiology
The incidence and prevalence are difficult to define
because this diagnosis is linked inherently to ambulatory
reflux testing and response to PPI, both of which are limited
 1372 Aziz et al
in their discriminative ability to define GERD. As many as
70% of patients with heartburn who undergo endoscopic
ESOPHAGEAL
evaluation will have a normal endoscopy19; these patients
are defined further into categories based on the presence or
absence of abnormal acid exposure and symptom-reflux
association. The breakdown of these groups is influenced
further by response to PPI therapy. Functional heartburn is
found in approximately 50% of PPI nonresponders and in
25% of PPI responders.5,6,11 This variation in PPI response
could be explained by day-to-day variation in reflux burden
influencing diagnostic designations.
The long-term natural history of functional heartburn is
incompletely known. As many as two thirds of patients with
functional heartburn remain symptomatic over 2 years of
follow-up evaluation, and symptom intensity and frequency
decrease in approximately 20%.20 This limited evidence
suggests that the diagnosis of functional heartburn is du-
rable over follow-up evaluation in the majority of patients.
Clinical Evaluation
The diagnosis of functional heartburn is made after a
careful history identifies the dominant symptom as burning
retrosternal discomfort, and stepwise evaluation supports
the absence of GERD, EoE, and a major esophageal motor
disorder. Most patients are identified when heartburn fails to
respond to optimal antisecretory therapy, and, thus, this is a
crucial component of our current diagnostic criteria. Endos-
copy typically is used in PPI nonresponders as the initial test
to evaluate for macroscopic evidence of reflux, esophagitis,
long-segment Barrett’s esophagus, or an alternative diag-
nosis, such as EoE or a nonpeptic inflammatory process.
The next step in the evaluation determines whether
pathologic gastroesophageal reflux is present using ambu-
latory reflux testing, but data are insufficient to recommend
the optimal technique. However, patients with unproven
GERD (ie, no prior documented evidence of reflux-related
pathology on endoscopy or ambulatory reflux monitoring)
will have the best yield if they are studied off antisecretory
therapy.11,21 The use of pH-impedance in this setting may
increase the yield of defining a positive symptom reflux
correlation, while extended pH monitoring will identify
patients with day-to-day variation in reflux burden.6,11 Pa-
tients are categorized with NERD if esophageal acid expo-
sure is increased, with reflux hypersensitivity if acid
exposure is normal but a positive association with acid and/
or weakly acidic reflux is present, and with functional
heartburn if none of these conditions is present (Figure 3).
Patients not responding to PPI in the context of proven
GERD (based on endoscopy and ambulatory reflux testing)
represent an interesting subgroup with several possible
pathophysiologic scenarios: truly refractory reflux (if acid
exposure is abnormal during pH impedance testing on PPI),
overlap between functional heartburn and GERD (if acid
exposure is normal with no symptom reflux association on
pH-impedance testing on PPI), or overlap between reflux
hypersensitivity and GERD (if acid exposure is normal with
positive symptom reflux association on pH impedance
testing on PPI). Definition of these phenotypes could be
Gastroenterology Vol. 150, No. 6
important, and functional overlap situations may prompt
therapeutic approaches different from true refractory GERD.
Diagnostic criteria for functional heart-
burn. Criteria must be fulfilled for the past 3 months with
symptom onset at least 6 months before diagnosis with a
frequency of at least twice a week. Must include all of the
following.
1. Burning retrosternal discomfort or pain.
2. No symptom relief despite optimal antisecretory
therapy.
3. Absence of evidence that gastroesophageal reflux
(abnormal acid exposure and symptom reflux asso-
ciation) or EoE is the cause of symptoms.
4. Absence of major esophageal motor disorders (acha-
lasia/EGJ outflow obstruction, diffuse esophageal
spasm, jackhammer esophagus, absent peristalsis).
Justification for Criteria Change
The most significant points discussed in ROME IV are the
definition and implication of PPI refractoriness, the inclu-
sion of findings on pH-impedance monitoring in some of the
designations, the implications of reflux testing on and off
PPI therapy, and the exclusion of EoE before a functional
diagnosis.
Ambulatory reflux monitoring can be associated with
variable sensitivity of acid burden assessments when
borderline, particularly with day-to-day variation in acid
exposure, which can shift functional heartburn diagnoses to
NERD.6 Symptom–reflux association analyses, integral to the
definition of functional heartburn and reflux hypersensitivity,
have their own pitfalls, and represent the weakest link
because they rely on patients promptly reporting symptoms
when they occur.22 Taking these limitations into account, lack
of response to PPI therapy should be considered as an
important diagnostic criterion to establish that symptoms are
not related to gastroesophageal reflux. Clinical experience
suggests that lack of response to PPI probably has a high
negative predictive value for the diagnosis of GERD.5
Whether incomplete (partial) response to PPI therapy
should be differentiated from complete absence of response
remains to be determined. Although not accepted universally,
physicians often increase PPI dosing, but only 20%–30% will
achieve adequate symptom control after 6–8 weeks of
double-dose therapy.23 Finally, mild heartburn occurring 2 or
more days/week negatively impacts quality of life in GERD,
and the same threshold could be applied in functional
heartburn. Therefore, functional heartburn should be
considered in patients who continue to report troublesome
symptoms at least 2 times a week for the previous 3 months
despite double-dose PPI taken appropriately before meals.
Esophageal biopsies are important in the definition of
functional heartburn, regardless of the gross appearance of
the esophageal mucosa, to rule out EoE despite its relatively
low prevalence (0.9%–4%) in this clinical setting.3 Although
the importance of mucosal integrity and histologic corre-
lates cannot be denied, additional data are needed before
May 2016 Functional Esophageal Disorders 1373

ESOPHAGEAL
Figure 3. Further classification of patients with heartburn and no evidence of esophagitis at endoscopy using ambulatory pH
monitoring and response to a therapeutic trial of PPIs. The subset of patients with functional heartburn had no findings that
would support a presumptive diagnosis of endoscopy-negative reflux disease. The precise thresholds for separation of
subjects at each step remain uncertain. The figure shows classification categories by findings and is not meant to suggest a
diagnostic management algorithm for use in clinical practice.

these histopathologic parameters can be included in the
definition of functional heartburn.
Physiological Features
The mechanism of symptom generation in functional
heartburn is unclear, with the prevailing view focused on
altered esophageal perception as a major factor.24 The
trigger for provoking heartburn rules out reflux in the
current definition and thus, hypotheses revolving around
impaired mucosal integrity and increased permeability must
be resolved with a lack of reflux correlation that is now
inherent in the definition. This has led to a focus on
increased sensitization of acid chemoreceptors; it is possible
that increased permeability may allow noxious sensitizing
luminal substances access to the deeper layers of the
esophagus where they may induce various inflammatory
cytokines without a temporally associated reflux trigger.25
In addition, a role for abnormal central processing of
esophageal signals also could support symptom generation
without a reflux event trigger.
Psychological Features
Psychological factors likely have a similar permissive
role in functional heartburn as in other functional disorders;
however, studies specifically focusing on functional heart-
burn are scarce. Several models of acute experimental stress
(eg, auditory stress or sleep deprivation) indicate that stress
enhances perception of esophageal acid in GERD patients. In
addition, patients with functional heartburn show greater
anxiety and somatization scores, and poor social support
compared with patients with reflux-associated symptoms,26
further supporting co-existing psychological factors within
functional heartburn.
Treatment
Therapies for functional heartburn remain largely
empiric and may be tailored to the proposed pathophysi-
ology of the condition, presumed mechanism of action of
medications, and underlying psychosocial issues. The clini-
cian should provide reassurance and avoid repetitive inva-
sive testing. In addition, an escalation of antireflux therapy,
particularly to antireflux surgery, should be avoided
because a lack of symptom response to PPI and normal acid
burden are predictors of poor outcome.
Given that abnormal peripheral sensitization and central
processing are considered relevant in the pathogenesis of
functional heartburn, it is reasonable to consider esophageal
pain modulators, such as low-dose TCAs and SSRIs similar
to that described in Table 1 (functional chest pain).17 One
 1374 Aziz et al
small pilot study supported the role of hypnosis in a subset
of patients.27 Psychological approaches such as behavioral
ESOPHAGEAL
modification, acupuncture, or relaxation therapy may be
beneficial, despite the paucity of literature for use in func-
tional heartburn.
A3. Reflux Hypersensitivity
Definition
Reflux hypersensitivity identifies patients with esopha-
geal symptoms (heartburn or chest pain) who lack evidence
of reflux on endoscopy or abnormal acid burden on reflux
monitoring, but show triggering of symptoms by physiologic
reflux. Some patients fulfilling criteria potentially could
respond to antireflux measures, however, the underlying
pathogenesis is more consistent with esophageal hyper-
sensitivity from a functional basis. Furthermore, overlap
could exist between true GERD and reflux hypersensitivity,
manifest as physiologic acid burden when monitored on PPI
therapy, but as symptom reflux correlation between iden-
tified reflux events and symptom episodes.
Epidemiology
The epidemiology and prevalence rates of reflux hyper-
sensitivity are not known, but inferences can be made from
the NERD population. It is estimated that 37%–60% of
NERD patients have normal ambulatory pH monitoring
studies off medication,28 and that less than 10% of patients
undergoing ambulatory pH monitoring show acid sensi-
tivity.29 In a study of 329 NERD patients, 36% showed
symptom–reflux correlation in the absence of abnormal
reflux parameters (reflux hypersensitivity), whereas 40%
had abnormal acid exposure (true NERD) and 24% had
normal pH–impedance monitoring (functional heartburn).30
An increased number of weakly acidic reflux events and a
higher rate of proximal reflux discriminated reflux hyper-
sensitivity from functional heartburn, with lesser degrees of
overlap between reflux hypersensitivity and healthy vol-
unteers, compared with high overlap between functional
heartburn and healthy volunteers.30
Clinical Evaluation
The clinical presentation of patients with reflux hyper-
sensitivity is indistinguishable from those with functional
heartburn and NERD. As with functional chest pain and
functional heartburn, evaluation starts with an empiric PPI
trial, the performance characteristics of which are described
in detail under the previous section on functional chest
pain.10 Some level of refractoriness to PPIs represents the
starting point for consideration of both functional heartburn
and reflux hypersensitivity23 and endoscopy is performed to
rule out esophagitis, Barrett’s esophagus, and EoE.3,31
The diagnosis of reflux hypersensitivity hinges on iden-
tifying sensitivity to acid-reflux events on reflux testing
(Figure 2).32 To make a diagnosis of reflux hypersensitivity,
acid parameters need to be within the physiologic range,
whether tested on or off PPI therapy. It generally is accepted
that acid exposure time thresholds of approximately
Gastroenterology Vol. 150, No. 6
3.9%–4.2% have discriminative value in assigning a GERD
etiology to symptoms when catheter-based pH studies are
performed off antisecretory therapy33; thresholds used are
slightly higher, approximately 5.3%, when wireless pH
testing is used. The distinction of reflux hypersensitivity from
functional heartburn lies in the presence of significant
symptom–reflux association in the former. Although contro-
versy exists as to the true clinical value of symptom–reflux
association,22 the identification of reflux events triggering
symptoms in the setting of physiologic reflux parameters is
key to the diagnosis of reflux hypersensitivity.29
As with other functional esophageal disorders, major
motor disorders (achalasia/EGJ outflow obstruction, diffuse
esophageal spasm, aperistalsis, and jackhammer esophagus)
need to be excluded.2
Diagnostic criteria for reflux hyper-
sensitivity. Criteria must be fulfilled for the past 3 months
with symptom onset at least 6 months before diagnosis with
a frequency of at least twice a week. Must include all of the
following.
1. Retrosternal symptoms including heartburn and chest
pain.
2. Normal endoscopy and absence of evidence that EoE
is the cause for symptoms.
3. Absence of major esophageal motor disorders (acha-
lasia/EGJ outflow obstruction, diffuse esophageal
spasm, jackhammer esophagus, absent peristalsis).
4. Evidence of triggering of symptoms by reflux events
despite normal acid exposure on pH or
pH–impedance monitoring (response to antisecretory
therapy does not exclude the diagnosis).
Justification for Change in Criteria
The ROME III classification of esophageal functional
disorders generated controversy by expanding the defini-
tion of NERD to include patients with normal esophageal
acid exposure but positive symptom association (acid-hy-
persensitive group).1 Because mechanisms of symptom
generation in the acid-sensitive esophagus focus on
enhanced sensitivity, and patients clinically behave akin to
functional heartburn in terms of PPI response, the reflux
hypersensitivity category was introduced to highlight this
specific subgroup. Patients with acid hypersensitivity
respond suboptimally to PPIs; similarly, the expected
response in patients with weakly acidic and non–acid reflux
also is poor. However, there is variability within this sub-
group; patients with sensitivity to acid-reflux events but
responding to PPIs may represent overlap with NERD,
wherein abnormal reflux burden fluctuates day-to-day.6
Further justification for separating patients with symp-
toms triggered by physiological acid and non–acid reflux
events from functional heartburn is that the former cohort
shows a greater likelihood of esophageal mucosal changes
(including dilated intercellular spaces, basal cell thickness,
and papillary elongation) compared with the functional
heartburn cohort.34
May 2016
Pathophysiology
Pathophysiologic mechanisms underlying reflux hyper-
sensitivity are believed to be similar to those underlying
functional chest pain and functional heartburn with the
caveat that symptoms are triggered by reflux events on
ambulatory reflux monitoring. The same mechanisms
driving symptom perception, including peripheral and/or
central sensitization, altered central processing of visceral
stimuli, altered autonomic activity, and psychological ab-
normalities, are hypothesized to drive reflux hypersensi-
tivity, the only difference is that the actual reflux trigger,
chemical or mechanical, is identified on reflux monitoring.
There also is evidence of up-regulation of acid-sensitive
receptors (eg, TRPV1 receptor) in response to acid expo-
sure, and neurogenic inflammation is suggested by an in-
crease in both substance P release and its receptor,
neurokinin 1–receptor expression.35
Psychological Features
In the setting of psychological stress, centrally mediated
processes can alter autonomic nervous system activity and
modulate spinal transmission of nociceptive signals, while
peripherally, permeability of gut mucosa can be altered by
mast cell degranulation.36 These mechanisms support the
concept of exaggerated perception of physiologic stimuli,
such as reflux events, in settings of psychological stress.
Therefore, psychological features are an important compo-
nent of reflux hypersensitivity, similar to other functional
esophageal disorders.
Treatment
Similar to management of functional heartburn, reas-
surance is provided, and patients are counseled that no
ominous diagnosis exists. Treatment remains empiric, but
response to antisecretory therapy may be better than in
other functional esophageal disorders. For instance, some
patients with acid-sensitive esophagus may respond to
standard or double-dose PPIs.37 However, patients with
weakly acid– and non–acid reflux–triggered symptoms
generally are refractory to PPIs.38 There is very limited evidence
suggesting that acid- or weakly acid reflux–triggered
symptoms refractory to PPI can respond to antireflux
procedures.39 Further large-scale controlled clinical trials
are necessary to confirm these preliminary findings before
this approach can be recommended uniformly.
The mainstay of treatment of esophageal hypersensitiv-
ity is with pain modulators including TCAs, SSRIs, serotonin
noradrenergic reuptake inhibitors, and gabapentenoids, as
described in Table 1. However, therapeutic trials with these
agents remain empiric because clinical trials specifically
showing efficacy of these treatments in functional reflux
sensitivity are scarce.40
A4. Globus
Definition
Globus sensation is a persistent or intermittent non-
painful sensation of a lump or foreign body in the throat.1
Functional Esophageal Disorders 1375
The symptom is nonpainful, commonly episodic, located in
the midline between the thyroid cartilage and sternal notch,
ESOPHAGEAL
unassociated with dysphagia or odynophagia, and
frequently improves with eating and swallowing. The diag-
nosis of globus requires the absence of structural lesions,
mucosal abnormalities such as a gastric inlet patch, GERD,
or major motor disorders.
Epidemiology
Globus sensation is a common symptom and is re-
ported by up to 46% of apparently healthy individuals.41
However, similar to other functional disorders that
require a systematic exclusion of identifiable causes, the
actual prevalence is unknown. The symptom has a peak
onset in middle age and is prevalent equally in both sexes,
but women are more likely to seek health care for this
complaint. The condition is durable, and symptoms typi-
cally persist for more than 3 years in 75% of patients,
although as many as 50% have persistent symptoms after
7 years.42
Clinical Evaluation
The diagnosis is made primarily by eliciting a compatible
clinical history and ruling out an identifiable cause, such as a
structural lesion, GERD, or a major motor disorder, as with
other functional esophageal disorders; there must be no
dysphagia and no alarm features (eg, sore throat, odyno-
phagia, weight loss). Physical examination of the neck fol-
lowed by laryngoscopic examination of the pharynx are
advised as the initial evaluation. Once localized structural or
inflammatory causes are excluded, the work-up may pro-
ceed with an empiric trial of PPI therapy for 4–8 weeks. If
the patient responds, the management shifts to GERD. If the
patient does not respond, endoscopy to assess for a gastric
inlet patch or other mucosal processes can be considered to
identify an alternative cause. Manometry may be helpful to
rule out a major motor disorder, however, there are limited
data to support a distinct motor pattern associated with
globus. Patients not responding to PPI and without an
identifiable cause in the oropharynx and esophagus are
diagnosed with globus.
Diagnostic criteria for globus. Criteria must be ful-
filled for the past 3 months with symptom onset at least 6
months before diagnosis with a frequency of at least once a
week. Must include all of the following.
1. Persistent or intermittent, nonpainful, sensation of a
lump or foreign body in the throat with no structural
lesion identified on physical examination, laryngos-
copy, or endoscopy.
a. Occurrence of the sensation between meals.
b. Absence of dysphagia or odynophagia.
c. Absence of a gastric inlet patch in the proximal
esophagus.
2. Absence of evidence that gastroesophageal reflux or
EoE is the cause of the symptom.
 1376 Aziz et al
3. Absence of major esophageal motor disorders (acha-
lasia/EGJ outflow obstruction, diffuse esophageal
ESOPHAGEAL
spasm, jackhammer esophagus, absent peristalsis).
Justification for Criteria Change
The diagnostic criteria have been modified relative to the
recent insights into the gastric inlet patch in globus symp-
tom generation, and a concerted effort to support endo-
scopic evaluation of the oropharynx. Similar to other
functional disorders, separating out major motor disorders
not encountered in health from the borderline motor dis-
orders found in asymptomatic controls also was included in
the definition of globus.
Physiological Features
Globus sensation may be a function of the perception of
a space occupying lesion, a manifestation of GERD, associ-
ated with a gastric inlet patch and potentially related to a
major motor disorder. When no identifiable cause is found,
globus likely is related mechanistically to the same patho-
physiologic processes associated with abnormal visceral
hypersensitivity and central processing of peripheral stimuli
seen with other functional esophageal disorders.
Consistent evidence is lacking to attribute globus to any
specific anatomic abnormality, including the cricophar-
yngeal bar. Upper esophageal sphincter mechanics do not
seem relevant, and the pharyngeal swallow mechanism is
normal. Esophageal balloon distention can reproduce globus
sensation at low distending thresholds, suggesting some
degree of esophageal hypersensitivity.43 Globus is report-
edly more common in conjunction with reflux symptoms,
although a strong relationship between GERD and globus
has not been established.44 However, the symptom does not
respond well to antireflux therapy. Although gastroesopha-
geal reflux and distal esophageal motor disorders can
include globus in their presentations, these mechanisms are
thought to play a minimal role in the pathophysiology of
globus.
Psychological Features
Psychiatric diagnoses are prevalent in globus patients
seeking health care, but an explanation distinct from ascer-
tainment bias has not been established, and no specific psy-
chological characteristic has been identified in globus
subjects. Increased reporting of stressful life events preceding
symptom onset has been observed in several studies, sug-
gesting that life stress might be a cofactor in symptom genesis
or exacerbation.45 Up to 96% of sufferers report symptom
exacerbation during periods of high emotional intensity.
Treatment
Given the benign nature of the condition, the likelihood of
long-term symptom persistence, and absence of highly
effective pharmacotherapy, the mainstay of treatment rests
with explanation and reassurance. Expectations for prompt
symptom resolution are low because symptoms persist in up
to 75% of patients at 3 years.42 Controlled trials of
Gastroenterology Vol. 150, No. 6
antidepressants and behavioral therapy for globus are un-
available, but there is anecdotal evidence for their utility.46,47
A5. Functional Dysphagia
Definition
Functional dysphagia is defined as a sensation of
abnormal bolus transit through the esophageal body in the
absence of structural, mucosal, or motor abnormalities to
explain the symptom. The diagnosis of functional dysphagia
requires thorough exclusion of oropharyngeal mechanisms
of dysphagia, structural lesions in the tubular esophagus,
GERD, EoE, and major motor disorders.
Epidemiology
The true prevalence of functional dysphagia is unknown.
A population survey of functional disorders estimated that
7%–8% of dysphagia was unaccounted for by exclusionary
criteria,48 and a validation study of Rome II criteria esti-
mated 0.6% of functional gastrointestinal disease patients
complained of frequent dysphagia.49 Functional dysphagia
is estimated to be the least prevalent of functional esopha-
geal disorders.
Clinical Evaluation
A careful history is taken to exclude oropharyngeal
dysphagia, and to evaluate for conditions mimicking or
contributing to dysphagia (globus, xerostomia, odynopha-
gia). GERD and EoE are important conditions to exclude,
typically with a combination of a trial of PPI therapy and
upper endoscopy with biopsy. Barium contrast studies,
especially using solid boluses (tablet, cookie, marshmallow),
can evaluate for subtle strictures often overlooked on
endoscopy or other obstructive processes such as para-
esophageal or axial hiatus hernias.50 In the absence of
structural lesions, esophageal manometry is performed to
exclude major motor disorders. Borderline or minor motor
disorders remain compatible with a diagnosis of functional
dysphagia because these disorders can be seen in asymp-
tomatic controls and patients without dysphagia,2 even
though these disorders may be identified more often in
nonobstructive dysphagia. Provocative testing with multiple
rapid swallows, free water drinking, or food ingestion dur-
ing manometry may enhance detection of obstructive motor
mechanisms to explain dysphagia.51,52
New investigative modalities such as endoscopic func-
tional luminal imaging probe and high-frequency ultrasound
may show abnormal esophageal distensibility and lack of
coordination between circular and longitudinal muscle
contraction, respectively.53,54 However, these findings have
not been correlated consistently with dysphagia. As newer
investigative modalities identify additional structural or
motor mechanisms for nonobstructive dysphagia over-
looked on routine evaluation, the prevalence of functional
dysphagia is anticipated to decrease further.
Diagnostic criteria for functional dysphagia. Cri-
teria must be fulfilled for the past 3 months with symptom
May 2016
onset at least 6 months before diagnosis with a frequency of
at least once a week. Must include all of the following.
1. Sense of solid and/or liquid foods sticking, lodging, or
passing abnormally through the esophagus.
2. Absence of evidence that esophageal mucosal or
structural abnormality is the cause of the symptom.
3. Absence of evidence that gastroesophageal reflux or
EoE is the cause of the symptom.
4. Absence of major esophageal motor disorders (acha-
lasia/EGJ outflow obstruction, diffuse esophageal
spasm, jackhammer esophagus, absent peristalsis).
Justification for Criteria Change
The diagnostic criteria for functional dysphagia have
been revised to ensure exclusion of subtle mucosal or
structural processes, including those encountered in GERD
and EoE. Dysphagia can occur even without overt structural
lesions in EoE, necessitating histopathology for exclusion of
this condition. Finally, major motor disorders can be asso-
ciated with abnormal bolus transit leading to dysphagia, and
therefore need to be excluded with manometry.
Physiological Features
The relationship between esophageal bolus stasis and
the sensation of dysphagia is not perfect. Bolus transit is
highly dependent on bolus consistency and patient posture,
and it can take several swallows to clear dry solid boluses
even in normal individuals.55 Therefore, despite reports of
simultaneous contractions, spastic contractions, or ineffec-
tive esophageal motility in nonobstructive dysphagia, it is
difficult to attribute dysphagia consistently to these motor
abnormalities.56,57 In contrast, premature peristalsis,
hypercontractility, or absent contractility seen as part of
major motor disorders are associated consistently with
abnormal bolus transit, and therefore can explain dysphagia.
Similar to other functional esophageal disorders,
abnormal esophageal sensory perception is theorized to
participate in symptom generation in functional dysphagia.
For instance, a feeling of food sticking can be induced with
balloon distension or acidification of the esophagus, both of
which also can induce peristaltic dysfunction58; correlation
with provoked dysphagia is high but imperfect.59 In this
context, minor peristaltic disorders may represent epiphe-
nomena associated with abnormal sensitivity to the dis-
tending stimulus. Therefore, although both peristaltic
dysfunction and abnormal visceral sensitivity are potential
contributory mechanisms, the latter is more in keeping with
common pathophysiologic themes in functional disorders.
Psychological Features
There are limited data supporting a higher likelihood of
psychological distress, anxiety, depression, and somatization
disorders in patients with unexplained dysphagia, similar to
observations in functional chest pain.60 Acute stress ex-
periments can provoke peristaltic dysfunction and abnormal
Functional Esophageal Disorders 1377
bolus transit in the esophagus,1 but these results cannot be
extrapolated directly to chronic symptoms seen with func-
ESOPHAGEAL
tional dysphagia.
Treatment
Functional dysphagia may regress over time, and
aggressive management approaches may not be necessary.
Reassurance and simple nonpharmacologic measures such
as eating in the upright position, avoiding precipitating food
items, careful chewing of food, and chasing food with liquids
may suffice in mild cases.61 A short trial of PPI may be
useful because dysphagia can be part of the reflux spectrum.
Despite a lack of proven efficacy, antidepressants, particu-
larly TCAs, can be tried. Empiric bougie dilation has been
reported to benefit 68%–85% of patients with intermittent
food dysphagia without an identifiable source,62,63 a benefit
not observed with through-the-scope balloon dilators tar-
geting the EGJ.64 Thus, bougie dilation to 50–54F can be
considered because this may impact subtle rings or stric-
tures that may be overlooked on routine testing.
Recommendations For Future
Research
Despite their high prevalence rates and increasing
awareness, functional esophageal disorders have not been
well studied. Therefore, effective management approaches
have been difficult to establish. Several areas requiring
additional research are identified.
1. Studies validating the diagnostic criteria are needed
and methods for improving the accuracy of symptom-
based criteria are encouraged.
2. The fundamental mechanisms of symptom production
remain poorly defined. Further application of new
technologies for measuring reflux events, motor
physiology, and esophageal sensation, as well as
central signal modulation, is recommended (eg,
multichannel intraluminal impedance monitoring,
high-resolution manometry, functional lumen imag-
ing, high-frequency ultrasound, brain imaging).
3. Well-designed, controlled treatment trials would be
welcomed in any of these disorders.
4. Treatment trials should include measures of quality of
life and functional outcome. The impact of in-
terventions on health care resource use should be a
focus in measuring treatment success.
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44. Wilson JA, Heading RC, Maran AG, et al. Globus
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and patients with dysphagia. Neurogastroenterol Motil
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Reprint requests
Address requests for reprints to: John E. Pandolfino, MD, Division of
Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern
University, Chicago, Illinois. e-mail: j-pandolfino@northwestern.edu; fax: (312)
695-3999.
Conflicts of interest
The authors disclose no conflicts.
 Gastroenterology 2016;150:1380–1392

Gastroduodenal Disorders
GASTRODUODENAL

Vincenzo Stanghellini,1,2 Francis K. L. Chan,3 William L. Hasler,4 Juan R. Malagelada,5

Hidekazu Suzuki,6 Jan Tack,7 and Nicholas J. Talley8
1
Department of the Digestive System, University Hospital S. Orsola-Malpighi, Bologna, Italy; 2Department of Medical and
Surgical Sciences, University of Bologna, Bologna, Italy; 3Institute of Digestive Disease, The Chinese University of Hong Kong,
Hong Kong, China; 4Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan; 5Digestive
System Research Unit, University Hospital Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona,
Barcelona, Spain; 6Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University, School of
Medicine, Tokyo, Japan; 7Translational Research Center for Gastrointestinal Disorders (TARGID), Department of
Gastroenterology, University Hospitals Leuven, Leuven, Belgium; and 8University of Newcastle, New Lambton, Australia

Symptoms that can be attributed to the gastroduodenal
region represent one of the main subgroups among func-
tional gastrointestinal disorders. A slightly modified
classification into the following 4 categories is proposed:
(1) functional dyspepsia, characterized by 1 or more of
the following: postprandial fullness, early satiation,
epigastric pain, and epigastric burning, which are unex-
plained after a routine clinical evaluation; and includes 2
subcategories: postprandial distress syndrome that is
characterized by meal-induced dyspeptic symptoms and
epigastric pain syndrome that does not occur exclusively
postprandially; the 2 subgroups can overlap; (2) belching
disorders, defined as audible escapes of air from the
esophagus or the stomach, are classified into 2 sub-
categories, depending on the origin of the refluxed gas as
detected by intraluminal impedance measurement belch-
ing: gastric and supragastric belch; (3) nausea and vom-
iting disorders, which include 3 subcategories: chronic
nausea and vomiting syndrome; cyclic vomiting syn-
drome; and cannabinoid hyperemesis syndrome; and (4)
rumination syndrome.
early satiation, epigastric pain, and epigastric burning that
are unexplained after a routine clinical evaluation.1
Symptom definitions remain somewhat vague, and
potentially difficult to interpret by patients, practicing phy-
sicians and investigators alike, as documented by the major
misunderstandings that characterize many of the therapeutic
trials on FD that claim to have been carried out according to
the Rome criteria, although better inclusion criteria were
obtained when the Rome III definition was adopted.2 In or-
der to overcome at least some of these problems, the com-
mittee proposed more detailed descriptive definitions of
symptoms that should be enriched by pictograms.3
The broad term functional dyspepsia comprises patients
from the diagnostic categories of PDS, which is character-
ized by meal-induced dyspeptic symptoms; EPS, which re-
fers to epigastric pain or epigastric burning that does not
occur exclusively postprandially, can occur during fasting,
and can be even improved by meal ingestion, and over-
lapping PDS and EPS, which is characterized by meal-
induced dyspeptic symptoms and epigastric pain or burning.

Uninvestigated vs Investigated Dyspepsia

Keywords: Dyspepsia; Nausea; Vomiting; Belching; Rumination. From an etiological viewpoint, patients with dyspeptic
symptoms can be subdivided into 2 main categories as

A
t least 20% of the population has chronic symptoms
that can be attributed to disorders of gastroduo-
denal function, and the majority of these people have no
evidence of organic causes.1 Functional gastroduodenal
disorders are classified into 4 categories: functional
dyspepsia (FD) (comprising postprandial distress syndrome
[PDS] and epigastric pain syndrome [EPS]), belching disor-
ders (comprising excessive gastric and supragastric belch-
ing), chronic nausea and vomiting disorders (comprising
chronic nausea vomiting syndrome [CNVS], cyclic vomiting
syndrome [CVS], and cannabinoid hyperemesis syndrome
[CHS]), and rumination syndrome.
B1: Functional Dyspepsia
Definition
FD is a medical condition that significantly impacts on
the usual activities of a patient and is characterized by one
or more of the following symptoms: postprandial fullness,
follows:
1. Those with an organic, systemic, or metabolic cause
for the symptoms that can be identified by traditional
diagnostic procedures where, if the disease improves
or is eliminated, symptoms also improve or resolve
(eg, peptic ulcer disease, malignancy, pan-
creaticobiliary disease, endocrine disorders, or
medication use) and is described by the term
secondary dyspepsia. Helicobacter pylori associated
Abbreviations used in this paper: CHS, cannabinoid hyperemesis syn-
drome; CNVS, chronic nausea and vomiting syndrome; CVS, cyclic vom-
iting syndrome; EPS, epigastric pain syndrome; FD, functional dyspepsia;
GERD, gastroesophageal reflux disease; IBS, irritable bowel syndrome;
LES, lower esophageal sphincter; PDS, postprandial distress syndrome;
UES, upper esophageal sphincter.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.011
May 2016 Gastroduodenal Disorders 1381

dyspepsia is diagnosed in a subset of dyspepsia

1. Bothersome postprandial fullness (ie, severe
patients whose symptoms are treated by H pylori
enough to impact on usual activities)
eradication.
2. Bothersome early satiation (ie, severe enough to
2. Those in whom no identifiable explanation for the
prevent finishing a regular-size meal)
symptoms can be identified by traditional diagnostic

GASTRODUODENAL
procedures that are exemplified under the “umbrella” No evidence of organic, systemic, or metabolic disease
term functional dyspepsia. that is likely to explain the symptoms on routine in-
vestigations (including at upper endoscopy)

Epidemiology
a
Criteria fulfilled for the last 3 months with symptom
Large-scale studies reported a 10% 30% prevalence of onset at least 6 months before diagnosis.
FD worldwide.4 The reported prevalence of dyspepsia var- Supportive remarks
ies considerably in different populations, due to different
interpretation and expression of symptoms, diagnostic  Postprandial epigastric pain or burning, epigastric
criteria adopted, environmental factors, and local preva- bloating, excessive belching, and nausea can also be
lence of organic diseases, such as peptic ulcer and gastric present
cancer. Patients with dyspepsia have reduced quality of life
 Vomiting warrants consideration of another
and emotional distress because of their symptoms, with
disorder
heavy economic burdens through direct medical expenses
and loss of productivity. Different studies have identified  Heartburn is not a dyspeptic symptom but may
different risk factors for dyspepsia, including female sex, often coexist
increasing age, high socioeconomic status, decreased degree
 Symptoms that are relieved by evacuation of feces
of urbanization, H pylori infection, nonsteroidal anti-
or gas should generally not be considered as part of
inflammatory drug use, low educational level, renting ac-
dyspepsia
commodation, absence of central heating, sharing a bed with
siblings, and being married. Interestingly, smoking is only Other individual digestive symptoms or groups of
marginally associated with dyspepsia, and alcohol and cof- symptoms, eg, from gastroesophageal reflux disease and
fee are not.4,5 the irritable bowel syndrome may coexist with PDS
B1b. Epigastric Pain Syndrome
Gastroduodenal Disorders Diagnostic criteriaa
B1. Functional Dyspepsia Must include at least 1 of the following symptoms at
Diagnostic criteria least 1 day a week:

1. One or more of the following: 1. Bothersome epigastric pain (ie, severe enough to
impact on usual activities)
a. Bothersome postprandial fullness
b. Bothersome early satiation AND/OR

c. Bothersome epigastric pain 2. Bothersome epigastric burning (ie, severe enough

to impact on usual activities)
d. Bothersome epigastric burning
No evidence of organic, systemic, or metabolic disease
AND that is likely to explain the symptoms on routine in-
vestigations (including at upper endoscopy).
2. No evidence of structural disease (including at
upper endoscopy) that is likely to explain the
a
Criteria fulfilled for the last 3 months with symptom
symptoms onset at least 6 months before diagnosis
Supportive remarks
a
Must fulfill criteria for B1a. PDS and/or B1b. EPS.
1. Pain may be induced by ingestion of a meal,
b
Criteria fulfilled for the last 3 months with symptom
relieved by ingestion of a meal, or may occur while
onset at least 6 months before diagnosis.
fasting
B1a. Postprandial Distress Syndrome
2. Postprandial epigastric bloating, belching, and
Diagnostic criteria nausea can also be present
Must include one or both of the following at least 3 days 3. Persistent vomiting likely suggests another
per week: disorder
 1382 Stanghellini et al
4. Heartburn is not a dyspeptic symptom but may
often coexist
5. The pain does not fulfill biliary pain criteria
6. Symptoms that are relieved by evacuation of feces
GASTRODUODENAL
or gas generally should not be considered as part
of dyspepsia
Other digestive symptoms (such as from gastroesopha-
geal reflux disease and the irritable bowel syndrome)
may coexist with EPS
Justification for Changes to the Criteria
Only minor changes have been introduced after the
Rome III criteria,1 with the purpose of improving the
specificity of definitions. FD remains the accepted umbrella
term and refers to a patient who fulfills diagnostic criteria
for PDS and/or EPS.
This division was originally based on factor analyses of
dyspepsia in the general population and FD as defined by
Rome II criteria, which identified separate factors of meal-
related symptoms and epigastric pain6 and has been later
supported by endoscopy-driven epidemiological studies.7
Importantly, several therapeutic trials on the effects of H
pylori eradication, antisecretory, and prokinetic agents
provide a clinically relevant support to the existence of PDS
and EPS as substantially different subsets of dyspepsia, as
detailed in the section on therapy.
Pathophysiological studies investigating the effect of meal
ingestion on symptom generation have demonstrated that, in
dyspeptic patients, not only postprandial fullness and satiety,
but also epigastric pain/burning and nausea may increase
after meal ingestion (Figure 1).8 Thus, the definition of PDS
was slightly modified by acknowledging that, beyond post-
prandial fullness and early satiety that occur postprandially
by definition, other digestive symptoms including epigastric
pain and epigastric burning, can be perceived by the patient as
Gastroenterology Vol. 150, No. 6
being induced or worsened by a meal. Epigastric bloating,
belching, and nausea can be present in both PDS and EPS and
should be considered as possible adjunctive features of the 2
subgroups. Vomiting, on the other hand, is unusual and should
prompt the search for other diagnoses.
Although relief of fullness or pain by the passage of stool
or gas likely indicates a lower gut symptom origin, there is
insufficient evidence to include this requirement in the
criteria. The Committee has confirmed that heartburn is
excluded from the definition of dyspepsia, even though it
can often occur simultaneously with gastroduodenal
symptoms, perhaps because of overlapping pathophysi-
ology.9 Typical biliary pain is quite distinctive, being severe
or very severe, episodic, and unpredictable, and can clini-
cally be distinguished from EPS by appropriate history
taking and physical examination.
Other minor changes were introduced to more precisely
define the minimal thresholds for frequency and severity of
each individual symptom, primarily for scientific purposes,
but data still need to be collected to define thresholds based
on the frequency and/or severity of symptoms that impair
quality of life. Severity should be at least sufficient to identify
symptoms as “bothersome,” which should be clinically
defined as “severe enough to impact on usual activities.” For
research purposes “bothersome” can be semi-quantitatively
defined as 2 in a 5-point adjectival scale linked to the ef-
fect exerted by symptoms on usual activities (ie, severe
enough to at least distracting from usual activities).10 Fre-
quency of symptoms was not detailed in the Rome III Criteria.
It is proposed to introduce a minimal frequency to distinguish
those with disease based on symptom thresholds obtained
from normal subjects for the Rome IV consensus. Thus, cutoffs
for frequencies of symptoms and syndromes were based on
data indicating no more than 5% of the normal population
would experience each symptom this frequently.11
Pathophysiology
The pathophysiology of FD is likely complex and multi-
factorial (Figure 2), and not completely elucidated.
Figure 1. Postprandial
symptom severity in 218
patients with functional
dyspepsia. Symptoms
were defined as meal-
related if their severity
increased within 30 mi-
nutes after meal ingestion.
May 2016
Gastroduodenal motor and sensory dysfunction, as well as
impaired mucosal integrity, low-grade immune activation,
and dysregulation of the gut brain axis have all been
implicated.12
Gastric emptying. Gastric emptying is delayed in a
sizable fraction (estimates vary from about 25% to 35%) of
unselected FD patients, while rapid gastric emptying is
uncommon probably occurring in under 5% of cases.13
Correlation between gastric emptying and dyspeptic
symptoms remains unsettled. Severely delayed gastric
emptying in patients diagnosed as gastroparesis is associ-
ated with more vomiting and loss of appetite, but can be
asymptomatic.13
Impaired gastric accommodation. Gastric accom-
modation is controlled by a vago-vagal reflex triggered by
meal ingestion and mediated by the activation of nitrergic
nerves in the gastric wall. Abnormal distribution of food in
the stomach, with antral pooling of chyme and decreased
proximal reservoir content, has long been known to occur.14
A reduced gastric relaxatory response to ingestion of a meal
has been seen in about one-third of FD patients observed,
and it appears to be more likely in post-infection
dyspepsia.15 The potential relation between impaired
gastric accommodation and dyspeptic symptoms also re-
mains unclear.
Gastric and duodenal hypersensitivity to distention,
acid, and other intraluminal stimuli. Hypersensitivity to
mechanical stimulation of the stomach and upper small
bowel is frequent in FD patients, but underlying mecha-
nisms of the putative relationship between fasting gastric
hypersensitivity and dyspeptic symptoms remain unset-
tled. FD patients may show hypersensitivity to chemical
stimuli, such as intraluminal acid and lipids,16 but evi-
dence provided so far is not conclusive. Independent of
acid-related effects, proton pump inhibitors may reduce
duodenal eosinophils and H2 blockers may work via
antihistamine effects (via mast cell recruitment in a subset
of patients with functional dyspepsia.17
Figure 2. Putative patho-
physiological mechanisms
of functional dyspepsia.
CNS, central nervous
system.
Gastroduodenal Disorders 1383
Helicobacter pylori infection. H pylori infection is
considered a possible cause of FD symptoms if successful
eradication leads to sustained resolution of all cardinal
symptoms, as reviewed recently.18 Both acid secretion and
hormonal status can be affected to some extent with H pylori
eradication therapy, and restoration of these changes may
GASTRODUODENAL
explain, in part, the beneficial effect of eradication on
dyspeptic symptoms, although this hypothesis needs to be
confirmed. In fact, antibiotic therapies can affect dyspeptic
symptoms by mechanisms other than H pylori eradication,
including prevention of unrecognized peptic ulcers or
modification of intestinal microbiota.
Duodenal low-grade inflammation, mucosal
permeability, and food antigens. The mucosal barrier
serves as the first line of defense against pathogens and
noxious substances in the lumen.12 Duodenal eosinophilia
has been reported in FD patients and is apparently related
to early satiety.19 Infections, stress, duodenal acid exposure,
smoking, and food allergy have all been implicated in the
pathogenesis of duodenal mucosal inflammatory and
permeability changes.
Environmental exposures. Acute infection can
trigger upper gastrointestinal symptoms in 10% 20% of
infected individuals,12,20 although post-infectious dyspepsia
can be short-lived compared with post-infection IBS.21
Features of the infective agents and genetic predisposition
of infected individuals likely modulate the probability of
developing post-infectious digestive syndromes.
Psychosocial factors. The association between
dyspepsia and psychiatric disorders, especially anxiety,
depression, and neuroticism is commonly recognized.22 A
meta-analysis confirmed an association between anxiety,
depression, and FD.23 Also, physical and emotional abuse in
adulthood and difficulty in coping with life events might be
involved. Whether FD is more prevalent in patients pre-
senting with psychiatric disorders or is characterized by a
higher prevalence of anxiety and depression than organic
dyspepsia is unclear. A bidirectional relationship probably
 1384 Stanghellini et al
exists between gut and psyche because patients with func-
tional gastrointestinal disorders are more prone to develop
psychological problems, and vice versa.24 Neuroimaging
studies suggest that symptom perception can be influenced
by cognition and emotion.
GASTRODUODENAL
Clinical Evaluation
Management strategy of un-investigated dyspepsia
should be based on history taking, including alarm features
and iatrogenic causes, treatment of overlapping gastro-
esophageal reflux disease (GERD), H pylori “test and treat,”
especially in high-prevalence regions, while prompt endos-
copy should be performed in all patients with alarm features
(Figure 3). If FD is diagnosed, patients should be divided
into PDS and/or EPS and treated accordingly (Figure 4).
Treatment
Treatment of dyspepsia has been reviewed recently.25
Reassurance, education, lifestyle, and dietary recommenda-
tions (more frequent, smaller meals and avoiding meals
with high fat content) are frequently recommended to FD
patients, but they have not been studied systematically.
Avoidance of nonsteroidal anti-inflammatory drugs, coffee,
alcohol, and smoking is commonly recommended and seems
sensible, although not of established value.
There is evidence of a small but statistically significant
benefit in eradicating H pylori in patients with chronic
dyspepsia, with a number needed to treat of 14. Dyspeptic
symptom can be attributed to H pylori gastritis, termed by H
pylori associated dyspepsia, if successful eradication is
followed by long-term sustained (6 months or longer)
remission.26,27 Economic analyses suggest that H pylori
eradication is the most cost-effective approach for infected
dyspeptic patients compared with alternative medical
therapies that need to be taken long term. It is unclear
Gastroenterology Vol. 150, No. 6
whether H pylori eradication therapy has a different efficacy
in different FD subgroups.
Proton pump inhibitors and H2RAs are regarded as
effective treatment for FD, based on several controlled trials
with a therapeutic gain over placebo of 10% 15%, although
the effect of overlapping or misdiagnosed GERD cannot be
ruled out. Proton pump inhibitors are ineffective in relieving
PDS symptoms.
Prokinetic drugs exert a significant benefit for proki-
netics over placebo, with a relative risk reduction of 33%
and number needed to treat of 6, but these results were
mainly driven by studies using cisapride and domperidone,
and concerns were raised about publication bias. Pure
prokinetic treatments without central antiemetic effects (eg,
erythromycin, azithromycin, ABT 229) unphysiologically
accelerate gastric emptying by inducing a fasting type of
gastroduodenal motility in the postprandial period and may
be less effective than therapies with combined prokinetic
and antiemetic action. Itopride is a novel prokinetic agent
that works by antagonizing dopamine D2-receptors and
inhibiting acetylcholinesterase, and has been shown to
improve postprandial fullness and early satiety with a low
rate of adverse reactions.
Botulinum toxin pyloric injections are not superior to
placebo on gastroparesis and dyspeptic symptoms. In un-
controlled series, gastric electrical stimulation reduces
vomiting without influencing gastric emptying.
Acotiamide (Z-338) is a novel compound with fundus-
relaxing and gastroprokinetic properties, based on a pro-
cholinergic effect that improves dyspepstic symptoms
over placebo, with a number needed to treat of 6. Notably,
the drug benefited PDS but not EPS. Other potentially
effective fundic relaxants include 5-HT1A receptor agonists
tandospirone and buspirone, 5HT1B/D receptor agonist
sumatriptan and the herbal product STW-5 and
rikkunshito.
Figure 3. Clinical manage-
ment of patients com-
plaining of symptoms that
can be attributed to disor-
ders of gastroduodenal
functions (see text for
details).
May 2016
Figure 4. Clinical manage-
ment of patients affected
by functional dyspepsia
(see text for details).
Psychotropic drugs, especially antidepressants, are often
used as second-line drugs in functional gastrointestinal
disorders. A systematic review24 suggested that psychotro-
pic drug therapy in FD is associated with a significant
symptom improvement over placebo, but most trials were
small and of poor quality; often used levosulpiride, which
also bears prokinetic properties; and often recruited in
psychiatric rather than gastroenterological settings. A
multicenter placebo-controlled trial recently carried out in
North America comparing selective serotonin reuptake
inhibitors and tricyclics showed no effect and poor tolerance
of the former, while low-dose amitryptyline showed some
advantages over placebo, although confined to epigastric
pain with no signal in PDS cases or in those with delayed
gastric emptying.28
Psychological therapies are advocated as rescue therapy
for FD symptoms that are severe and not responding to
Figure 5. Frequency of vomiting episodes over time in cyclic
and chronic vomiting syndromes, the former being charac-
terized by stereotypical, brief (less than 1 week) episodes of
intense vomiting with acute onset that are separated by pe-
riods of at least 1 week in the absence of vomiting.
Gastroduodenal Disorders 1385
GASTRODUODENAL
pharmacotherapy. Available controlled trials suggested
clinical benefit, but lacked convincing evidence because of
small sample sizes and poorly matched treatment groups.
The concept that a subset of FD cases is mediated by
intestinal inflammation via eosinophils with or without mast
cells is intriguing, and both the anti-asthma drug mon-
telukast, a cysLT receptor antagonist that stabilizes eosin-
ophils, and histamine H1 antagonist represent promising
approaches but require rigorous testing. The use of herbal
medicines in FD also still needs scientific support.
B2: Belching Disorders
Definition
Belching is defined as an audible escape of air from the
esophagus or the stomach into the pharynx. It occurs
commonly and can only be considered a disorder when it is
excessive and becomes troublesome. Depending on the
origin of the refluxed gas, belching is classified into 2 types:
the gastric belch and the supragastric belch.
Epidemiology
The epidemiology of excessive belching in the general
population remains to be carefully defined; however, it is
not encountered uncommonly in the clinical setting.
Diagnostic Criteria
The previous Rome III consensus focused on aerophagia
as a mechanism of belching disorders, based on the obser-
vation of the occurrence of excessive air swallowing.1
Studies using intraluminal impedance measurement of air
transport in the esophagus have demonstrated that different
mechanisms of excessive belching occur.29
 1386 Stanghellini et al
Belching activity follows a distinct pattern, characterized
by rapid antegrade and retrograde flow of air in the esoph-
agus that usually does not reach the stomach. This phe-
nomenon of “supragastric belching” is not accompanied by
the transient relaxation of the lower esophageal sphincter
(LES), as is observed in gastric belching.28 Supragastric
GASTRODUODENAL
belching is defined as a behavior in which the eructated air
does not originate from the stomach, but is sucked or injected
into the esophagus from the pharynx and expelled immedi-
ately after, through the oral route, in the absence of excessive
air swallowing. Belching is a frequent manifestation of GERD
due to both gastric and supragastric belching.
B2. Diagnostic Criteriaa for Belching Disorders
Must include all of the following:
Bothersome (ie, severe enough to impact on usual ac-
tivities) belching from the esophagus or stomach more
than 3 days a week
B2a: Excessive supragastric belching (from esophagus)
B2b: Excessive gastric belching (from stomach).
Supportive remarks
 Supragastric belching is supported by observing
frequent, repetitive belching
 Gastric belching has no established clinical correlate
 Objective intraluminal impedance measurement can
be used to distinguish supragastric from gastric
belching.
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis.
Justification for Change in Criteria
The current Rome IV committee clearly distinguished
such excessive supragastric belching from gastric belching,
but both remained within the category of gastroduodenal
disorders because of the common presenting symptom.
Because not all cases with belching arise from swallowing
air, aerophagia is a confusing term when applied to exces-
sive belching, and is now considered historical. Most
importantly, supragastric belching can be objectively
distinguished from gastric belching by high-resolution
manometry and impedance.30
Pathophysiology
Physiological features. Air swallowing is normal.
Through esophageal peristalsis and LES relaxation, this air
is transported to the stomach along with the rest of the
bolus. The ingested air accumulates in the proximal stom-
ach. A physiologic venting system is present to protect the
stomach against extreme dilatation: LES relaxes in response
to distension of the stomach due to the gas, and this is
followed by relaxation of the upper esophageal sphincter
Gastroenterology Vol. 150, No. 6
(UES). In the majority of patients, supragastric belches are
initiated by the creation of subatmospheric pressure in the
thoracic cavity by movement of the diaphragm in the aboral
direction, similar to deep inspiration, whereas gastric
belches occur while the LES is relaxed and intrathoracic
pressure is slightly elevated. UES relaxation occurs in both
supragastric and gastric belches; during supragastric
belches, UES relaxation precedes the onset of the antegrade
airflow, and during gastric belches, UES relaxation occurs
after the onset of the retrograde esophageal airflow.30
Psychological features. Supragastric belching stops
during speaking, distraction, and sleeping. It significantly
impairs health-related quality of life and is associated with
stressful events and a high prevalence of anxiety disorders.
Excessive belching can also occur in patients with obsessive
compulsive disorder, bulimia nervosa, and encephalitis.31,32
Clinical Evaluation
Diagnosis is based on a careful history evaluation.
Observation of air swallowing provides supportive infor-
mation. Patients who complain of isolated excessive belch-
ing are more likely to suffer from excessive uncontrolled
supragastric belching, and from episodes of frequent
belching in which they may belch up to 20 times per minute.
If symptoms are troublesome and the technology is avail-
able, esophageal impedance/manometry will provide useful
information to guide therapy.
Treatment
Supragastric belching. There is little evidence on the
treatment of patients with supragastric belching. Reassur-
ance and explanation of the symptoms as well as the
mechanism of belching are important.33 The habit can oc-
casionally be inhibited by demonstrating chest expansion
and air ingestion as the patient belches. Dietary modification
(avoiding sucking candies or chewing gum, eating slowly
and encouraging small swallows, and avoiding carbonated
beverages) is traditionally recommended. When patients
with FD or GERD complain of excessive belching, it seems
reasonable to treat the other symptoms first. Successful
treatment of excessive belching by speech therapy per-
formed by a well-informed speech therapist, biofeedback,
and diaphragmatic breathing training, is reported in an
open-label study, demonstrating that speech therapy per-
formed by a well-informed speech therapist can lead to a
significant reduction in symptoms,34 but appropriate
studies are needed. When there is a suspicion that excessive
belching is secondary to a psychiatric disorder, the patient
should be referred for an evaluation by a psychiatrist. The
treatment of associated psychiatric disease or employment
of stress-reduction techniques may theoretically be
beneficial.
Gastric belching. Acute and severe episodes are rare
and occur mainly in mentally disabled patients and can
result in volvulus of organs, as well as obstruction and
breathing difficulties, because of increased abdominal
pressure. In this case, a nasogastric tube to relieve gastric
air appears to be reasonable treatment, and sedatives may
May 2016
help to reduce repetitive air swallowing. Patients with
chronic gastric belching should avoid carbonated beverages
and eat slowly. Treatment with speech therapy to reduce air
swallowing seems reasonable. Diaphragmatic breathing may
be helpful. Baclofen, a g-aminobutyric acid-B receptor
agonist that reduces the frequency of transient LES re-
laxations and suppresses swallowing rate through a pre-
sumed central mechanism of action, may decrease both
gastric and supragastric belching events.35 Surface tension-
reducing drugs, such as dimethicone and simethicone, might
prevent gas formation in the intestines and alleviate
symptoms as well, but there is no consistent evidence to
support their use.
B3: Nausea and Vomiting Disorders
Definitions
Nausea is a subjective symptom and can be defined as an
unpleasant sensation of the imminent need to vomit typi-
cally experienced in the epigastrium or throat. Vomiting
refers to the forceful oral expulsion of gastrointestinal
contents associated with contraction of the abdominal and
chest wall muscles.
Epidemiology
Nausea is less prevalent than epigastric pain or meal-
related symptoms in the community.36 Unexplained
chronic nausea is often associated with other gastroduo-
denal symptoms. Unexplained vomiting occurring at least
once monthly is distinct from occasional vomiting reported
with FD, and is believed to be rare, occurring in approxi-
mately 2% of women and 3% of men.36 The prevalence of
CNVS is unknown.
CVS is estimated to cause symptoms in 3% 14% of
adults referred for unexplained nausea and vomiting.37 CVS
presents in young adults across all races and in both sexes.
Adult patients present to emergency departments a median
of 15 times before diagnosis 5–6 years after symptom
onset.37 CVS may be linked to the menses (catemenial CVS),
precipitated by pregnancy, or associated with diabetes
mellitus. Common precipitants of CVS episodes include
stress, sleep deprivation, infections, foods, motion sickness,
and medications. Most patients show gradual symptom re-
ductions over time. However, some adults progress to daily
nausea and vomiting without asymptomatic intervals.
CHS resolves with cessation of marijuana smoking. One-
third of patients with presumed CVS report marijuana use.
Cannabinoid use is more often reported in CVS compared
with chronic functional vomiting. CHS typically occurs in
males with prolonged daily cannabis use (3–5 times daily)
over at least 2 years. As with CVS, delays in CHS diagnosis
and numerous emergency department visits before diag-
nosis are typical.37
B3. Diagnostic Criteriaa for Nausea and Vomiting
Disorders
B3a: Chronic Nausea and Vomiting Syndrome (CNVS)
Gastroduodenal Disorders 1387
Must include all of the following:
1. Bothersome (ie, severe enough to impact on usual
activities) nausea, occurring at least 1 day per
week and/or 1 or more vomiting episodes per
week
GASTRODUODENAL
2. Self-induced vomiting, eating disorders, regurgi-
tation, or rumination are excluded
3. No evidence of organic, systemic, or metabolic
diseases that is likely to explain the symptoms on
routine investigations (including at upper
endoscopy).
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis
B3b: Cyclic Vomiting Syndrome (CVS)
Must include all of the following:
Stereotypical episodes of vomiting regarding onset
(acute) and duration (less than 1 week)
1. At least e discrete episodes in the prior year and 2
episodes in the past 6 months, occurring at least 1
week apart
2. Absence of vomiting between episodes, but other
milder symptoms can be present between cycles
Supportive remarks:
 History or family history of migraine headaches
B3c: Cannabinoid Hyperemesis Syndrome (CHS)
Diagnostic criteriaa
Must include all of the following:
1. Stereotypical episodic vomiting resembling cyclic
vomiting syndrome (CVS) in terms of onset,
duration, and frequency
2. Presentation after prolonged excessive cannabis
use
3. Relief of vomiting episodes by sustained cessation
of cannabis use
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis
Supportive remarks:
 May be associated with pathologic bathing behavior
(prolonged hot baths or showers).
Justification for Change in Criteria
The previous separate sections were merged into a
single entity entitled Chronic Nausea and Vomiting
 1388 Stanghellini et al
Syndrome due to a paucity of data delineating differences
in diagnostic approach and management of 2 symptoms
that are frequently associated. Chronic nausea can present
in the absence of vomiting. Vomiting in the absence of
nausea might prompt suspicion of an organic central ner-
vous system disease. Nausea may be meal-related or un-
GASTRODUODENAL
related, suggesting potential pathogenic heterogeneity.
Minor changes to the CVS criteria were made to
acknowledge the observation that some affected adult
patients report inter-episodic symptoms other than vom-
iting, and being free of vomiting for at least a week be-
tween episodes was a distinguishing feature in adults
(Figure 5). CHS is distinct from CVS, as it exhibits different
epidemiology and has specific bathing behavior and
therapy.
Pathophysiology
Physiologic defects associated with CNVS, CVS, and CHS
are incompletely characterized. No correlation has been
established between abnormal gastric emptying or fundic
accommodation and CNVS, CVS, and CHS. Autonomic neural
disorders are found in CVS, including complex regional pain
syndrome, postural orthostatic tachycardia syndrome,
orthostatic pulse and blood pressure changes, impaired
parasympathetic responses to deep breathing, and
abnormal sympathetic skin responses.38
Psychological dysfunction presents in some patients
with nausea and vomiting disorders. Although psychiatric
diagnoses, including major depression and conversion dis-
order, have been described in different emetic profiles, a
correlation has not been confirmed. CVS attacks share fea-
tures with migraines, including episodic attacks, intervening
well periods, stereotypic onset, and associated pallor, hy-
persensitivity, and fatigue.
The pathophysiology of CHS is poorly understood. Some
cannabinoids have antiemetic actions, and others may
contribute to recurrent vomiting, their effects also depend-
ing on doses.39
Masses occupying intracranial space, such as tumors of
the third ventricle; inner ear diseases, such as vestibular
neuronitis; and medication other than cannabinoids, such as
opiates, are all possible causes of secondary intermittent
vomiting with or without associated nausea. Food allergies
and intolerances may elicit a presentation similar to CVS.
Gene mutations and mitochondrial DNA polymorphisms
have been described in CVS patients.40
Clinical Evaluation
Symptom profiles. CNVS is primarily distinguished
from CVS by distinct temporal characteristics. CVS typi-
cally comprises 4 phases: (1) a pre-emetic period with
pallor, diaphoresis, and nausea; (2) intense emesis up to
30 episodes daily, often with associated epigastric or
diffuse abdominal pain and/or diarrhea; (3) a recovery
phase with gradual symptom resolution of nausea and
vomiting; and (4) an interepisodic period without vomit-
ing. CVS attacks are generally longer and more frequent in
adults than in children.41 Similarly, CHS is divided into
Gastroenterology Vol. 150, No. 6
prodromal, hyperemetic, and recovery phases. Hot baths
or showers during attacks provide relief of the hypere-
metic phase.
Differential diagnosis. The differential diagnosis of
recurrent vomiting is extensive. Gastroparesis, intestinal
pseudo-obstruction, mechanical obstruction, and some
metabolic and central nervous system diseases present
with recurrent nausea and/or vomiting. Rumination syn-
drome presents with effortless regurgitation of undigested
food, often with re-swallowing or spitting within minutes
of eating, which can be mistaken for vomiting. Although
there is no associated nausea, weight loss can occur.
Patients with bulimia nervosa may have self-induced
vomiting associated with binge episodes. Several rare
conditions have presentations that mimic CVS, including
acute intermittent porphyria (which also has associated
neurologic symptoms) and disorders of fatty acid
oxidation.
Diagnostic testing
Performance of diagnostic testing is dictated by the
clinical presentation. Those with bilious vomiting, abdom-
inal tenderness, abnormal neurologic findings, or a wors-
ening pattern of vomiting episodes warrant more aggressive
investigation.42 Biochemical testing can exclude electrolyte
and acid base abnormalities, hypercalcemia, hypothyroid-
ism, and Addison’s disease. Drug screening may be consid-
ered if CHS is a possibility but is denied. Upper endoscopy,
small bowel radiography, or computed tomography or
magnetic resonance enterography can evaluate for gastro-
duodenal disease and small bowel obstruction. Computed
tomography head is necessary to exclude space-occupying
lesions. If these tests are normal, the clinician can
consider a gastric-emptying evaluation. If severe symptoms
persist, antroduodenal manometry can assess for enteric
neuropathy or myopathy, but a normal manometric
recording is most helpful. Esophageal pH testing can be
considered to exclude vomiting as an atypical presentation
of GERD.
Consideration of rare conditions is warranted in some
CVS patients, including urine measurements of amino-
levulinic acid and porphobilinogen, plasma ammonia
levels, plasma amino acid, and urine organic acid
quantification.42
Treatment
Chronic nausea vomiting syndrome. Limited
investigation has focused on treatment of what is now called
CNVS. Agents with antiemetic capabilities have been devel-
oped in several drug classes, including histamine H1
antagonists, muscarinic M1 antagonists, dopamine D2
antagonists, serotonin 5-HT3 antagonists, neurokinin NK1
antagonists, and cannabinoids.43 5-HT3 antagonists exhibit
superior control of vomiting compared with nausea.
Uncontrolled series of patients with presumed functional
causes of nausea and vomiting report significant benefits by
tricyclic antidepressant agents, gastric electrical stimulation,
and cognitive and social skills training. Pain negatively
May 2016
impacts symptom reductions, while gastric emptying rates
do not predict responses. Notably, a noradrenergic and
specific serotonergic antidepressant mirtazapine is often
used clinically to treat patients with nausea, and recently
has shown benefit in patients with dyspeptic symptoms
associated with weight loss.
Cyclic vomiting syndrome. Therapies for acute CVS
attacks include supportive care and aggressive medication
regimens. Intravenous hydration with 10% dextrose with
potassium replenishment as needed associated with anti-
emetics (especially serotonin 5-HT3 antagonists) may pro-
vide substantial benefit in some cases.42 Acute vomiting
episodes requiring emergency department or inpatient care
can benefit from additional induction of sedation with
intravenous benzodiazepines. Opiate agents or nonsteroidal
anti-inflammatory drugs may be needed for control of pain
associated with CVS flares; some benefits of parenteral
ketorolac also have been described. Anecdotal success has
been noted with antimigraine serotonin 5-HT1B,1D agonists
(eg, sumatriptan), especially in children with personal or
family histories of migraines, but these drugs can be
considered also in adults in the absence of such histories.
Tricyclic agents exhibit efficacy for preventing recurrent
CVS attacks, with poor responses being related to co-
existent psychiatric disease, marijuana or opiate use, and
poorly controlled migraines. Anticonvulsant drugs (eg,
phenobarbital, phenytoin, caramazepine, topiramate, and
valproate) can be offered to individuals with CVS who fail
tricyclic prophylaxis. Other classes with prophylactic effects
in CVS include anticonvulsant drugs, b-blockers, cyprohep-
tadine, and over-the-counter mitochondrial stabilizers (eg, L-
carnitine and co-enzyme Q10), alone or in combinations. In
a retrospective report, 75% of 20 CVS patients unable to
take or respond to tricyclics exhibited benefits taking either
zonisamide or levetiracetam over 9 months, with a mean
62% reduction in vomiting episodes.
Cannabinoid hyperemesis syndrome. CHS should
be managed by withdrawal of marijuana, but many patients
are unwilling to follow this advice. Tricyclic agents may also
be used in an attempt to abort attacks
B4: Rumination Syndrome
Definition
In human patients, rumination syndrome is character-
ized by the repetitive, effortless regurgitation of recently
ingested food into the mouth followed by rechewing and
reswallowing or expulsion of the food bolus.
Epidemiology
Although initially described in infants and the develop-
mentally disabled, it is now known that rumination syn-
drome occurs in males and females of all ages and cognitive
function. The epidemiology of adult rumination syndrome is
not well characterized. In a large database of patients with
unexplained nausea and vomiting, 3.3% of women and 3.5%
of men satisfied Rome III criteria for rumination
syndrome.44
Gastroduodenal Disorders 1389
B4. Diagnostic Criteriaa for Rumination Syndrome
Must include all of the following:
1. Persistent or recurrent regurgitation of recently
ingested food into the mouth with subsequent
GASTRODUODENAL
spitting or remastication and swallowing
2. Regurgitation is not preceded by retching.
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis.
Supportive remarks:
 Effortless regurgitation events are usually not pre-
ceded by nausea
 Regurgitant contains recognizable food that might
have a pleasant taste
 The process tends to cease when the regurgitated
material becomes acidic.
Justification for Change in Criteria
The criteria for rumination are essentially unchanged
but effortless regurgitation is emphasized as a major diag-
nostic point in the supportive remarks. Rumination is a
heterogeneous syndrome that can present with an acid-
tasting regurgitant that should not lead to a misdiagnosis
of GERD. Supportive remarks are based on clinical experi-
ence, but lack scientific support.
Pathophysiology
Physiological features. Different mechanisms for the
rumination events have been proposed, including simulta-
neous LES relaxations occurring during episodes of
increased intra-abdominal pressure and voluntary relaxa-
tion of the diaphragmatic crura that permits the normal
postprandial gastric pressure increase to exceed the barrier
pressure provided by the LES.45
Many patients show evidence of “pathological
gastroesophageal reflux” on ambulatory pH testing or
show macroscopic or microscopic damage to the lower
esophagus on endoscopy. However, rapid pH oscillations
are most prominent in the first postprandial hour and
result from regurgitation and reswallowing of food.
Conversely, nocturnal esophageal pH usually is normal.
“Rumination waves” characterized by simultaneous con-
tractions in all recording sites soon after meal ingestion
can be recorded by antroduodenal manometry. Rumina-
tion events are identified on combined impedance and
high-resolution manometry, as elevations in intragastric
pressure before or concurrently with oral esophageal
fluid propulsion that are generally nonacidic. Upper
esophageal sphincter relaxes during all rumination
events, suggesting potential participation of this struc-
ture as well.46
 1390 Stanghellini et al
Psychological features. Psychological dysfunction
can be related to some cases of rumination syndrome.
Stressful life events can be identified around the time of
symptom onset in some patients.47 Rumination can be
associated with bulimia nervosa, although bulimics with
rumination more commonly expel rather than reswallow
GASTRODUODENAL
meal residues.
Clinical Evaluation
Symptom profiles. Rumination syndrome most often
presents with the clinical features reported here. Symptoms
can be present with every meal, including liquids, which
often are better tolerated in conditions with true vomiting.
In contrast to most patients, a subset reports that the
regurgitant is sour or bitter tasting and that the behavior
does not stop when the regurgitant becomes “acidic.” Many
individuals with rumination report additional symptoms,
including nausea, heartburn, abdominal discomfort, diar-
rhea, and/or constipation. Weight loss can be prominent,
particularly in adolescents.
Differential diagnosis. Discriminating rumination
syndrome from regurgitation in GERD can sometimes be
challenging, especially in those with associated heartburn.
Rumination is contrasted to emetic conditions, such as
gastroparesis, in which vomiting typically occurs later in the
postprandial period, the food residue is not recognizable,
and there is preceding nausea and/or retching. Given the
female predominance of rumination and the frequent
development of weight loss, patients are often misdiagnosed
with bulimia or anorexia nervosa. Achalasia generally pre-
sents with dysphagia, which is not typical of the rumination
syndrome, and its diagnosis require esophageal manometric
testing.
Diagnostic testing. Combined esophageal
impedance/high-resolution manometry or antroduodenal
manometry can provide typical findings that confirm the
diagnosis in selected cases. Recent proposed impedance/
high-resolution manometry criteria for rumination
included reflux events extending to the proximal esophagus
that are closely associated with abdominal pressure in-
creases >30 mm Hg.48
Treatment
Treatment of rumination syndrome has been reviewed
recently.49 Lifestyle, medication, surgical, and behavioral
therapies have been offered for rumination syndrome with
varying degrees of success. Gum chewing has anecdotal
benefits in children with rumination. Proton pump in-
hibitors suppress heartburn and protect the esophageal
mucosa during regurgitations, however, such drugs can
prolong rumination by blunting the intragastric meal
acidification that normally serves to terminate events. The
g-aminobutyric acid agonist baclofen may elicit reductions
in rumination, possibly by blunting transient LES re-
laxations, but data are insufficient to support the clinical
application of the drug. Most prokinetics induce relatively
minor LES increases and levosupiride was used as part of
Gastroenterology Vol. 150, No. 6
a multidisciplinary program due to its antidepressant
effects.
The mainstay of treatment for rumination syndrome
involves behavioral modification. For most patients, this
consists of habit reversal using diaphragmatic breathing
techniques to compete with the urge to regurgitate
because rumination and the breathing technique
cannot proceed at the same time.50 Nissen fundoplication
has been proposed in nonresponders, but data are
insufficient.
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lower esophageal sphincter relaxations in an adult pa-
tient with the rumination syndrome. Am J Gastroenterol
1990;85:1621–1625.
46. Kessing BF, Govaert F, Masclee AA, et al. Impedance
measurements and high-resolution manometry help to
better define rumination episodes. Scandi J Gastro-
enterol 2011;46:1310–1315.
47. Malcolm A, Thumshirn MB, Camilleri M, et al. Rumination
syndrome. Mayo Clin Proc 1997;72:646–652.
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48. Kessing BF, Bredenoord AJ, Smout AJ. Objective rumination. J Pediatr Gastroenterol Nutr 1998;
manometric criteria for the rumination syndrome. Am J 27:596–598.
Gastroenterol 2014;109:52–59.
49. Tack J, Blondeau K, Boecxstaens V, et al. Review article: Reprint requests
the pathophysiology, differential diagnosis and man- Address requests for reprints to: Vincenzo Stanghellini, MD, Department of the
Digestive System, University Hospital S. Orsola-Malpighi, Department of
agement of rumination syndrome. Aliment Pharmacol Medical and Surgical Sciences, University of Bologna, Via Massarenti 9,
GASTRODUODENAL

Ther 2011;33:782–788. 40138 Bologna, Italy. e-mail: v.stanghellini@unibo.it; fax: 0039051392486.

50. Wagaman JR, Williams DE, Camilleri M. Conflicts of interest
Behavioral intervention for the treatment of The authors disclose no conflicts.

Bowel Disorders
Brian E. Lacy,1 Fermín Mearin,2 Lin Chang,3 William D. Chey,4 Anthony J. Lembo,5
Magnus Simren,6 and Robin Spiller7
1
Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; 2Institute of
Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain; 3David Geffen School of Medicine at
UCLA, Los Angeles, California; 4University of Michigan Health System, Ann Arbor, Michigan; 5Beth Israel Deaconess Medical
Center, Harvard Medical School, Boston, Massachusetts; 6Institute of Medicine, Department of Internal Medicine and Clinical
Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and 7Cantab, University of Nottingham,
United Kingdom
Functional bowel disorders are highly prevalent disorders
found worldwide. These disorders have the potential to
affect all members of society, regardless of age, sex, race,
creed, color, or socioeconomic status. Improving our un-
derstanding of functional bowel disorders (FBD) is critical,
as they impose a negative economic impact to the global
health care system in addition to reducing quality of life.
Research in the basic and clinical sciences during the past
decade has produced new information on the epidemi-
ology, etiology, pathophysiology, diagnosis, and treatment
of FBDs. These important findings created a need to revise
the Rome III criteria for FBDs, last published in 2006. This
article classifies the FBDs into 5 distinct categories: irri-
table bowel syndrome, functional constipation, functional
diarrhea, functional abdominal bloating/distention, and
unspecified FBD. Also included in this article is a new sixth
category, opioid-induced constipation, which is distinct
from the functional bowel disorders (FBDs). Each disorder
will first be defined, followed by sections on epidemiology,
rationale for changes from prior criteria, clinical evalua-
tion, physiologic features, psychosocial features, and
treatment. It is the hope of this committee that this new
information will assist both clinicians and researchers in
the decade to come.
Keywords: Abdominal Pain; Bloating; Distension; Constipation;
Diarrhea; Functional Bowel Disorders; Irritable Bowel
Syndrome.
F unctional bowel disorders (FBD) are a spectrum of
chronic gastrointestinal (GI) disorders characterized
by predominant symptoms or signs of abdominal pain,
bloating, distention, and/or bowel habit abnormalities (eg,
constipation, diarrhea, or mixed constipation and diarrhea).
The FBDs can be distinguished from other GI disorders
based on chronicity (
6 months of symptoms at the time of
presentation), current activity (symptoms present within
the last 3 months), frequency (symptoms present, on
average, at least 1 day per week), and the absence of
obvious anatomic or physiologic abnormalities identified by
routine diagnostic examinations, as deemed clinically
appropriate. The FBDs are classified into 5 distinct cate-
gories: irritable bowel syndrome (IBS), functional con-
stipation (FC), functional diarrhea (FDr), functional
Gastroenterology 2016;150:1393–1407
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abdominal bloating/distention, and unspecified FBD
(Table 1). Also included in this article is a new sixth cate-
gory, opioid-induced constipation (OIC), which is distinct
from the FBDs by having a specific etiology that can produce
similar symptoms as FC. Clinically, OIC can overlap with FC
and so is included in this article, as clinicians may need to
evaluate both concurrently and may use different treat-
ments. This classification scheme is designed to assist both
researchers and clinicians; however, it is important to
acknowledge that significant overlap exists between these
disorders, and these disorders should be thought of as
existing on a continuum, rather than discrete disorders
(Figure 1). As these disorders exist on a continuum, it may
not always be possible to confidently separate them. Using
evidence from the scientific literature and a consensus-
based approach, the 2016 working team has revised the
Rome III diagnostic criteria and updated the clinical evalu-
ation and treatment for all FBDs.
C1. Irritable Bowel Syndrome
Definition
IBS is an FBD in which recurrent abdominal pain is
associated with defecation or a change in bowel habits.
Disordered bowel habits are typically present (ie, con-
stipation, diarrhea, or a mix of constipation and diarrhea), as
are symptoms of abdominal bloating/distention. Symptom
onset should occur at least 6 months before diagnosis and
symptoms should be present during the last 3 months.
Abbreviations used in this paper: BSFS, Bristol Stool Form Scale; CBC,
complete blood count; CC, chronic constipation; DD, dyssynergic
defecation; FAB, functional abdominal bloating; FAD, functional abdom-
inal distention; FBD, functional bowel disorder; FC, functional
constipation; FDr, functional diarrhea; FODMAP, fermentable oligosac-
charides, disaccharides, monosaccharides, and polyols; GI, gastrointes-
tinal; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome;
IBS-C, irritable bowel syndrome with constipation; IBS-D, irritable bowel
syndrome with diarrhea; IBS-M, irritable bowel syndrome with con-
stipation and diarrhea; IBS-U, irritable bowel syndrome unclassified; OIC,
opioid-induced constipation.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.031
 1394 Lacy et al Gastroenterology Vol. 150, No. 6

Table 1.Functional Gastrointestinal Disorders

3. Associated with a change in form (appearance) of
C. Functional bowel disorders stool
C1. Irritable bowel syndrome
C2. Functional constipation a
Criteria fulfilled for the last 3 months with symptom
C3. Functional diarrhea
C4. Functional abdominal bloating/distension
onset at least 6 months before diagnosis.
C5. Unspecified functional bowel disorders
C6. Opioid-induced constipation

Rationale for Changes From Previous Criteria

In contrast to the Rome III criteria, the term discomfort
Epidemiology has been eliminated from the current definition and diag-
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The world-wide prevalence of IBS is 11.2% (95% con-
fidence interval: 9.8%12.8%) based on a meta-analysis of
80 studies involving 260,960 subjects.1 The incidence of IBS
is estimated to be 1.35%1.5%, based on 2 separate lon-
gitudinal population studies lasting 10 and 12 years.2,3
Prevalence rates are higher for women than for men;
younger people are more likely to be affected than those
older than age 50 years.1
C1. Diagnostic Criteriaa for Irritable Bowel Syndrome
Recurrent abdominal pain, on average, at least 1 day per
week in the last 3 months, associated with 2 or more of
the following criteria:
1. Related to defecation
2. Associated with a change in frequency of stool
nostic criteria because not all languages have a word for
“discomfort,” it has different meanings in different lan-
guages, and the term is ambiguous to patients. One study of
IBS patients found that patients exhibited wide variations in
their understanding of this term.4 Another study demon-
strated that in 4 of 5 cases, the same individual would be
diagnosed with IBS regardless of which descriptor was
used.5
The current definition involves a change in the fre-
quency of abdominal pain, stating that patients should have
symptoms of abdominal pain at least 1 day per week during
the past 3 months. This is in contrast to Rome III criteria,
which defined IBS as the presence of abdominal pain (and
discomfort) at least 3 days per month. The requirement for
an increase in the frequency of abdominal pain is based on
data from the Report on Rome Normative GI symptom
survey.6

Figure 1. Conceptual framework to explain FBDs. The FBDs are classified into 5 distinct categories: IBS, FC, FDr, FAB/FAB,
and unspecified FBD (U-FBD). Although often thought of as existing as completely separate and discrete disorders, it is
important to acknowledge that significant overlap exists between these disorders. These disorders should be thought of as
existing on a continuum, rather than as in isolation. This figure illustrates that a patient with IBS (right) will have symptoms of
abdominal pain, in contrast to a patient with FC or FDr, who does not have abdominal pain. Bloating and distention are
common symptoms frequently reported by patients with any FBD.
May 2016
The phrase “improvement with defecation” was modi-
fied in the current definition to “related to defecation” as a
large subset of IBS patients do not have an improvement in
abdominal pain with defecation, but instead report a
worsening. Similarly, the word onset was deleted from
criteria 2 and 3 of the Rome III definition, as not all IBS
patients report the onset of abdominal pain directly coin-
ciding with a change in stool frequency or form.
Clinical Evaluation
The diagnosis of IBS requires a thoughtful approach,
limited diagnostic tests, and careful follow-up. The goal of
diagnostic criteria is to provide a readily useable framework
that can be easily applied, recognizing that no single test and
no single definition are perfect.7 Because a number of con-
ditions have symptoms that can mimic IBS (eg, inflamma-
tory bowel disease [IBD], celiac disease, lactose and fructose
intolerance, and microscopic colitis), limited testing may be
required to accurately distinguish these disorders. However,
for the majority of patients, when diagnostic criteria for IBS
are fulfilled and alarm features are absent, the need for
diagnostic tests should be minimal.8 Using the criteria out-
lined here, clinicians should make a positive diagnosis of IBS
based on symptoms and limited testing; performing a bat-
tery of tests in all patients suspected of having IBS is not
warranted. The diagnosis of IBS should be made based on
the following 4 key features: clinical history; physical
examination; minimal laboratory tests; and, when clinically
indicated, a colonoscopy or other appropriate tests.
The diagnosis of IBS begins with a careful history.
Abdominal pain must be present; the absence of abdominal
pain precludes the diagnosis of IBS. Pain can be present
anywhere throughout the abdomen, although it is more
common in the lower abdomen. A history of disordered
bowel habits (eg, constipation or diarrhea or both) should
be identified, along with their temporal association with
episodes of abdominal pain (see “Diagnostic Criteria for
Irritable Bowel Syndrome Subtypes”). Unpredictable bowel
pattern (
3 different stool form types/week) reinforces the
diagnosis of IBS in the diarrhea subtype (IBS-D).9 An
increasing number of consecutive days without a bowel
movement is associated with the diagnosis of constipation-
predominant (IBS) (IBS-C).10 Abnormal stool frequency
(>3 bowel movements/day and <3 bowel movements/
week), abnormal stool form (types 12 or 67 of the
Bristol scale; Figure 2), excessive straining during defeca-
tion, defecatory urgency, feelings of incomplete evacuation,
and mucus with bowel movements, although common in
IBS, are not specific. Abdominal bloating is present in a
majority of IBS patients; abdominal distention may be re-
ported as well, although neither is required to make the
diagnosis of IBS.
Diagnostic criteria for IBS subtypes (Figure 11-11,
FM 12)
Predominant bowel habits are based on stool form on
days with at least one abnormal bowel movement.a
Bowel Disorders 1395
IBS with predominant constipation: More than one-
fourth (25%) of bowel movements with Bristol stool
form types 1 or 2 and less than one-fourth (25%) of
bowel movements with Bristol stool form types 6 or 7.
Alternative for epidemiology or clinical practice: Patient
reports that abnormal bowel movements are usually
constipation (like type 1 or 2 in the picture of Bristol
Stool Form Scale (BSFS), see Figure 2A).
IBS with predominant diarrhea (IBS-D): more than one-
fourth (25%) of bowel movements with Bristol stool
form types 6 or 7 and less than one-fourth (25%) of
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bowel movements with Bristol stool form types 1 or 2.
Alternative for epidemiology or clinical practice: Patient
reports that abnormal bowel movements are usually
diarrhea (like type 6 or 7 in the picture of BSFS, see
Figure 2A).
IBS with mixed bowel habits (IBS-M): more than one-
fourth (25%) of bowel movements with Bristol stool
form types 1 or 2 and more than one-fourth (25%) of
bowel movements with Bristol stool form types 6 or 7.
Alternative for epidemiology or clinical practice: Patient
reports that abnormal bowel movements are usually
both constipation and diarrhea (more than one-fourth of
all the abnormal bowel movements were constipation
and more than one-fourth were diarrhea, using picture
of BSFS, see Figure 2A).
IBS unclassified (IBS-U): Patients who meet diagnostic
criteria for IBS but whose bowel habits cannot be
accurately categorized into 1 of the 3 groups above
should be categorized as having IBS unclassified.
For clinical trials, subtyping based on at least 2 weeks of
daily diary data is recommended, using the “25% rule.”
a
IBS subtypes related to bowel habit abnormalities (IBS-
C, IBS-D, and IBS-M) can only be confidently established
when the patient is evaluated off medications used to
treat bowel habit abnormalities.
Diagnostic Criteria for Irritable Bowel
Syndrome Subtypes
IBS is classified into 3 main subtypes according to the
predominant disorder in bowel habits: IBS-C, IBS-D, and
IBS-M (Table 1). Patients who meet diagnostic criteria for
IBS but whose bowel habits cannot be accurately catego-
rized into 1 of the 3 groups should be categorized as having
IBS unclassified. This group is not prevalent; difficulty in
accurately classifying a patient into 1 of the 3 main sub-
groups might occur as a result of frequent changes in diet or
medications, or inability to stop medications that affect
gastrointestinal transit. Subtyping should be based on the
patient’s reported predominant bowel habit on days with
abnormal bowel movements. The Bristol Stool Form Scale
(BSFS; Figure 2) should be used to record stool consis-
tency.11 In order to accurately classify bowel habit
 1396 Lacy et al Gastroenterology Vol. 150, No. 6
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Figure 2. (A) The BSFS is a

useful tool to evaluate
bowel habit. The BSFS has
been shown to be a reli-
able surrogate marker for
colonic transit.19 (B) IBS
subtypes should be
established according to
stool consistency, using
the BSFS. IBS subtyping is
more accurate when
patients have at least 4 days
of abnormal bowel habits
per month. Bowel habit
subtypes should be based
on BSFS for days with
abnormal bowel habits.

abnormalities, patients should not be on any type of medi-
cation used to treat bowel habit abnormalities (eg, evalua-
tion should occur off laxatives and off antidiarrheal agents).
For clinical trials, the IBS subtype should be based on 14
days of daily diary reports.12 Figure 2 illustrates a 2-
dimensional display of the 4 possible IBS subtypes.
IBS patients frequently report that symptoms are
induced or exacerbated by meals, although these symptoms
are not specific enough to be included in IBS diagnostic
criteria. A variety of other GI (ie, dyspepsia) and non-GI
symptoms (ie, migraine headaches, fibromyalgia, intersti-
tial cystitis, dyspareunia) are frequently present in IBS
patients; the presence of these concomitant symptoms lends
further support to the diagnosis.13–16 The presence of alarm
features (a positive family history of colorectal cancer, rectal
bleeding in the absence of documented bleeding hemor-
rhoids or anal fissures, unintentional weight loss, or anemia)
does not improve the performance of IBS diagnostic
criteria.17,18 However, it is reasonable to include them in a
directed review, as one study showed that the absence of
alarm symptoms reduced the likelihood of organic disease
in subjects with IBS-D symptoms.19 Patients should be
questioned about their diet, with special attention paid to
the ingestion of dairy products, wheat, caffeine, fruits, veg-
etables, juices, sweetened soft drinks, and chewing gum,
because these can mimic or exacerbate IBS symptoms.
Lastly, a brief psychosocial review should be performed.
A physical examination should be performed in every
patient evaluated for IBS. This reassures the patient and
helps to exclude an organic etiology. The presence of ascites,
May 2016
hepatosplenomegaly, or an abdominal mass warrants
further evaluation. An anorectal examination is mandatory
to identify anorectal causes of bleeding, evaluate anorectal
tone and squeeze pressure, and identify dyssynergic
defecation.
The third step in the diagnosis of IBS is to perform
limited laboratory studies, if not previously performed. A
complete blood count (CBC) should be ordered, as the
finding of anemia or an elevated white blood cell count
warrants further investigation. A C-reactive protein or fecal
calprotectin should be measured, as a systematic review and
meta-analysis showed that these tests are helpful in
excluding IBD in patients with symptoms suggestive of
nonconstipated IBS.20 If inflammatory markers are mildly
elevated, but the probability of IBD is low, then tests should
be remeasured before performing colonoscopy (if no other
indication for colonoscopy exists).21 Inflammatory markers,
including fecal calprotectin, may not be useful in patients
with constipation symptoms. Routine thyroid tests are not
indicated in all patients, but can be checked if clinically
warranted. Serologic tests for celiac disease should be per-
formed in patients with IBS-D and IBS-M who fail empiric
therapy. Upper gastrointestinal endoscopy with duodenal
biopsies should be performed if serologic tests for celiac
disease are positive or if clinical suspicion is high; duodenal
biopsies can also be used to identify tropical sprue, which
can mimic IBS symptoms.22 Stool analysis (bacteria, para-
sites, and ova) may be useful if diarrhea is the main
symptom, especially in developing countries where infec-
tious diarrhea is prevalent.
A screening colonoscopy is indicated in patients 50 years
and older in the absence of warning signs (45 years in
African Americans), based on national recommendations.
Colonoscopy is also indicated for the presence of alarm
symptoms or signs, a family history of colorectal cancer and
persistent diarrhea that has failed empiric therapy. Biopsies
of different segments of the colon may be required in
patients with chronic diarrhea to rule out microscopic
colitis.23 Bile acid malabsorption may be the cause of
persistent, watery diarrhea in some patients.24 If empiric
therapy fails, scintigraphic evaluation (75SeHCAT test) or
postprandial serum C4 (7a-hydroxy-4-cholesten-3-one) or
fibroblast growth factor 19 are diagnostic options, although
none are currently widely available. Breath tests to rule out
carbohydrate malabsorption may be useful in some patients
with IBS symptoms and persistent diarrhea.
Physiologic Features
IBS is a multifactorial disorder with a complex patho-
physiology. Factors that increase the risk of developing IBS
include genetic, environmental, and psychosocial factors.
Factors that trigger the onset or exacerbation of IBS symp-
toms include a prior gastroenteritis, food intolerances,
chronic stress, diverticulitis, and surgery.25 The resulting
pathophysiologic mechanisms are variable and patient
independent, and include altered GI motility, visceral
hyperalgesia, increased intestinal permeability, immune
activation, altered microbiota, and disturbances in
braingut function (Figure 2).
Bowel Disorders 1397
Psychosocial Features
Psychological disturbance is associated with IBS, espe-
cially in patients who seek medical care,26 and psychosocial
factors affect outcome.27 Regardless of care-seeking status,
IBS is associated with more psychiatric distress, sleep
disturbance, “affective vulnerability,” and “over-adjustment
to the environment.”28
Treatment
IBS treatment begins by explaining the condition,
providing reassurance as to the benign natural history, and
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educating the patient about the utility and safety of diag-
nostic tests and treatment options. Treatment should be
based on symptom type and severity. In research trials, the
validated IBS symptom severity scale can be used to quan-
tify symptom severity.29
Although data are limited, lifestyle modifications that
may improve IBS symptoms include exercise, stress reduc-
tion, and attention to impaired sleep.30 Dietary fiber sup-
plementation remains a cornerstone of IBS management,
although its optimal use can be quite nuanced. A recent
systematic review and meta-analysis identified 12 trials
comparing fiber with control and found only a marginal
difference in the proportion of IBS patients with persistent
symptoms after any type of fiber vs the control interven-
tion.31 Subgroup analysis suggested that benefits for IBS
symptoms were confined to soluble (psyllium/ispaghula
husk) and not insoluble (bran) fiber. Certain forms of fiber,
and particularly bran, can exacerbate problems of abdom-
inal distention and flatulence.32
Dietary restriction of gluten may improve symptoms in
some IBS patients. Two small prospective studies in IBS
patients, in which celiac disease was carefully excluded,
demonstrated global symptom improvement.33,34 Dietary
FODMAP (fermentable oligosaccharides, disaccharides,
monosaccharides, and polyols) restriction is associated with
reduced fermentation and significant symptom improve-
ment in some IBS patients.35 In a randomized, controlled,
single-blind cross-over trial, 30 IBS patients who had not
previously tried dietary manipulation reported significant
reduction in overall gastrointestinal symptom scores
compared with those on a standard Australian diet.36 Add-
ing a gluten-free diet to IBS patients already on a low
FODMAP diet does not offer additional benefit.37 Another
recent comparative effectiveness study concluded that a low
FODMAP diet and standardized traditional teaching from a
dietitian yielded similar results in IBS patients.38
Several peripherally acting agents are available to treat
IBS-C symptoms (Table 2). A randomized controlled trial
(RCT) of polyethylene glycol (PEG) vs placebo demonstrated
improvements in stool frequency, stool consistency, and
straining, but not abdominal pain or bloating during the 4-
week study.39 Lubiprostone is a luminally acting prostone
that selectively activates type 2 chloride channels.40,41 In 2
large, placebo-controlled, randomized studies lubiprostone
(8 mg twice daily) resulted in significantly higher overall
symptom response compared with placebo during 12 weeks
of treatment.42 A subsequent 52-week extension study
 1398 Lacy et al Gastroenterology Vol. 150, No. 6

Table 2.Therapeutic Options for Irritable Bowel Syndrome Based on Predominant Symptom

Symptom Therapy Dose

Diarrhea Opioid agonists Loperamide; 24 mg; when necessary

Titrate up to 16 mg/d
Diet Low/no gluten; low FODMAP
Bile salt sequestrants cholestyramine (9 g bidtid)
colestipol (2 g qdbid)
colesevelam (625 mg qdbid)
Probiotics Multiple products available
Antibiotics Rifaximin, 550 mg po tid  14 d
5-HT3 antagonists Alosetron (0.51 mg bid)
Ondansetron (48 mg tid)
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Ramosetron 5 mg qd
Mixed opioid agonists/antagonists Eluxadoline, 100 mg bid
Constipation Psyllium up to 30 g/d in divided doses
PEG 1734 g/d
Chloride channel activators Lubiprostone, 8 mg bid
Guanylate Cyclase C agonists Linaclotide 290 mg qd
Abdominal Smooth muscle antispasmodics dicycylomine (1020 mg qdqid)
pain
Otilonium (4080 mg bidtid)
Mebeverine (135 mg tid)
Peppermint oil Enteric-coated capsules, 250750 mg, bidtid

Tricyclic antidepressants Desipramine (25100 mg qhs), amitriptyline (1050 mg qhs)

SSRIs paroxetine (1040 mg qd)

Chloride channel activators
Guanylate cyclase C agonists
5-HT3 antagonists
sertraline (25100 mg qd)
citalopram (1040 mg qd)
Lubiprostone 8 mg bid
Linaclotide 290 mg qd
Alosetron 0.51.0 mg bid

SSRI, selective serotonin reuptake inhibitor; qhs, at bedtime.

identified the most common adverse events as nausea and
diarrhea.43 Linaclotide is a 14-amino acid peptide that acts
as a guanylate cyclase C agonist. In 2 large phase 3 trials,
linaclotide was found to be more effective than placebo at
improving bowel and abdominal symptoms in IBS-C
patients.44–46 A 6-month, double-blind, placebo-controlled
phase 3 trial utilized a combined end point, which required
improvement of
30% from baseline in mean daily worst
abdominal pain score, as well as an increase of
1 complete
spontaneous bowel movement from baseline for
6 and 12
weeks. Linaclotide proved superior to placebo in 12- and
26-week studies. Diarrhea was the most commonly reported
adverse event with linaclotide. A second guanylate cyclase C
agonist, plecanatide, is currently in development.47 A small
pilot study showed that supplementation of bile acids using
sodium chenodeoxycholic acid may improve IBS-C symp-
toms in some patients.48
Loperamide, a synthetic peripheral m-opioid receptor
agonist that decreases colonic transit, and increases water
and ion absorption, is commonly used to treat IBS-D
patients. In one small placebo RCT, loperamide improved
stool consistency, pain, urgency, and subjective overall
response.49 In another study, loperamide improved stool
consistency, reduced bowel frequency, and reduced in-
tensity of pain, although it increased nightly abdominal
pain.50 There is increasing evidence to support a role for
bile acids in the pathophysiology of IBS-D.24 In small pilot
studies, bile acid sequestrants (eg, colesevelam and coles-
tipol) improved stool passage and stool consistency.51,52
Antispasmodics are used to treat abdominal pain and
spasms in all IBS subtypes. A meta-analysis involving 12
different antispasmodics found this class of drugs to be
superior to placebo for the prevention of recurrent IBS
symptoms.31 A recent meta-analysis found peppermint oil,
which also has antispasmodic properties, to be significantly
superior to placebo for global improvement of IBS symp-
toms and improvement in abdominal pain. Heartburn was
the most common adverse effect.53
Probiotics may benefit IBS patients through multiple
mechanisms.54 Bifidobacterium infantis 35624 led to sig-
nificant improvements in abdominal pain/discomfort,
bloating/distention, and/or bowel movement difficulty
compared with placebo in 2 randomized, placebo-controlled
trials conducted in IBS patients.55,56 A recent meta-analysis
that included 43 clinical trials using different products
found probiotics to offer benefits for global IBS symptoms,
pain, bloating, and flatulence.57
The US Food and Drug Administration approved rifax-
imin, a nonabsorbable antibiotic, for the treatment of IBS-D.
In 2 large clinical trials, 2 weeks of treatment with rifaximin
May 2016
550 mg 3 times daily in patients with nonconstipated IBS
resulted in significantly more patients reporting adequate
relief of global IBS symptoms and bloating during the first 4
weeks of follow-up.58 Improvement in symptoms relative to
placebo persisted for the 10-week follow-up period, even
though a gradual loss of symptom response was noted.
Repeat treatment with rifaximin appears to offer similar
efficacy to an initial course of therapy. Patients with IBS-D
who relapsed during an 18-week follow-up period were
more likely to respond to retreatment with rifaximin
compared with placebo.59
Alosetron, a highly selective 5-HT3 antagonist, is effective
at relieving pain and reducing stool frequency and rectal
urgency in women with IBS-D.31,40 Alosetron is approved
with restrictions in the United States for women with severe
IBS-D beginning at 0.5 mg twice daily. Uncommon adverse
events include ischemic colitis and constipation, 0.95 and
0.36 cases per 1000 patient-years, respectively.60 The 5-HT3
antagonists ondansetron and ramosetron also appear effec-
tive in the treatment of IBS-D.61,62
Eluxadoline is a novel mixed m-receptor agonist/d-opioid
receptor antagonist that has been developed as a treatment
for patients with IBS-D.63 In 2 large phase 3 trials involving
>2,400 IBS-D patients, a greater percentage of eluxadoline-
treated patients (75 and 100 mg oral once daily) were
combined responders (both abdominal pain and diarrhea)
during weeks 112 or 126 compared with patients on
placebo. The most common adverse events were nausea
(8%), constipation (8%), and abdominal pain (5.0%). A
small number of patients experienced sphincter of Oddi
dysfunction or self-limited pancreatitis. All of these patients
had a history of cholecystectomy or significant ethanol
consumption. Eluxadoline should be used at the lower dose
and with careful monitoring in these patients.64
Tricyclic antidepressant agents appear effective in
treating IBS symptoms.65 In a 2-month trial of IBS-D
patients, 10 mg of amitriptyline significantly improved over-
all IBS symptoms and reduced the frequency of loose stool and
feelings of incomplete defecation, and led to a complete
response (defined as loss of all symptoms).66 A recent sys-
tematic review and meta-analysis summarized the efficacy
data for selective serotonin reuptake inhibitors. Seven trials
were included, demonstrating benefits of selective serotonin
reuptake inhibitors over placebo for overall IBS symptoms.65 A
number of clinical characteristics, including the predominant
stool complaint, the presence of insomnia, or comorbid anxiety,
can influence the choice of antidepressant in an individual IBS
patient. Few data are available on the use of selective norepi-
nephrine reuptake inhibitors in IBS.
Disodium cromoglycate, a mast cell stabilizer, may
improve symptoms in some IBS-D patients.67 Two recent
appropriately powered, high-quality RCTs demonstrated no
significant efficacy of mesalazine vs placebo in IBS-D.68,69
Fecal microbiota transplantation, herbal therapies, and
complementary therapies are also potential treatments,
however, these have not been rigorously studied. RCTs have
consistently failed to show benefit of acupuncture compared
with sham acupuncture.70 The efficacy of psychological/
behavioral therapies including cognitive behavioral therapy
Bowel Disorders 1399
and hypnotherapy is discussed in detail in the article on
psychological therapies.
Psychological and behavioral treatments relates to
helping patients control and reduce pain and discomfort and
are seen as ancillary to or augmenting medical treatments.
Treatments include cognitive behavioral therapy, hypnosis,
and various relaxation methods to reduce muscle tension
and autonomic arousal believed to aggravate GI symptoms.
A large number of studies in IBS confirm the values of these
treatments and are discussed in detail in this issue (Bio-
psychosocial Aspects of Functional Gastrointestinal
Disorders).
BOWEL
C2. Functional Constipation
Definition
FC is a functional bowel disorder in which symptoms of
difficult, infrequent, or incomplete defecation predominate.
Patients with FC should not meet IBS criteria, although
abdominal pain and/or bloating may be present but are not
predominant symptoms. Symptom onset should occur at
least 6 months before diagnosis, and symptoms should be
present during the last 3 months.
Epidemiology
Few studies have evaluated the incidence and preva-
lence of FC. Most studies have focused on patients with
chronic constipation (CC), who may or may not meet strict
criteria for FC. One study reported onset rates of 40/1000
person-years when patients were resurveyed a median of
14.7 months after the initial survey.71 Using modified Rome
II criteria, a community study identified a 12-year cumula-
tive incidence of constipation of 17.4%.72 In adults, the
mean prevalence rate of CC is approximately 14%, with
rates that range from 1.9% to 40.1%.73 Self-report rates of
constipation are generally higher compared with use of
Rome criteria. Risk factors for FC include female sex,
reduced caloric intake, and increasing age.74,75
C2. Diagnostic Criteriaa for Functional Constipation
1. Must include 2 or more of the following:b
a. Straining during more than one-fourth (25%)
of defecations
b. Lumpy or hard stools (BSFS 12) more than
one-fourth (25%) of defecations
c. Sensation of incomplete evacuation more than
one-fourth (25%) of defecations
d. Sensation of anorectal obstruction/blockage
more than one-fourth (25%) of defecations
e. Manual maneuvers to facilitate more than one
fourth (25%) of defecations (eg, digital evacu-
ation, support of the pelvic floor)
f. Fewer than 3 spontaneous bowel movements
per week
 1400 Lacy et al
2. Loose stools are rarely present without the use of
laxatives
3. Insufficient criteria for irritable bowel syndrome
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months prior to diagnosis.
b
For research studies, patients meeting criteria for OIC
should not be given a diagnosis of FC because it is
difficult to distinguish between opioid side effects and
other causes of constipation. However, clinicians recog-
BOWEL
nize that these 2 conditions might overlap.
Rationale for Changes From Previous Criteria
The following points highlight notable changes from the
Rome III criteria. It is now specified that abdominal pain
and/or bloating may be present but are not predominant
symptoms (ie, the patient does not meet criteria for IBS).
This supports the concept that FC and IBS-C are disorders
that exist on a continuous spectrum.
Clinical Evaluation
FC can be diagnosed by both subjective and objective
(measurable) variables. A survey study of patients with CC
determined that the most frequent symptoms were strain-
ing (79%), hard stools (71%), abdominal discomfort (62%),
bloating (57%), infrequent bowel movements (57%), and
feelings of incomplete evacuation after a bowel movement
(54%).76 When necessary, objective tests can be performed
and these measures of stool frequency, daily stool weight
(<35 g/d), colonic transit, and anorectal function. Diag-
nostic evaluations should be performed while the patient is
not taking laxatives. Mechanical obstruction, medications,
and systemic illnesses can cause constipation, and these
causes of secondary constipation must be excluded, espe-
cially in patients presenting with new onset constipation.
Most often, however, constipation is caused by disordered
function of the colon or rectum. CC can be divided into 3
broad categories: normal-transit constipation, slow-transit
constipation, and defecatory or rectal evacuation disorders.
Colonic transit time can be estimated by using the BSFS
(Figure 2): stool forms 1 and 2 are associated with slower
transit, while stool forms 6 and 7 are associated with more
rapid transit.11 The committee recognizes that a subset of
patients with symptom criteria for FC have slow colonic
transit.77 As well, some FC patients have overlapping dys-
synergic defecation (DD).31 It is the opinion of this com-
mittee that all cases of CC without evidence of structural or
metabolic abnormalities to explain symptoms should be
considered under the “umbrella” of FC. We acknowledge,
however, that the diagnosis of slow transit constipation or a
DD requires diagnostic tests (discussed later), which may
modify treatment strategies.
The diagnosis of FC should be made using the following
5 key features: clinical history, physical examination, mini-
mal laboratory tests, colonoscopy or other tests (if clinically
indicated and available), and specific tests to evaluate
Gastroenterology Vol. 150, No. 6
constipation pathophysiology (if clinically indicated and
available).
When taking a history, it is important to understand
what the patient means when reporting constipation. A
detailed history should include the duration of symptoms;
frequency of bowel movements; associated symptoms, such
as abdominal pain, bloating, or distention; and an assess-
ment of stool consistency, stool size, and degree of straining
during defecation. The presence of alarm features, such as
unintentional weight loss (>10% in 3 months), rectal
bleeding (in the absence of documented bleeding hemor-
rhoids or anal fissures), and a family history of colon cancer
(or familial polyposis syndromes) should be elicited. A long
duration of symptoms refractory to conservative measures
is suggestive of an FBD. By contrast, the new onset of con-
stipation might indicate a structural disease.31 It is impor-
tant to identify DD because it has a distinct pathophysiology
and is more likely to respond to specific treatments. DD can
be suspected by using specific questionnaires and by per-
forming a thorough physical examination, although objec-
tive measures are often required (discussed later).78,79
A physical examination should exclude central nervous
system disorders and spinal lesions. The abdomen should be
examined for distention, hard stool in a palpable colon, or a
mass. A careful rectal examination is essential. The peri-
neum should be observed both at rest and after the patient
strains as if to have a bowel movement. A digital rectal
examination can identify a fecal impaction, anal stricture, or
rectal mass. Inappropriate contraction of the puborectalis
muscle and/or anal sphincter during simulated evacuation
is consistent with DD.78,79
A CBC should be obtained if not recently performed.
Thyroid-stimulating hormone and serum calcium should be
performed when clinically indicated. All patients aged older
than 50 years (45 years and older in African Americans) should
have a screening colonoscopy based on national recommen-
dations. The presence of alarm symptoms or a family history of
colorectal cancer should prompt earlier intervention.
Testing for slow colonic transit and/or DD is neither
required nor justified in all patients. Patients who do not
respond to reasonable trials of empiric therapy should un-
dergo diagnostic evaluation to identify physiological sub-
groups. Radiopaque markers can be used to evaluate colonic
transit; this is inexpensive, simple and safe.80,81 A radio-
isotope technique involves less radiation than x-ray studies
and may provide more information,82 although it is avail-
able in very few centers. Anorectal manometry and balloon
expulsion testing may help identify DD.83 Defecography may
detect anatomic etiologies, such as intussusception and
rectocele with stool retention, as well as inability to relax
the puborectalis or decrease the anorectal angle with
straining, features typical of DD.84 Electromyography and
pudendal nerve latency testing are adjunctive techniques
(see section on Anorectal Disorders).
Physiologic Features
Similar to IBS, symptoms of FC arise due to a variety of
pathophysiologic processes. Several studies suggest
May 2016
constipation shows familial clustering.85,86 Data supporting
a direct genetic cause are sparse.87,88 Limited data from
pediatric studies raise the possibility that lifestyle factors in
childhood (low fiber intake, low fluid intake, and ignoring
the call to stool) may play a role in the development of
constipation.89–93 Two studies have shown that high fiber
intake reduced the risk of constipation.75,94 Regular exercise
is associated with a significantly reduced risk of con-
stipation.75,95,96 Small RCTs have shown that there is no
benefit in increasing fluid intake in those who are hydrated
normally.97
Transit studies in constipated subjects show disparate
results, with slow colonic transit in some patients but
normal transit in others.98–100 In those with delayed transit,
variations exist with regard to which colonic segment is
affected.101,102 Most FC patients do not have evidence of
visceral hypersensitivity when evaluated by rectal barostat
testing, although some have rectal hyposensitivity.103
Autonomic dysfunction, morphologic changes in the myen-
teric and submucosal plexus, and reduced neurotransmitter
levels (eg, VIP, NO, 5-HT) have been demonstrated in some
patients with slow transit constipation.103–108 Confocal mi-
croscopy studies and pathology specimens from patients
with slow-transit constipation undergoing colectomy have
showed reduced numbers of interstitial cells of Cajal.109–111
Psychosocial Features
There is no specific psychological feature or personality
that is associated with constipation, but constipation
reporting, stool output, and gut dysmotility may be affected
by personality, stress, and early toilet training.112 Patients
with severe constipation and normal intestinal transit often
have increased psychological distress, and may have mis-
perceptions about their bowel frequencies.112,113 In addi-
tion, abnormal illness behavior is more common in patients
with chronic constipation compared with nonpatients.114
Constipation behavior can be learned in early life; delib-
erate suppression of defecation leads to reduced stool fre-
quency and weight and increased transit time.115
Treatment
Treatment should begin by educating the patient about
FC, eliminating medications (prescription, over-the-counter,
complementary) that can cause or worsen constipation,
asking the patient to maintain a diet that contains an
adequate amount of fiber, scheduling routine bathroom time
after the morning or evening meal, and elevating the feet
with a foot stool or using a toilet that is lower to the ground.
If symptoms persist, empiric therapy can be initiated in the
absence of warning signs. If empiric therapy fails after an
appropriate clinical trial (ie, 48 weeks), then physiological
testing should be considered to identify the underlying
disorder and initiate the most appropriate treatment.
Empiric therapy should begin with a fiber supplement
(Table 3).116 Insoluble, nonfermentable fiber accelerates
transit by increasing stool biomass leading to direct stimu-
lation of secretion and motility. Soluble, more fermentable
forms of fiber may accelerate transit via hydrophilic
Bowel Disorders 1401
Table 3.Therapeutic Options for Functional Constipation
Drug Dose
Psyllium Up to 30 mg/d in divided doses
PEG 1734 g/d
Chloride channel activators Lubiprostone, 24 mg bid
Guanylate cyclase C agonists Linaclotide 145 mg qd
Prucalopride 24 mg/d
properties and the osmotic effects of fermentation by-
BOWEL
products. Total fiber intake of 2030 g/d is recom-
mended, although dose-dependent bloating, distention, and
flatulence can affect tolerability and compliance. Consti-
pated patients with severely delayed colon transit and/or
obstructed defection are less likely to improve with
fiber.31,77
Prospective RCTs dictating the choice of therapy after a
patient fails fiber therapy are not available. However, os-
motic agents are often used next, given their safety, cost,
and efficacy.31,73,117,118 Osmotic laxatives (eg, lactulose,
lactitol, mannitol, and sorbitol) are not absorbed by the
small intestine; ingestion causes net water and electrolyte
secretion, resulting in reduced stool viscosity and increased
fecal biomass with secondary effects on peristalsis.113–115
Side effects include dose-dependent abdominal cramping
and bloating.115 PEG, another osmotic agent, has been
evaluated in high-quality RCTs of up to 6 months.116 PEG is
superior to placebo and lactulose in adults and child-
ren.119–123 Adverse effects of PEG include distention and
diarrhea. Saline laxatives, including magnesium citrate,
magnesium sulfate, and sodium and disodium phosphate,
induce movement of water into the small intestine and
colon. RCTs evaluating the efficacy of these agents have not
been performed; they should be used cautiously in the
elderly and avoided in those with renal impairment.124
Stimulant laxatives (diphenylmethane derivatives, eg,
bisacodyl, sodium picosulfate, and conjugated anthraqui-
none derivatives, eg, cascara sagrada, aloe, and senna)
decrease water absorption and stimulate intestinal motility
and prostaglandin release.125–127 RCTs have demonstrated
clinical benefits for stool frequency and other constipation-
associated symptoms with bisacodyl and sodium picosulfate
in patients with CC.128,129 The most common side effects are
abdominal pain and diarrhea.128,129
Two pro-secretory agents (secretagogues) improve
symptoms of CC. In 4 week, RCTs of patients with CC,
lubiprostone (24 mg twice daily with food) proved superior
to placebo at increasing stool frequency, improving stool
consistency and reducing straining and overall constipation
symptoms.130–132 Nausea and diarrhea were the most
common adverse events. In 12-week RCTs, linaclotide (145
mg once daily) was more effective than placebo at increasing
stool frequency, improving stool consistency, straining, and
overall constipation symptoms.133 The most common
treatment-associated side effect was diarrhea. Plecanatide,
another guanylate cyclase C agonist, at 3 mg once daily, may
also be effective for FC.134
 1402 Lacy et al
Elobixibat is a nonabsorbed, small molecule that inhibits
ileal bile acid transporters. Still under development at this
time, elobixibat improves stool frequency and other con-
stipation associated symptoms in patients with CC. The most
commonly reported adverse events have been dose-
dependent abdominal pain and diarrhea.135–137
5-HT4 receptor agonists stimulate peristalsis and accel-
erate gastrointestinal transit.138–140 Tegaserod, a highly
selective, partial 5-HT4 receptor agonist, was found superior
to placebo at improving stool frequency and other con-
stipation associated symptoms.141,142 Tegaserod was with-
drawn from the United States and most other markets in
BOWEL
2007 due to concerns involving possible cardiovascular
adverse events. Prucalopride is a dihydrobenzofur-
ancarboxamide derivative with greater selectivity for the
5-HT4 receptor compared with other 5-HT4 agonists. RCTs
have reported that prucalopride (14 mg daily) improves
CC symptoms, including stool frequency, stool consistency,
and straining. The most common adverse events of head-
aches, nausea, and diarrhea tended to occur within 24 hours
of initiating treatment and were often transient.143,144
Prunes (50 g or roughly 6 prunes twice daily)145 and hemp
seed extract (7.5 g twice daily) improved stool frequency and
constipation severity during separate 8-week trials.146 A sys-
tematic review that included the results of 5 RCTs concluded
that probiotics may increase stool frequency and improve
stool consistency in patients with CC—organisms studied
included Bifidobacterium lactis DN-173 010, Lactobacillus
casei Shirota, and Escherichia coli Nissle 1917.147
C3. Functional Diarrhea
Definition
Functional diarrhea (FDr) is an FBD characterized by
recurrent passage of loose or watery stools. Patients with FDr
should not meet criteria for IBS although abdominal pain
and/or bloating may be present, but are not predominant
symptoms. Recurrent passage of loose or watery stool onset
should have occurred at least 6 months before diagnosis and
symptoms should be present during the last 3 months.
Epidemiology
The incidence and prevalence of FDr have not been well
investigated. Using a matched, casecontrol approach, the
incidence of FDr was estimated at 5 per 100,000 patient-
years, and a preceding infectious gastroenteritis was a sig-
nificant risk factor.148 Reported prevalence rates for FDr
range from 1.5% to 17%.149–153
C3. Diagnostic Criteriona for Functional Diarrhea
Loose or watery stools, without predominant abdominal
pain or bothersome bloating, occurring in >25% of
stools.b
a
Criterion fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis
b
Patients meeting criteria for diarrhea-predominant IBS
should be excluded
Gastroenterology Vol. 150, No. 6
Rationale for Changes From Previous Criteria
Changes from Rome III criteria include removing the
term mushy, as this was felt to be redundant, and specifying
that abdominal pain and/or bloating may be present but are
not predominant symptoms (ie, patients do not meet
criteria for IBS). In addition, 75% of stools being loose has
been changed to >25% based on data from the Rome
Normative GI symptom survey.6
Clinical Evaluation
The diagnosis of FDr should be made based on 3 key
features: clinical history; physical examination; and limited
diagnostic tests. The evaluation should start with a careful
history. Diarrhea should be defined by stool form, not fre-
quency, as stool consistency correlates well with colon
transit.11 IBS should be excluded (see section on IBS). A
stool diary incorporating the BSFS (Figure 2) helps to verify
stool consistency and excludes pseudodiarrhea.154 A dietary
history should be taken to exclude lactose and fructose
malabsorption, and the ingestion of excess amounts of fiber
or poorly absorbed carbohydrates. Alarm features, such as
unintentional weight loss, diarrhea awakening the patient,
recent antibiotic use, hematochezia (in the absence of
documented bleeding hemorrhoids or anal fissures), high-
volume diarrhea (>250 mL/d), very frequent bowel
movements (>610 per day), evidence of malnutrition, or a
family history of colorectal neoplasia, celiac disease, or in-
flammatory bowel disease, should prompt further
investigation.155,156
The physical examination of a patient with FDr should be
normal. A careful anorectal examination should be per-
formed to assess anal sphincter tone (especially important
in patients with incontinence), and to identify a mass,
fissure, or hemorrhoidal disease (especially important in a
patient with hematochezia).
A CBC and C-reactive protein should be checked in all
patients with chronic diarrhea. A thyroid profile can be
performed if there is clinical suspicion of hyperthyroidism.
Serologic tests for celiac disease should be checked in those
that fail empiric therapy (and consider esophagogas-
troduodenoscopy with duodenal biopsies if antibody tests
are positive or if clinical suspicion is high). Stool analysis
(bacteria, parasites, and ova) should be performed in
endemic areas, and fecal calprotectin should be checked if
clinical suspicion for an inflammatory process is high.
Giardiasis and tropical sprue should be excluded in the
appropriate clinical setting.
For patients with persistent symptoms, stool specimens
can be analyzed for fecal elastase-1 and fat to identify a
malabsorptive process; a negative test should minimize the
need for further diagnostic studies.157 Colonoscopy should
be considered in those who have failed empiric therapy, in
those with alarm symptoms, and in all patients older than
age 50 years for screening purposes (older than age 45
years in African Americans) based on national recommen-
dations. When performed, random biopsies should be
obtained from both the right and left colon to rule out
microscopic colitis. Bile acid malabsorption, which is an
May 2016
often overlooked diagnosis in patients with longstanding
diarrhea, can be identified, when available, by using
75
SeHCAT.158 Breath tests can identify carbohydrate
malabsorption, but if not available, then dietary exclusion
of the suspected carbohydrate (eg, 34 weeks) is
recommended.
Physiologic Features
Similar to other FBDs, no single pathophysiological ab-
normality can explain the cause of FDr in every patient.
Rather, a number of diverse mechanisms seem to contribute
to symptom generation, including altered GI motility,
braingut disturbances, genetic and environmental factors,
prior infections, and psychosocial factors.159 Genetic studies
in FDr patients have not been performed. One study reported
that fasting and postprandial colonic propagating contrac-
tions are increased in FDr, while a small pilot study showed
normal left colonic tone during fasting and a reduced dura-
tion of increased tone postprandially.160,161 Similar to IBS, a
prior infection can lead to post-infectious FDr.162,163
Psychosocial Features
There are few data on psychological features in FDr
patients. While anxiety often accompanies IBS, few data
apply specifically to FDr. Acute stress accelerates colonic
transit in humans and animals,164 but the relevance of this
finding to chronic stress, and to FDr patients, is uncertain.
Treatment
Few studies have evaluated specific treatments for FDr
patients. Data from studies in patients with other conditions
like IBS-D tend to be extrapolated to the treatment of
patients with FDr. Dietary interventions and fiber supple-
mentation have not been evaluated. Loperamide, a m-opioid
agonist, improves stool frequency and consistency, as well
as urgency and incontinence, in patients with FDr and
IBS-D.49,50,165 Cholestyramine (4 g twice daily) is effective
and safe for short-term treatment of patients with FDr
presumably secondary to bile acid malabsorption.166 Pro-
biotics, antibiotics, and 5-HT3 antagonists may all improve
diarrhea symptoms but have not been tested specifically in
FDr patients.
C4. Functional Abdominal
Bloating/Distension
Definition
Functional abdominal bloating (FAB)/distention (FAD)
is characterized by symptoms (subjective) of recurrent
abdominal fullness, pressure, or a sensation of trapped gas
(FAB), and/or measurable (objective) increase in abdominal
girth (FAD). Patients should not meet criteria for other
FBDs, although mild abdominal pain and/or minor bowel
movement abnormalities may coexist. Symptom onset
should be at least 6 months before diagnosis and the pre-
dominant symptom (bloating or distention) should be pre-
sent during the last 3 months.
Bowel Disorders 1403
FAB and FAD should be classified as a single entity
(functional abdominal bloating/distention) although they
encompass 2 different symptoms/signs. These conditions
may exist independently, although they frequently coincide
in the same individual. The distinct nature of these disor-
ders is demonstrated by research showing that only 50%
60% of patients with bloating have abdominal distention
and the correlation between abdominal bloating and an
increase in abdominal girth is poor.167,168 Further research
may allow FAB and FAD to be considered separate entities.
Epidemiology
BOWEL
The incidence of functional bloating has not been evalu-
ated in large prospective studies. The prevalence of bloating
is better described. A large (n ¼ 2510) telephone survey of US
adults reported that 15.9% had symptoms of bloating or
distention in the month before the interview.169 Women were
more likely to report bloating than men (19.2% vs 10.5%) to
rate their bloating as severe (23.8% vs 13%). Two other large
prospective studies of US adults identified similar prevalence
rates of bloating (21% and 19%).170,171 Patients with FGIDs
are more likely to report co-existing symptoms of bloating,
especially those with IBS-C and FC.172–177
Rationale for Changes From Previous Criteria
The current definition includes the addition of the
phrase “abdominal fullness, pressure or a sensation of
trapped gas” to reflect commonly reported symptoms. FAD
has been added as a separate diagnosis. This addition helps
distinguish subjective sensations of bloating from the
objective finding of an increase in abdominal girth seen in
patients with FAD. The change in definition also reflects the
use of new technologies (eg, abdominal plethysmography)
and a new understanding of the pathophysiology of
distention. FAD is typically seen in conjunction with FAB,
although it can occur independently. A further change from
the Rome III criteria is the acknowledgment that FAB/FAD
patients may also report symptoms of mild abdominal pain
and/or minor bowel movement abnormalities.
C4. Diagnostic Criteriaa for Functional Abdominal
Bloating/Distension
Must include both of the following:
1. Recurrent bloating and/or distention occurring,
on average, at least 1 day per week; abdominal
bloating and/or distention predominates over
other symptoms.b
2. There are insufficient criteria for a diagnosis of
irritable bowel syndrome, functional constipation,
functional diarrhea, or postprandial distress
syndrome.
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months prior to diagnosis.
Mild pain related to bloating may be present as well as
b
minor bowel movement abnormalities.
 1404 Lacy et al
Clinical Evaluation
FAB/FAD should be diagnosed based on the following 3
key features: clinical history, physical examination, and
limited diagnostic studies.
The evaluation of a patient with abdominal bloating
and/or distention should begin with a careful history, which
includes the onset of symptoms, the relationship to diet (eg,
wheat, dairy, fructose, fiber, nonabsorbable sugars) and
bowel habits, and the presence of symptoms suggestive of
other FGIDs. Alarm features, such as anemia and uninten-
tional weight loss, should be assessed, as these symptoms
may be evidence of a malabsorptive process. Patients with
BOWEL
FAB/FAD typically report a worsening of symptoms as the
day progresses, particularly after meals, but alleviation of
symptoms overnight.178,179 Diurnal worsening of bloating is
frequently accompanied by increased girth.180
During the physical examination, bloating (subjective)
and distention (objective) should be differentiated and
explained to the patient. The term abdominal distention
should be reserved for patients who show a visible increase
in abdominal girth. Evidence of a partial bowel obstruction
or organomegaly warrants further evaluation. A pelvic ex-
amination should be performed when appropriate.
Validated guidelines for the evaluation of bloating do not
exist. Many clinicians favor empiric therapy in the absence of
warning signs. Alternatively, limited testing may be useful. An
abdominal x-ray can evaluate for possible obstruction. A CBC
should be performed if there are warning signs of anemia.
Serologic tests can be used to identify celiac disease. If the
clinical suspicion for celiac disease is high, or if serological
test are positive, an upper endoscopy with duodenal biopsies
should be performed. Small intestinal bacterial overgrowth
can be evaluated by culturing the jejunal aspirate or by per-
forming a breath test, preferably with glucose.181
Physiologic Features
The pathophysiology of bloating remains incompletely
understood, in part, because the etiopathophysiology varies
from patient to patient. Potential causes include visceral
hypersensitivity, abnormal intestinal gas transit, impaired
evacuation of rectal gas, colonic fermentation, small intes-
tine bacterial overgrowth, and gut microbiota alterations.75
The pathophysiology of abdominal distention is better
understood due to innovations in technology, including
abdominal inductance plethysmography, a novel technique
that can measure abdominal distention. An abnormal vis-
cerosomatic reflex involving the diaphragm and the
abdominal wall muscles seems to be responsible for the
symptom of distention in many FGID patients.182 The pre-
cise etiology of this reflex is unknown; one study of IBS
patients identified a relationship with rectal hypo-
sensitivity.183 Slow intestinal transit may contribute to
distention in some patients.184
Psychosocial Features
Questionnaire studies evaluating the psychosocial fea-
tures of patients with functional abdominal bloating/
distention have not been published.
Gastroenterology Vol. 150, No. 6
Treatment
Few therapeutic trials have been conducted in patients
with FAB/FAD. Most studies have evaluated abdominal
bloating in patients with other FGIDs (Tables 2 and 3).
Simethicone, an anti-foaming agent, was reported to
improve the frequency and severity of gas, distention, and
bloating in one small old study of patients with upper
gastrointestinal symptoms.185 a-Galactosidase improved
symptoms of gas and bloating in healthy volunteers fed a
high-fat meal.186 In 2 separate 4-week trials, peppermint oil
resulted in a significant decrease in abdominal distention
compared with placebo.187,188 Lubiprostone improved
symptoms of bloating in 2 phase 2 studies in IBS-C patients
(8 mg twice daily) compared with placebo.42 Similarly,
linaclotide also improved bloating symptoms in the phase 3
studies for chronic idiopathic constipation133 and
IBS-C.44–46 In CC patients with predominant symptoms of
bloating, linaclotide showed a significant improvement in
bloating symptoms.189 Desipramine, in conjunction with
cognitive behavioral therapy, resulted in an improvement in
bloating, although the effects of desipramine alone remain
unclear.190 A small, crossover-trial with citalopram showed
an improvement in the number of days without bloating at 3
and 6 weeks.191 In a study of 28 patients with abdominal
bloating, intravenous neostigmine caused immediate clear-
ance of infused jejunal gas compared with placebo.192
However, in patients with IBS and bloating, pyridostig-
mine provided only minimal improvement in bloating.193
C5. Unspecified Bowel Disorders
Definition
In some cases, a patient may not fulfill diagnostic criteria
for any of the 4 specific FBDs categories, in which case the
patient should be considered to have an unspecified FBD.
C5. Diagnostic Criteriona for Unspecified Functional
Bowel Disorder
Bowel symptoms not attributable to an organic etiology
that do not meet criteria for IBS or functional con-
stipation, diarrhea, or abdominal bloating/distention
disorders.
a
Criterion fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis.
C6. Opioid-Induced Constipation
Opioid-induced bowel disorders refers to a spectrum of
disorders that develop secondary to the actions of opioids
on the GI tract and the central nervous system. As opiate use
has increased, so has the recognition that these agents have
a number of adverse effects on the GI tract. It is the opinion
of this committee that opioid-induced effects on the GI tract
should not be considered a distinct FGID, but rather should
be categorized as an opioid-induced adverse effect. There is,
however, frequently overlap between these disorders. For
example, FC may overlap with, or exacerbate, OIC (and vice
May 2016
versa). For that reason, it is important to recognize one of
the most common opioid-induced bowel disorders, OIC,
which is the focus of this section.
Definition
OIC can be defined as a change, when initiating opioid
therapy, from baseline bowel habits and defecation patterns,
that is characterized by any of the following: reduced bowel
frequency; development or worsening of straining; a sense
of incomplete evacuation; or a patient’s perception of
distress related to bowel habits.194 The occasional patient
may also develop fecal impaction with overflow inconti-
nence, while others may report symptoms compatible with
overlapping opioid-induced bowel disorders (eg, reflux,
nausea, bloating).
C6. Diagnostic Criteria for Opioid-Induced Constipation
1. New, or worsening, symptoms of constipation
when initiating, changing, or increasing opioid
therapy that must include 2 or more of the
following:
a. Straining during more than one-fourth (25%)
of defecations
b. Lumpy or hard stools (BSFS 12) more than
one-fourth (25%) of defecations
c. Sensation of incomplete evacuation more than
one-fourth (25%) of defecations
d. Sensation of anorectal obstruction/blockage
more than one-fourth (25%) of defecations
e. Manual maneuvers to facilitate more than one-
fourth (25%) of defecations (eg, digital evacu-
ation, support of the pelvic floor)
f. Fewer than three spontaneous bowel move-
ments per week
2. Loose stools are rarely present without the use of
laxatives
Epidemiology
The prevalence of OIC is 41% in patients with chronic
noncancer pain taking opioids, based on a systematic review
of 8 placebo-controlled studies.195 In a study of cancer
patients taking opioids for pain, the incidence of con-
stipation was approximately 94%.196
Clinical Evaluation
The diagnosis of OIC should be made based on the
following 3 key features: clinical history, physical examination,
and limited diagnostic tests. The first step in the diagnosis of
OIC is to ascertain the relationship of constipation symptoms
with the use of opioids to determine whether a temporal
relationship exists (see diagnostic criteria). If a temporal
Bowel Disorders 1405
relationship exists, then the clinician should identify the type,
severity, and frequency of constipation symptoms (eg,
reduced stool frequency, straining, sense of incomplete evac-
uation, hard stools). The presence of alarm features, such as
unintentional weight loss (>10% in 3 months), rectal bleeding
(in the absence of documented bleeding hemorrhoids or anal
fissures), and a family history of colon cancer (or familial
polyposis syndromes) should be elicited. A physical exami-
nation should be performed to determine whether an organic
problem exists to account for symptoms; a careful anorectal
examination can identify structural issues and DD. Few data
are available regarding the clinical utility of tests in patients
BOWEL
with suspected OIC. If clinically indicated, simple laboratory
tests (eg, CBC, complete metabolic profile, serum calcium and
thyroid-stimulating hormone) are reasonable, while an
abdominal x-ray (kidney, ureter, and bladder) can identify
fecal impaction and the level of stool burden. Patients aged
older than 50 years (45 years and older in African Americans)
should have a screening colonoscopy based on national rec-
ommendations, as should patients with warning signs (eg,
anemia, hematochezia not thought due to hemorrhoidal
bleeding or fissures, and a family history of colorectal cancer).
Physiologic Features
The 3 classes of opioid receptors in the GI tract (m, k, and
d) are all G-proteincoupled receptors that reduce acetyl-
choline release.197 OIC develops when GI tract opioid
receptors are activated by oral opioids leading to a decrease
in propulsive activity; an increase in nonpropulsive con-
tractions; a decrease in pancreatic, biliary, and gastric se-
cretions; and an increase in anal tone. These physiologic
changes may lead to the symptoms of constipation
described previously.
Psychosocial Features
Although not as extensively studied as IBS or functional
constipation, patients with OIC report a significant reduction
in quality of life.198,199 One-third of patients treated with
opioids missed or decreased the dose of prescribed opioids
due to GI side effects; this can further reduce quality of life.198
Treatment
The initial treatment of OIC is similar in many ways to
the treatment of FC. Laxatives are recommended for both
the prophylaxis and management of OIC in patients with
cancer by the European Association for Palliative Care.200
Lubiprostone, a chloride channel activator, is FDA
approved for the treatment of OIC in adults with noncancer
pain.201
Additional treatment options for patients with OIC
involve the use of opioid receptor antagonists that block
opioid actions either centrally or peripherally, thereby
minimizing or preventing the negative effects of opioids on
intestinal secretion and colonic propulsion.202 Naloxone and
nalbuphine are 2 medications classified as centrally active
agents. Because these agents cross the bloodbrain barrier,
they may precipitate opioid withdrawal symptoms.203,204 A
combination product of an opioid antagonist (naloxone) and
 1406 Lacy et al
an opioid agonist (oxycodone) is available in Europe and has
received approval for patients with severe pain.
Peripherally acting m-opioid receptor antagonists block
opioid receptors in the GI, but not central, receptors and thus
do not lead to symptoms of withdrawal. Three agents are
now available. Subcutaneous methylnaltrexone is approved
for OIC in patients with chronic noncancer pain and for
patients with advanced illness receiving palliative care who
have had an inadequate response to laxative therapy.205,206
The European Association for Palliative Care guidelines
recommend subcutaneous methylnaltrexone as a second-line
treatment option for OIC in patients with chronic cancer pain
BOWEL
when traditional laxatives are not effective.200 Alvimopan,
available in the United States but not in Europe, is a
peripherally acting m-opioid receptor antagonist indicated
only for preventing or shortening the course of postoperative
ileus after bowel resection and is therefore available for
hospital use only.207 It is not currently approved for use in
OIC in either Europe or the United States. Naloxegol, an oral
PEGylated derivative of naloxone, was approved by the FDA
for the treatment of OIC in adult patients with noncancer
pain in September 2014.208 Naloxegol was approved by the
European Medicines Agency for the treatment of OIC, but
without the limitation of restricting use to noncancer pain
patients. Another peripherally acting m-opioid receptor
antagonist, Naldemedine, has successfully completed early
clinical trials at the time of this publication.
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. Visit the online version of
Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.031.
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Reprint requests
Address requests for reprints to: Brian E. Lacy, PhD, MD, Division of
Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, 1
Medical Center Drive, Lebanon, New Hampshire 03755. e-mail:
Brian.E.Lacy@hitchcock.org; fax: (603) 650-5225.
Conflicts of interest
The authors disclose no conflicts.
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 Gastroenterology 2016;150:1408–1419

Centrally Mediated Disorders of Gastrointestinal Pain

Laurie Keefer,1 Douglas A. Drossman,2 Elspeth Guthrie,3 Magnus Simrén,4
Kirsten Tillisch,5 Kevin Olden,6 and Peter J. Whorwell7
1
Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; 2Center for Functional GI and
Motility Disorders, University of North Carolina and Center for Education and Practice of Biopsychosocial Care LLC, Drossman
Gastroenterology PLLC, Chapel Hill, North Carolina; 3Mental Health and Social Care Trust, Manchester Royal Infirmary,
Manchester, UK; 4Department of Internal Medicine and Clinical Nutrition, Institute of Medicine Sahlgrenska Academy,
University of Gothenburg, Gothenburg, Sweden; 5Oppenheimer Family Center for Neurobiology of Stress Division of Digestive
Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California; 6SJHMC Internal Medicine Department, Phoenix,
Arizona; and 7Education and Research Centre Wythenshawe Hospital, Manchester, UK
CNS-PAIN

Centrally mediated abdominal pain syndrome, formerly
known as functional abdominal pain syndrome, can be
distinguished from other functional gastrointestinal dis-
orders by its strong central component and relative inde-
pendence from motility disturbances. Centrally mediated
abdominal pain syndrome is a result of central sensitiza-
tion with disinhibition of pain signals rather than
increased peripheral afferent excitability. A newly
described condition, narcotic bowel syndrome/opioid-
induced gastrointestinal hyperalgesia, is characterized by
the paradoxical development of, or increases in, abdominal
pain associated with continuous or increasing dosages of
opioids. Patients only have relief when opioids are with-
drawn. We define both conditions in the context of epide-
miology, pathophysiology, clinical evaluation, and
treatment, emphasizing the importance of a physicianL
patient relationship in all aspects of care.
Keywords: Chronic Abdominal Pain; Narcotic Bowel; Functional
Abdominal Pain; Centrally Mediated Pain; Rome IV.
disorder using currently available diagnostic methods.
Abdominal pain can be produced by or attributed to non-
digestive organs, such as those in the urinary or gynecologic
systems, and disorders in these locations that explain such
pain should be excluded before the diagnosis of CAPS can be
established. A substantial proportion of CAPS patients suffer
significant negative contributions from multiple, probably
unnecessary, surgical interventions performed in an attempt
to address their pain complaints,1 and attribute their pain to
“adhesions.” Adhesions can cause symptoms of acute or
subacute obstruction, which in turn cause pain, but there is
no good evidence that adhesions themselves are a cause for
chronic unrelenting pain, such as that seen in CAPS.2
The predominance of pain as the central complaint,
almost to the exclusion of other symptoms, distinguishes
CAPS from other painful FGID, such as irritable bowel syn-
drome (IBS) and functional dyspepsia (FD), primarily by the
poor relationship of pain with food intake or defecation.
CAPS may represent the far end of the spectrum of IBS
severity, where psychosocial factors and more generalized
central hypersensitivity predominate. It is distinguished
from chronic pelvic pain by its abdominal location and from

T
his paper describes our approach and recommen-
dations related to 2 gastrointestinal (GI) disorders
whose primary symptoms are believed to have a central
determinant—centrally mediated abdominal pain syndrome
(CAPS), formerly known as functional abdominal pain syn-
drome, and a new condition, narcotic bowel syndrome
(NBS)/opioid-induced GI hyperalgesia.
D1. Centrally Mediated Abdominal
Pain Syndrome
Definition
CAPS is characterized by continuous, nearly continuous,
or frequently recurrent abdominal pain that is often severe
and only rarely related to gut function. CAPS is associated
with loss of function across several life domains, including
work, intimacy, social/leisure, family life, and caregiving for
self or others, and must be present for at least 6 months
before diagnosis.
Like other functional gastrointestinal disorders (FGID),
CAPS cannot be explained by a structural or metabolic
“abdominal migraine” in that the pain from CAPS is constant
rather than cyclical.
Pain associated with CAPS may be colicky in nature, as in
IBS, although it tends to be more prolonged and widespread.
Another description that is quite common, especially after a
previous surgery, is that pain is burning in character; this
form is particularly challenging to treat.3 CAPS can be
associated with other unpleasant somatic symptoms and
syndromes, such as fibromyalgia and chronic fatigue syn-
drome. While not part of the diagnostic criteria, psycho-
logical comorbidities are common when pain is persistent
Abbreviations used in this paper: CAPS, centrally mediated abdominal
pain syndrome; FD, functional dyspepsia; FGID, functional gastrointestinal
disorder; GI, gastrointestinal; IBS, irritable bowel syndrome; NBS, narcotic
bowel syndrome; SNRI, serotonin-norepinephrine reuptake inhibitor;
SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant;
TLR, Toll-like receptor.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.034
May 2016
over a long period of time, are further associated with
chronic pain behaviors, and dominate the patient’s life. 3
Epidemiology
CAPS is considered less common than other FGIDs, such
as functional heartburn, FD, or IBS, with prevalence data
ranging from 0.5% to 2.1%.4 CAPS seems to be between 1.5
and 2 times more common in women,4,5 and its prevalence
reaches a peak in the fourth decade of life (35
44 years in
the US householder survey) and then decreases with age.6
Approximately 80% of CAPS patients have consulted a
physician, and half had seen a physician between 1 and 3
times per year specifically for abdominal pain,4,7 4 times
more frequently than people without abdominal complaints.
CAPS patients in the United Kingdom required 5.7 consul-
tant visits, completed 6.4 endoscopic or imaging in-
vestigations, and underwent 2.7 surgical interventions
(primarily hysterectomy and exploratory laparotomy) dur-
ing a follow-up period of 7 years.8 In the United States, CAPS
patients missed work a mean of 11.8 days in the previous
year, 3 times more than subjects without abdominal
symptoms, and “felt too sick to go to work” at the moment of
the survey in 11.2% of cases, about 3 times more frequently
than respondents without FGIDs.4
D1. Diagnostic Criteriaa for Centrally Mediated Abdom-
inal Pain Syndromeb
Must include all of the following:
 Continuous or nearly continuous abdominal pain
 No or only occasional relationship of pain with
physiological events (eg, eating, defecation, or
menses)c
 Pain limits some aspect of daily functioningd
 The pain is not feigned
 Pain is not explained by another structural or
functional gastrointestinal disorder or other medical
condition
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis.
b
CAPS is typically associated with psychiatric comor-
bidity, but there is no specific profile that can be used for
diagnosis.
c
Some degree of gastrointestinal dysfunction may be
present.
d
Daily function could include impairments in work, in-
timacy, social/leisure, family life, and caregiving for self
or others.
Pathophysiology
The biology of CAPS is likely similar to other chronic
visceral pain disorders, such as IBS, FD, and interstitial
Centrally Mediated Disorders of GI Pain 1409
cystitis. While these disorders are all defined by discrete
symptom criteria, they have in common comorbidity with
other pain syndromes, predisposing life events, and treat-
ment responses. As with many chronic somatic pain disor-
ders, CAPS does not fit easily into the traditional categories
of neuropathic or inflammatory pain. Rather, alterations in
modulatory and motivational pain dimensions play a major
role in both the generation and perpetuation of CAPS.
Altered central sensory processing in gastroin-
testinal pain syndromes: lessons learned from irri-
table bowel syndrome and functional dyspepsia. The
brain receives interoceptive input from the abdominal
viscera, which is then combined with cognitive, emotional,
and other sensory information for conscious interpretation
in the anterior insula. Neuroimaging studies in IBS are
consistent with an abnormality in central processing of pain
signals, with functional and structural abnormalities noted
CNS-PAIN
in sensory (mid-cingulate, insular, and somatosensory
cortices, and thalamus), emotional arousal (anterior cingu-
late cortex, amygdala), and prefrontal cortical modulatory
regions. Modulation of descending pain regulatory pathways
in the brainstem by these cortical regions can lead to
exaggerated sensitivity to both noxious and innocuous
stimuli. Evidence that patterns of brain activation during
anticipation of experimental pain are abnormal in IBS
further supports this pathophysiologic model. Patients with
FD show similar abnormalities compared with healthy
control subjects.9
One way in which CAPS differs from IBS and FD is that
the pain symptoms are, by definition, reported as more
constant and unrelated to peripheral events, such as food
intake or defecation. This suggests that, unlike IBS and FD,
the phasic, physiologic visceral afferent input from the gut
plays a lesser role in symptom generation. These observa-
tions, along with the common responsiveness of CAPS
symptoms to low-dose tricyclic antidepressants (TCA), rai-
ses the question of whether some CAPS patients have a
peripheral or gut-based neuropathic pathophysiologic pro-
cess. Unfortunately, neither the characteristically enlarged
pain referral areas nor the response to TCAs (which work
on both peripheral and central neuropathic pain conditions)
make it possible to differentiate between these possibilities.
However, even in the setting of a peripheral insult, once
central sensitization is established, symptoms can persist in
the absence of ongoing abnormal peripheral stimulation or
worsen with minimal stimulation.10 Because no consistent
initiating triggers are noted in CAPS, and the risk factors
seem to be primarily psychosocial, it is presumed that
central processes, such as altered descending pain modu-
lation, are responsible for the chronicity of CAPS.11
Altered brain structure in chronic pain. Altered
brain structure has also been described in multiple visceral
and somatic pain disorders. In women with IBS, increased
cortical thickness in the somatosensory cortex and
decreased cortical thickness in regions of pain processing,
including the insula and anterior cingulate cortex, is
observed.12 IBS symptom severity was negatively correlated
with the cingulate thickness, suggesting a role for loss of
neural density in symptom generation. Using another metric
 1410 Keefer et al
of brain structure, gray matter volume, IBS patients had
decreased volumes in widespread regions, including the
insula, amygdala, cingulate, and brainstem, with early life
trauma playing a role in these differences.13 Patients with
FD also exhibit altered brain structure, with decreased gray
matter density in multiple brain regions, including the
insula and prefrontal cortex.14 Both IBS and FD have been
shown to have abnormal structure of the brain’s white
matter tracts, with similar areas involved in the processing
of pain and emotion. The role of structural change in func-
tional pain disorders is not clear, with some debate as to
whether these changes are pre-existing vulnerability factors
for chronic pain, or side effects of the pain itself. Given the
severity and chronicity of pain symptoms in patients with
CAPS, the likelihood that structural brain changes exist is
high.
CNS-PAIN
Genetic and environmental vulnerability to cen-
trally mediated abdominal pain syndrome. Animal
models and human studies suggest that complex genetic
influences play an important role in the predisposition to
chronic pain. It is considered likely that this predisposition
is a combination of genetic, environmental, and behavioral
factors. Early evidence suggests genes related to serotonin
reuptake, mucosal barrier function, pro- and anti-
inflammatory cytokines, among others, may be involved.
Clinical and preclinical evidence suggests that there is a
strong association of aversive early life events and certain
types of psychosocial stressors with increased pain reports
and changes in brain function among patients with
FGID.15,16 The combination of genetic factors, learned
behavioral factors, adverse early life events, and adult stress
might determine, in part, the effectiveness of endogenous
pain modulation systems and thereby influence develop-
ment of CAPS.
Psychological factors can amplify the experience of
pain, lending further rationale for the use of psychological
interventions for the management of CAPS. For example,
depression and anxiety mediate the effect of pain on
function in chronic low back pain17 and a trauma history
can negatively influence pain experience, coping, and the
doctor
patient relationship.18 Finally, there is strong
empirical support for the importance of pain catastroph-
izing,19 fear avoidance behavior,20 self-efficacy,21 lack of
perceived control,22 and passive pain coping23 on pain
experience.
Clinical Evaluation
A wide range of disorders produce abdominal pain, and
the clinician should be aware of the large number of dif-
ferential diagnoses.24 Of great importance is the duration
of symptoms—the diagnostic approach to patients with
acute abdominal pain is completely different from patients
with long-standing abdominal pain. Evaluation should
consist of a clinical and psychosocial assessment, obser-
vation of symptom-reporting behaviors, a physical exami-
nation, and, in the absence of alarm features, conservative
efforts to exclude other medical conditions in a cost-
effective manner. Notably, for patients meeting diagnostic
criteria for CAPS who exhibit a longstanding history of pain
Gastroenterology Vol. 150, No. 6
behaviors, certain psychosocial correlates and no alarm
features, the clinical evaluation usually fails to disclose any
other specific medical etiology to explain the illness and, in
line with this, clinical investigations could be limited.25
However, occasionally the evaluation might incidentally
identify other medical conditions of uncertain relation to
the presentation (eg, hepatic and/or renal cysts or gall-
stones). Efforts then must be directed toward under-
standing the relative contributions of CAPS, and the elicited
findings or diagnoses, to the pain reported. A number of
clinical and behavioral features typify, but are not specific
for, CAPS. Their presence may aid in the planning of
diagnostic testing and are essential to designing the
treatment approach.
Medical History
Description of the pain. A carefully taken history
focused on the description of pain is crucial in these
patients, as pain is the central feature. Typically, the pain in
CAPS is constant, nearly constant, or frequently recurring,
with pain occurring more or less every day. The pain is
associated with loss of daily functioning, which is often quite
severe (eg, work and school absenteeism, limitations in
social activities). The pain is not, or only occasionally,
associated with physiological events, such as bowel move-
ments, eating, or menses. In addition, the patient often
describes the pain in emotional terms; the pain involves a
large anatomic area, rather than a precise location. Patients
with CAPS also frequently complain of several other painful
extraintestinal symptoms (eg, musculoskeletal pain) and
often there is a continuum of painful experiences beginning
in childhood or recurring over time.25
Symptom behaviors. Although there are symptom-
related behaviors that typify CAPS, they are neither sensi-
tive nor specific and have limited diagnostic value, as they
might also occur in patients with a structural disease. These
behaviors are usually considered maladaptive but poten-
tially modifiable (Figure 1).
Presence of other medical diagnoses. Symptoms
compatible with CAPS may coexist with other structural or
functional diagnoses, or at least these diagnoses have been
obvious or even dominating the picture initially. This
coexistence reflects a transition from more peripherally
based afferent neural activity due to bowel dysfunction, to a
pattern of central disinhibition usually associated with more
constant pain. A proportion of patients with CAPS may also
affirm abnormal bowel habit, but without any association
with their constant and severe pain. Patients with a struc-
tural painful disease might, over time, develop a condition
more compatible with CAPS, when the pain pattern evolves
as more continuous, severe, and nonresponsive to existing
treatment alternatives.
Concurrent psychosocial features and clinical/
psychocial assessment. Patients with CAPS show no
consistent psychological profile, but psychosocial diffi-
culties/problems often contribute to poor health outcomes
in this group of patients. Many patients with CAPS fulfill
diagnostic criteria for comorbid psychiatric diagnoses,
including anxiety, depression, and somatization,26 but,
May 2016 Centrally Mediated Disorders of GI Pain 1411

Figure 1. Symptom-
related behaviors are
common in CAPS. These
symptoms lack sensitivity
and specificity to a CAPS
diagnosis, but awareness
of these behaviors can
facilitate the clinical

CNS-PAIN
examination.

unlike patients with these primary diagnoses, patients
with CAPS are often reluctant to accept that these could
contribute to their symptom profile. A history of unre-
solved losses (eg, death of a parent, surgery),27 as well as
a history of sexual and physical abuse, are common fea-
tures in patients with CAPS,28 but it should be noted that
their presence is by no means diagnostic of CAPS, but
rather can explain the severity of the condition. Inde-
pendent of diagnosis, a history of abuse predicts poor
health outcomes.29 By answering a few questions, the
physician can appraise effectively the clinical features of
CAPS, identify the key psychosocial contributions to the
disorder, and increase confidence in the diagnosis30
(Figure 2).
Physical Examination
The physical examination does not establish a diagnosis
of CAPS, and only rarely does it identify other etiologies in
chronic pain patients. Nevertheless, there is no substitute
for examining the patient to clarify pain location and radi-
ation patterns, and to legitimize the patent’s symptoms.
Additionally, in the previously uninvestigated patient,
important physical findings can direct the diagnostic
workup and might expeditiously lead to an underlying cause
(eg, abdominal wall pain).24,31
Investigations. Tests to exclude other diagnoses
should not be done on a routine basis, but based only on the
presence of “alarm signs” or “red flags” indicating a clinical
suspicion of organic disease.32 A minimal diagnostic workup
should include routine laboratory tests to exclude inflam-
mation and signs of GI bleeding (anemia, fecal blood loss). If
alarm features are identified by history, physical examina-
tion or laboratory screening investigations, the physician
should examine the patient for causes of abdominal pain
other than CAPS. However, in the absence of alarm features
or screening abnormalities, no further tests are indicated,
and in the presence of longstanding stable symptoms, the

Figure 2. These questions

can provide a clinical and
psychosocial overview of
the patient’s condition to
support the diagnosis of
CAPS and to assist in
formulating a treatment
plan.
 1412 Keefer et al
diagnosis of CAPS is highly probable if all criteria for this
diagnosis have been met.33 The appropriateness of this
approach is supported by several recent studies demon-
strating that diagnostic failures are very rare,34 and that the
health-related quality of life for patients with an FGID does
not increase after the patients have undergone in-
vestigations.35 Figure 3 displays an algorithm for the eval-
uation of CAPS.
Treatment
The management of CAPS relies on establishing an
effective patient
physician relationship,36 following a gen-
eral treatment plan (eg, setting treatment goals and basing
treatment on symptom severity), and offering management
that encompasses a combination of treatment options,
including pharmacologic and/or psychologic treatments37
CNS-PAIN
(Figure 4).
Establishing an Effective Patient
Physician
Relationship
Patients and physicians must share responsibility for
the treatment. For example, patients must hold realistic
expectations about treatment and the provider can help
adjust expectations through questions such as “How do you
believe I can be helpful to you?” Patients must be ready to
enter into a therapeutic relationship with a provider—in
CAPS, the focus needs to move away from evaluation and
cure toward facilitating adaptation to constant symptoms.
Finally, patients must be ready to take responsibility in
their care—this is associated with improvement in clinical
outcomes.
Physicians and patients both benefit when physicians
listen actively, accept CAPS as a true disorder, offer
empathy, use an open-ended question style with matching
body language, validate the patients’ feelings,38 set realistic
treatment goals, educate the patient about the nature of
their condition, reassure, negotiate and provide choices
Gastroenterology Vol. 150, No. 6
around treatment rather than directives, maintain bound-
aries, and are aware of time constraints.
Some additional principles to consider:
1. Base treatment on symptom severity and degree of
disability. If pain is continuous and severe, or if the
patient is reluctant to participate in a psychological
intervention, antidepressants (eg, TCAs or serotonin-
norepinephrine reuptake inhibitors [SNRIs]) are
used for their analgesic effects.
2. Know when to refer to a mental health professional.
Present the psychological referral as a means to help
the patient manage the pain and reduce the emotional
distress encumbered by the symptoms. Medical care
should continue concurrent with psychological
treatment.
3. Referral to a multidisciplinary functional GI or pain
treatment center. Multidisciplinary functional GI or
pain treatment centers provide comprehensive
assessment and treatment. Care must be taken to
avoid pain centers that focus on opioid treatment,
which is contraindicated and raises the risk for NBS.
General Principles of Treatment
Pharmacologic therapy. Pharmacologic therapy for
CAPS can be employed along with the general treatment
approaches outlined here. Medical treatment is most effec-
tive within the context of a well-developed patient

physician relationship,36 and a comprehensive bio-
psychosocial39 treatment plan (Table 1).
Tricyclic antidepressants. TCAs are the most widely
used psychotropic agents for treating medical (eg, post-
herpetic neuralgia, diabetic neuropathy) and functional
pain syndromes (eg, fibromyalgia).40–44 Their analgesic ef-
fect is probably unrelated to the antidepressant effect
because these drugs are helpful in many pain syndromes
where psychopathology is less prominent or absent, and
Figure 3. The differential
diagnosis for chronic
abdominal pain is broad.
The evaluation of sus-
pected CAPS can be
simplified using this algo-
rithm. (Reprinted from
Sperber AD, Drossman
DA. Functional abdominal
pain syndrome: constant
or frequently recurring
abdominal pain. Am J Gas-
troenterol 2010;105:770-
774).
May 2016
Figure 4. The management
of CAPS relies on a strong
patient-physician relation-
ship, early incorporation of
nonpharmacological thera-
pies, and referral to behav-
ioral health specialists
when needed.
also because they are usually given in low (“subpsychiatric”
dosages). Improvement in pain as with desipramine in IBS
was not related to blood levels or medication dosage.45
TCAs (eg, amitriptyline, imipramine, desipramine, dox-
epine, and trimipramine) are helpful in relieving pain and
reducing IBS symptoms in moderate to severe cases,40,46
with a pooled relative risk for clinical improvement with
TCA therapy of 1.93. The most common side effects of TCAs
include sedation or sometimes agitation, hypotension, con-
stipation, urinary retention, xerostomia, and effects on sleep
such as insomnia or nightmares.
Selective serotonin reuptake inhibitors. Selective
serotonin reuptake inhibitors (SSRIs) have lesser analgesic
effect compared with TCAs, likely due to a lack of effect on
noradrenalin synaptic levels, as evidenced by experimental
models.47 One multicenter study compared amitriptyline (a
TCA) to citalopram (an SSRI) and placebo among patients with
FD48 and showed significant reduction in symptoms relative to
placebo with the TCA, but not the SSRI. SSRIs are probably less
potent visceral analgesics than TCAs or SNRIs, but they will
have significant effects on global well-being and anxiety-
specific GI symptoms. Side effects may include nausea and
diarrhea; sexual dysfunction with decreased libido and
Table 1.Antidepressant treatment for CAPS
Tricyclic antidepressants
Treatment targets Pain, depression
Adverse events Sedation, hypo-tension, constipation,
dry mouth/eyes, arrhythmias,
weight gain, sex dysfunction
Risk from overdose Moderate
Dose adjustment Yes
Centrally Mediated Disorders of GI Pain 1413
CNS-PAIN
delayed orgasm; and neurologic/psychiatric symptoms, such
as anxiety, nervousness, tremor, insomnia, and nightmares.
Serotonin-norepinephrine reuptake inhib-
itors. The available SNRIs (eg, duloxetine, venlafaxine,
desvenlafaxine, and milnacipran), while used for depression,
are being used increasingly for treating chronic pain. Their
dual effects (analgesic and antidepressant) make them an
attractive choice in depressed patients with pain syn-
dromes,49 but their benefit for CAPS is theoretical (Table 1).
Decisions relating to which antidepressant to use (or
whether to combine them) will depend on several fac-
tors, including the agent’s potential to address pain and
side effects of diarrhea or constipation. These factors
depend largely on the main receptor sites of action
(Table 2).
Atypical antipsychotics. Quetiapine has been used in
lower doses for treating medical patients with anxiety,
sleep disturbance, and associated psychological comorbid
symptoms, and for augmentation treatment with painful
disorders like fibromyalgia.50 It can benefit patients with
chronic abdominal pain by reducing anxiety, restoring
normal sleep patterns, and possibly through a direct
analgesic effect.51,52 Overall, it appears to augment the
Selective serotonin Serotonin-norepinephrine
reuptake inhibitors reuptake inhibitors
Pain, depression, panic, anxiety, Pain, depression
obsessive compulsive disorder
Insomnia, agitation, diarrhea, Nausea, agitation, dizzi-ness,
night sweats, headache, sleep disturbance, fatigue,
weight loss, sex dysfunction liver dysfunction
Low Minimal
Not usual Not usual
 1414 Keefer et al Gastroenterology Vol. 150, No. 6

Table 2.Antidepressant Receptor Site Effects

Norepinephrine 5-hydroxytryptamine Histamine Acetylcholine

TCAs (25-150 mg)

Amitryptaline (3 ) þþþ þþþ þþþþ þþþþ
Doxepin (3 ) þþ þþþ þþþþ þþ
Desipramine (2 ) þþþ þþþ þ þ
Nortriptyline (2 ) þþþ þ þþ þþ
SSRIs (1-2 pills)
Citalopram nil þþþþ nil nil
Escitalopram nil þþþþ nil nil
Fluoxetine nil þþþþ nil nil
Paroxetine nil þþþþ nil nil
Sertraline nil þþþþ nil nil
SNRIs (variable)
Venlafaxine þþ þþ nil nil
Duloxetine þþþ þþþ nil nil
Milnacipran þþþ þþ nil nil
CNS-PAIN

benefits of TCAs or SNRIs in patients not having an
adequate clinical response.
Miscellaneous psychotropic medications. Mir-
tazapine, a tetracyclic antidepressant has increased norad-
renergic activity and 5-HT1A serotonergic activity, which
makes it helpful as an antiemetic and appetite stimulant,
leading to weight gain, as in patients with FD.53 Buspirone is
a nonbenzodiazepine, anti-anxiety agent that can augment
the effect of antidepressants, and with 5HT1 agonist ef-
fects,54 it can improve symptoms of FD.55
Anticonvulsants. Anticonvulsants, such as carbamaz-
epine, lamotrigine, and, more recently, the a2D ligand
agents, gabapentin and pregabalin, have been evaluated in
some chronic pain syndromes, but have not been studied for
chronic abdominal pain or CAPS.56,57 Brain imaging studies
showed that pregabalin reduced chronic pain reports and
this was associated with a reduction of the usually increased
functional connectivity seen between brain regions in
chronic pain states.58
Analgesics. Most analgesics (eg, aspirin and nonste-
roidal anti-inflammatory drugs) offer little benefit because
their actions are somatic in location. Narcotic analgesics
should be avoided because of the likelihood of addiction and
the possibility of narcotic bowel syndrome and other GI side
effects.59
Augmentation treatment. With CAPS, sequencing
high dosages of one medication after another may fail due to
incomplete response or side effects. Augmentation involves
the use, usually at lower dosages, of 2 or more treatments
that act on different receptor sites or areas of the brain to
enhance the therapeutic effect.54 Augmentation treatment
using multiple psychotropic agents should be prescribed in
consultation with or by a psychiatrist, psychopharmacolo-
gist, or medical physician with advanced training in the use
of these medications.
Psychological treatment and antidepressants. An
effective augmentation approach is to combine antide-
pressants with psychological treatment. Antidepressants
can improve pain and vegetative signs of depression,
while psychological treatments improve higher levels of
brain functioning, such as coping, reappraising of mal-
adaptive cognitions, and cognitive adaptation to previous
losses and trauma. Psychological treatment can improve
adherence to taking a medication, and conversely taking
an antidepressant can increase psychic energy to improve
the efficiency of the work of therapy. Studies have shown
that antidepressants work in subcortical areas, such as
the anterior cingulate cortex and insula, to improve con-
nectivity to prefrontal and other cortical areas (“bottom
up” effects), and psychological treatments work on pre-
frontal or cognitive (“executive”) areas, “top-down” ef-
fects.60 The effect size difference for combined treatment
can be 50% or more than either monotherapy
treatment.61,62 Four classes of psychotherapy hold
the most promise in CAPS: cognitive
behavioral therapy,
psychodynamic
interpersonal therapy, mindfulness/
acceptance-based therapies and hypnotherapy. These are
typically administered individually by a health psycholo-
gist or other mental health provider familiar with GI
physiology, always in conjunction with medical treatment.
Other Interventions
Patients seldom gain substantial relief from their
symptoms and seek out alternative treatment approaches.
However, peripherally based treatments are unlikely to be
more effective than centrally targeted modalities.
There is no evidence to support spinal manipulation, and
minimal evidence to support transcutaneous electrical
nerve stimulation or acupuncture, although the latter may
have some putative effect on the opioid system and could be
recommended. Neurolytic celiac plexus blockade in benign
disease has been restricted to chronic abdominal pain from
suspected structural sources, such as chronic pancreatitis,
and with only modest success. Many patients with CAPS
exhibit erythema ab igne, indicating the excessive use of hot
water bottles, electric heating pads, etc, suggesting that heat
seems to provide some degree of pain relief despite any
direct evidence. Although uncontrolled studies suggest a
significant diagnostic and therapeutic benefit of
May 2016
laparoscopic adhesiolysis in patients with chronic abdom-
inal pain,63 the outcome may be placebo-related, and the
detection of unsuspected diagnoses is rare.64 Repeated
adhesiolysis should be minimized to those situations where
it is likely that the adhesions are having a clinical effect such
as intermittent small bowel obstruction.
D2. Narcotic Bowel Syndrome/Opiate-
Induced Gastrointestinal Hyperalgesia
Definition
NBS is characterized by the paradoxical development of,
or increases in, abdominal pain associated with continuous
or increasing dosages of opioids.59 NBS can occur in patients
with functional GI disorders or chronic GI diseases (eg, IBD,
chronic pancreatitis), with painful malignant or nonmalig-
nant diseases, or even in patients receiving high dosages of
narcotics when recovering from surgery.65 Patients with
NBS will have relief or meaningful improvement of their
pain when the opioids are withdrawn.65
Epidemiology
Opioids are the most commonly prescribed drug cate-
gory in the United States.66 Most pain clinicians will not see
NBS; its recognition is more familiar in GI practices where
patients on opioids are referred for severe abdominal pain
and presumed to have an FGID.67
D2. Diagnostic Criteriaa for Narcotic Bowel Syndrome/
Opioid-Induced Gastrointestinal Hyperalgesia
Must include all of the following:
1. Chronic or frequently recurring abdominal painb
that is treated with acute high-dose or chronic
narcotics
2. The nature and intensity of the pain is not
explained by a current or previous GI diagnosisc
3. Two or more of the following:
a. The pain worsens or incompletely resolves
with continued or escalating dosages of
narcotics
b. There is marked worsening of pain when the
narcotic dose wanes and improvement when
narcotics are re-instituted (soar and crash)
c. There is a progression of the frequency, dura-
tion, and intensity of pain episodes
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis.
b
Pain must occur most days.
c
A patient may have a structural diagnosis (eg, inflam-
matory bowel disease, chronic pancreatitis), but the
character or activity of the disease process is not suffi-
cient to explain the pain.
Centrally Mediated Disorders of GI Pain 1415
Pathophysiology
Physiological features. While there are several puta-
tive mechanisms to explain the central hyperalgesia of
opioids, perhaps the most favored is that of glial cell acti-
vation in the dorsal horn of the spinal cord, which
up-regulates peripheral nociceptive signals going ceph-
alad.68 Dorsal horn glia (astrocytes and microglia), when
activated, produce proinflammatory cytokines, nitrous ox-
ide, and excitatory amino acids. This leads to central
hyperalgesia with enhanced pain. Glial cell activation occurs
in response to inflammation or infection, drugs such as
morphine, an endogenous chemokines (fractalkine), from
peripheral injury, other activated glial cells, or even in
response to signals from the central nervous system, which
opens the possibility for central effects of stress on
peripheral pain facilitation.69 The glia cell, the immuno-
CNS-PAIN
competent cell of the central nervous system, are activated
via Toll-like receptors (TLR4), which modify the pharma-
codynamics of opioids by eliciting a proinflammatory reac-
tion with disruption of glutamate homeostasis.70 Certain
pharmacologic agents could potentially interrupt this pain-
inducing pathway via disruption of TLR4 and TLR2
signaling,70 including TCAs.71
Another potential contributing factor is the bimodal
excitatory and inhibitory opioid modulation system in the
dorsal horn. The Gi/o protein inhibitory receptor is acti-
vated, leading to analgesia with short-term opioid use, but
also Gs protein excitatory receptor can be activated to
produce hyperalgesia in some individuals when chronic
high dosages of opioids are used.72 The Gs-coupled
excitatory opioid receptors become progressively sensi-
tized during chronic exposure of dorsal root ganglia to
opioid agonists over time leading to tolerance of inhibi-
tory pain effects and ultimately hyperalgesia via Gs-
coupled activation. Clinically, the use of prolonged high-
dose narcotic agonists may produce opioid hyperalgesia
and NBS.
Descending pathways originating from the cingulate and
prefrontal cortex, the rostral ventral medulla and peri-
aqueductal gray can produce antinociception, although
descending tracts through the dorsolateral funiculus can
enhance pro-nociceptive input.73 These responses have
been demonstrated to occur via activation or inactivation of
“on” and “off” cells in the rostral ventral medulla. Activation
of the off cells produces an inhibition of nociceptive input,
while activation of the on cells is believed to facilitate
nociceptive processing within the rostral ventral medulla
and descending projections to the spinal cord.74 An animal
model for NBS has been described in which morphine has
led to the development of central and visceral hyper-
algesia.75 Minocycline, a known inhibitor of microglia acti-
vation, resulted in normalization of the hyperalgesia during
the morphine treatment.
Clinical Evaluation
Patients with NBS most often report moderate to severe
colicky or constant abdominal pain, which is poorly local-
ized. They may have been prescribed opioids initially for
 1416 Keefer et al
intra-abdominal (eg, chronic pancreatitis, inflammatory
bowel disease, CAPS) or extra-abdominal (eg, orthopedic
pain, fibromyalgia, migraine headaches) conditions, or even
develop increasing pain after surgery. Although initially
receiving opioids for intermittent pain, patients soon
develop tolerance and tachyphylaxis, which require esca-
lating doses for continued clinical benefit. Eventually,
reduced or no pain periods diminish and the abdominal pain
becomes constant and severe despite ongoing treatment.59
The pain may be associated with other GI symptoms
consistent with opioid bowel dysfunction, including nausea,
vomiting, heartburn, constipation, and either overflow
diarrhea or diarrhea from opioid withdrawal. Associated
diagnoses may include gastroparesis, pseudo-obstruction,
and opioid-induced constipation.
Patients may show psychosocial disturbances, including
CNS-PAIN
anxiety, depression, somatization, post-traumatic stress
disorder, and personality disorders often associated with
high health care use and increased health care expenditures
due to procedures, surgery, and medications.65 Although
these features are not a part of the diagnostic criteria of NBS
per se, awareness of them is helpful in treatment planning.
Patients may have had extensive laboratory studies
done, which are usually normal, and radiologic studies
might show colonic fecal retention. Cross-sectional imaging
has usually been done to exclude obstruction, pancreatitis,
inflammatory or ischemic bowel, or other intra-abdominal
pathology. These negative studies, in addition to a focused
history and physical examination and meeting the diag-
nostic criteria, should be adequate to make a diagnosis of
NBS.
NBS is a positive diagnosis that can occur solely (eg, in a
patient developing abdominal pain after an operation or
treatment for back pain), or it can be present alongside
other structural GI diseases, when the pain is out of pro-
portion to the pain inferred to be from the structural dis-
ease. For example, patients may have had pancreatitis with
resolution of the lipase but worsening pain from the NBS, or
may have inflammatory bowel disease without complica-
tions of bowel obstruction, deep ulcers, or serologic evi-
dence for inflammation. The diagnosis is particularly
challenging when the patient has active bowel disease and is
also on opioids in the clinical setting of worsening abdom-
inal pain. As such, there is no specific diagnostic evaluation
recommended other than the good clinical judgment
required to evaluate the activity of other comorbid medical
diseases. In these cases, it might be reasonable to detoxify
patients as a therapeutic trial to see if NBS is present.
There is no particular time frame or dosage of opioids
required for diagnosis because NBS can occur within a few
weeks and with varying dosages. Therefore, the diagnosis is
based on the development of the clinical features in a setting
of opioid use, and it is observed that patients most often are
taking, on average, 75 mg or more daily of oral morphine
equivalent.65
A subset of patients with abdominal pain on opioids may
have opioid use disorder.76 These patients take opioids in
larger amounts than intended, with a persistent desire to
continue and crave for them, and fail to fulfill normal work,
Gastroenterology Vol. 150, No. 6
school, or home obligations.77 Patients with these features
should be referred to a substance abuse program, as the
likelihood of successful management of these patients in a
medical setting is extremely low.
Treatment
Understanding the patient. It helps to understand
that most patients with NBS want to be treated, but might
not see reduction of opioids as a logical option. These pa-
tients believe that opioids have been “all that has helped”
and fear being abandoned with worsening pain. They also
feel stigmatized by others who they perceive see them as
“drug seeking” or having a psychiatric problem.
Clinician considerations in the treatment. A sound
patient
physician relationship through good communica-
tion skills is a prerequisite to the treatment of patients with
NBS.78 The clinician must feel committed to work with these
patients and be aware of possible negative feelings toward
patients that s/he perceives as “difficult.”
Educating about the treatment. Once a commitment
is made to treat, the physician must engage with the patient
and discuss NBS and options for treatment, including opiate
detoxification. The Current Opioid Misuse Measure79 is a
useful tool to determine the severity of misuse and likeli-
hood of detoxification. The treatment protocol discussed
here involves complete detoxification because there is only
evidence of clinical improvement with this approach65 and
no evidence that NBS can be treated with continuation of
opioids.
Negotiating the treatment requires mutual trust and
patient engagement toward a shared plan of care,59 which
can be facilitated through empathy, acceptance, and vali-
dation of the reality of the pain and its impact on the pa-
tient’s life, an open dialogue about the mechanism of NBS
and the rationale for the recommended treatment, including
the specifics of opioid detoxification and eliciting/address-
ing the patient’s concerns directly. If the patient says opioids
have been the only effective treatment, the clinician can note
that, despite using high-dose opioids, the patient is still not
achieving benefit or it is incomplete; describe the value of
more effective treatments for the pain (eg, tricyclic or SNRI
antidepressants and central anxiety-reducing agents) to use
during and after detoxification; note that once beginning the
program, the protocol for opiate reduction will not change,
but alternative agents can be used for pain and anxiety;
provide realistic goals from the detoxification, which are to
improve the pain (not necessarily achieve complete pain
resolution) over the course of months; enlist friends and
family members in discussions of the goals and treatment to
ensure their support during the process and also to help
prevent relapse; indicate the role of ancillary providers (eg,
psychologists or psychiatrist, primary care physician, and
physician assistant) to help in the process; and reaffirm
their willingness to continue with the patient in the care
regardless of the outcome.
Treatment plan is provided in Table 2.
Clinical outcome. The single outcome study in NBS
detoxification included 39 patients who were systematically
detoxified in an inpatient facility during a 7-day period with
May 2016
a success rate of 89.7%. Sixty percent were considered
“responders”; 11% percent had worse pain after detoxifi-
cation.65 This committee believes that inpatient programs
provide much more control over detoxification, and can
usually be done in 1 week rather than outpatient programs,
which take several weeks.
Conclusions
We described a set of GI pain disorders with a central
determinant. These disorders are increasingly common and
complex and must be approached from a comprehensive
biopsychosocial model. The doctor
patient relationship is
at the core of all evaluation and management decisions.
CAPS is distinguished by chronic, unrelenting pain that in-
terferes with several life domains and has no clear triggers,
such as bowel movements, food, or menses. It may be at the
far end of the spectrum of other FGIDs, such as IBS. Our
newest disorder, NBS/opioid-induced GI hyperalgesia is
characterized by the paradoxical development of worsening
abdominal pain associated with increased use of opioids.
The only treatment for NBS is to withdraw opioids, which
requires a thoughtful and collaborative approach. Both CAPS
and NBS require a substantial research effort over the next
several years to more fully charaterize their prevalence and
features, understand their unique pathophysiology and
identify more effective therapeutic targets.
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Reprint requests
Address requests for reprints to: Laurie Keefer, PhD, Division of
Gastroenterology, Icahn School of Medicine at Mount Sinai, 17 East 102nd
Street, 5th Floor, New York, NY 10029. e-mail: laurie.keefer@mssm.edu; fax:
(646) 537-8921.
Conflicts of interest
The authors disclose no conflicts.
 Gastroenterology 2016;150:1420–1429

Gallbladder and Sphincter of Oddi Disorders

Peter B. Cotton,1 Grace H. Elta,2 C. Ross Carter,3 Pankaj Jay Pasricha,4
Enrico S. Corazziari5
1
Medical University of South Carolina, Charleston, South Carolina; 2University of Michigan, Ann Arbor, Michigan; 3Glasgow
Royal Infirmary, Glasgow, Scotland; 4Johns Hopkins School of Medicine, Baltimore, Maryland; and 5Universita La Sapienza,
Rome, Italy

The concept that motor disorders of the gallbladder, cystic

duct, and sphincter of Oddi can cause painful syndromes is
attractive and popular, at least in the United States. How-
ever, the results of commonly performed ablative treat-
ments (eg, cholecystectomy and sphincterotomy) are not
uniformly good. The predictive value of tests that are often
GALLBLADDER AND SOD
E1. Diagnostic Criteria for Biliary Pain
Pain located in the epigastrium and/or right upper
quadrant and all of the following:
1. Builds up to a steady level and lasting 30 minutes
or longer

used to diagnose dysfunction (eg, dynamic gallbladder

scintigraphy and sphincter manometry) is controversial.
Evaluation and management of these patients is made
2. Occurring at different intervals (not daily)
difficult by the fluctuating symptoms and the placebo effect 3. Severe enough to interrupt daily activities or lead
of invasive interventions. A recent stringent study has to an emergency department visit
shown that sphincterotomy is no better than sham treat-
ment in patients with post-cholecystectomy pain and little 4. Not significantly (<20%) related to bowel
or no objective abnormalities on investigation, so that the movements
old concept of sphincter of Oddi dysfunction type III is dis-
5. Not significantly (<20%) relieved by postural
carded. Endoscopic retrograde cholangiopancreatography
approaches are no longer appropriate in that context. There
change or acid suppression
is a pressing need for similar prospective studies to provide
better guidance for clinicians dealing with these patients. Supportive Criteria
We need to clarify the indications for cholecystectomy in The pain may be associated with:
patients with functional gallbladder disorder and the rele-
vance of sphincter dysfunction in patients with some evi- 1. Nausea and vomiting
dence for biliary obstruction (previously sphincter of Oddi
dysfunction type II, now called “functional biliary sphincter
2. Radiation to the back and/or right infra-
disorder”) and with idiopathic acute recurrent pancreatitis. subscapular region
3. Waking from sleep
Keywords: Cholecystectomy; Biliary Pain; Post-Cholecystectomy
Pain; Sphincter Manometry; Sphincterotomy; Idiopathic
Pancreatitis; Endoscopic Retrograde Cholangiopan This definition for biliary pain differs from Rome III only in
creatography. quantitating “not significantly” to mean <20%. We included
the Rome III criterion that pains should be “not daily” although
this is not evidence-based. Further studies are needed.

F unctional disorders of the gallbladder (GB) and the

sphincter of Oddi (SO) are controversial topics. They
have gone by a variety of names, including acalculous biliary
pain, biliary dyskinesia, GB dysmotility, and SO (or ampul-
lary) stenosis. This articles builds on the Rome III
consensus,1 recognizing that the evidence base is slim. This
articles does not cover the anatomy and physiology, which
are well described elsewhere.
Biliary Pain
The concept that disordered function of the GB and SO
can cause pain is based mainly on the fact that many
patients have biliary-type pain in the absence of recognized
organic causes, and that some apparently are cured by
removal of the GB or ablation of the sphincter.
Functional Gallbladder Disorder
Definition
In conformity with the Rome consensus that defines
functional gastrointestinal disorders as symptom complexes
Abbreviations used in this paper: CCK-CS, cholecystokinin-stimulated
cholescintigraphy; ERCP, endoscopic retrograde cholangiopancreatog-
raphy; EUS, endoscopic ultrasound; FGBD, functional gallbladder disor-
der; GB, gallbladder; GBEF, gallbladder ejection fraction; MRCP, magnetic
resonance cholangiopancreatography; SO, sphincter of Oddi; SOD,
sphincter of Oddi dysfunction.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.033
May 2016
not explained by a clearly identified mechanism or by a
structural alteration, we use the term functional gallbladder
disorder (FGBD) to describe patients with biliary pain and
an intact GB without stones or sludge.
E1a. Diagnostic Criteria for Functional Gallbladder
Disorder
1. Biliary pain
2. Absence of gallstones or other structural
pathology
Supportive Criteria
1. Low ejection fraction on gallbladder scintigraphy
2. Normal liver enzymes, conjugated bilirubin, and
amylase/lipase
Since the diagnosis is primarily one of exclusion, the
prevalence depends on the rigor of investigation. Ultraso-
nography is the usual primary investigation, but endoscopic
ultrasound (EUS) is more sensitive for detecting small
stones and biliary sludge, and can also detect small tumors,
and subtle changes of chronic pancreatitis.
The only change from Rome III is that normal liver and
pancreatic enzymes have been moved to the supportive
category. There can be other reasons for elevated liver en-
zymes, like fatty liver disease, that do not rule out GB
dysfunction. We have also added a low ejection fraction on
GB scintigraphy as supportive. It is not required for the
diagnosis, nor is it specific for the diagnosis when abnormal.2
Epidemiology
Biliary pain is a common clinical problem, and cholecys-
tectomy is a frequent operation. The number and proportion
done for FGBD seems to be increasing in the United States,
where case series now list it as the indication for
cholecystectomy in 10%
20% of adults2,3 and in 10%
50%
Figure 1. Potential etio-
logical pathways and clin-
ical outcomes in patients
with “biliary dyskinesia”
Gallbladder and Sphincter of Oddi Disorders 1421
of children.4 FGBD is rarely diagnosed outside the United
States.5
Pathophysiology
FGBD is often diagnosed by a low gallbladder ejection
fraction (GBEF) at cholecystokinin-stimulated cholescintig-
raphy (CCK-CS). Although the relationship between GBEF and
clinical outcome remains unclear, gallbladder dysmotility
may still play a role in the pathogenesis of symptoms, by
promoting gallbladder inflammation, which is commonly
found. Microlithiasis is associated with a delayed ejection
fraction on scintigraphy.6 Investigators have found multiple
defects in gallbladder contractility, including spontaneous
activity and abnormal responses to both CCK and neural
stimulation.7 A vicious cycle of stasis and inflammation exists
in the GB. Some patients may have intrinsic defects in
contractility, and subtle defects in bile composition may also
play a role. Studies have shown elevated sphincter of Oddi
GALLBLADDER AND SOD
(SO) pressures in patients with GB dyskinesia, but without
correlation between GBEF and SO pressure.8 GB dysfunction
may represent a more generalized dysmotility, as in irritable
bowel syndrome and chronic constipation, and perhaps
gastroparesis.9 Experimental evidence has implicated several
molecules that can link inflammation to motility, the most
important of which may be prostaglandin E2 (PGE2).10,11
Possible etiological mechanisms and outcomes in patients
with “biliary dyskinesia” are illustrated in Figure 1.
Clinical Evaluation
GB stones should be excluded by ultrasound scanning
(repeated if necessary), and complemented with EUS. Other
tests may be needed to rule out peptic ulcer disease, subtle
chronic pancreatitis, fatty liver disease, or musculoskeletal
syndromes. Esophageal manometry, gastric emptying tests,
and transit studies may be required if symptoms suggest
alternative dysfunctional syndromes. Further management
depends on the level of clinical suspicion. The diagnosis of
FGBD may be made by exclusion if the pains are typical and
 1422 Cotton et al
severe. A key issue is whether current methods for assess-
ing GB muscular function are useful.
Assessment of Gallbladder Emptying
CCK-CS is a popular diagnostic test, but its value is
controversial. The test involves the intravenous adminis-
tration of technetium 99m (Tc 99m)
labeled hepatobiliary
iminodiacetic acid analogs. These compounds are readily
excreted into the biliary tract, and are concentrated in the
GB. The net activity-time curve for the GB is derived from
serial observations, and GB emptying is expressed as the
GBEF, which is the percentage change of net GB counts.12
An interdisciplinary panel proposed a standardized test
and emphasized that proper patient selection is a critical
step when considering whether to perform CCK-CS, because
delayed emptying is seen in many other conditions,
including asymptomatic individuals and patients with other
functional gastrointestinal disorders. The injection of CCK
GALLBLADDER AND SOD
can cause biliary-like pain, but using this observation to
determine patient-care decisions was discouraged by the
panel, because CCK also increases bowel motility, which can
cause symptoms. In some countries, CCK preparations have
not been approved for human use.
Other imaging methods. GB emptying can be
assessed with ultrasound scanning after CCK or fatty meal
stimulation, but these methods have not become popular.
Attempts are being made to study emptying patterns during
magnetic resonance cholangiopancreatography (MRCP)13
and computed tomography (CT) scanning14 with results
that appear to mimic those of cholescintigraphy.
Treatment of Functional Gallbladder Disorder
Symptoms suggestive of FGBD often resolve spontane-
ously,3 so that early intervention is unwarranted. Patients
may respond to reassurance and medical treatments such as
antispasmodics, neuromodulators, or ursodeoxycholic acid,
Gastroenterology Vol. 150, No. 6
although their value has not been evaluated formally. Cho-
lecystectomy is considered when these methods fail, and
symptoms are severe. The reported results of surgery vary
widely.2,3,15 Many claim benefit in >80% of patients, but
most studies are of poor quality with several potential
biases; none have limited intervention to patients with
negative EUS exams. There has been only one small ran-
domized trial, favoring cholecystectomy.16 Several author-
ities have called for more definitive studies.3,17
The predictive value of the CCK-CS test is in question.
Two systematic reviews have concluded that there is
insufficient evidence to recommend its use.18,19 The review
by DiBaise and Oleynikov19 found that 19 of 23 papers
suggested that the GBEF was useful in selecting patients for
cholecystectomy. However, cholecystectomy is claimed to
benefit most patients with “typical biliary” symptoms,
raising the question as to what additional utility is afforded
by CCK-CS.20 One study reported symptomatic relief after
cholecystectomy in 94% of patients with a low GBEF, but
also in 85% of those with a normal GBEF.19 The degree of
dysfunction (ie, GBEF <20% vs <35%) did not improve the
predictive value.21 Similarly, in a study of patients with
reduced GBEF (<35%), CCK-CS was of minimal clinical
utility in predicting symptomatic relief in patients with
atypical symptoms, 30% resolving spontaneously, and of
those with persistent symptoms, only 57% benefitted from
cholecystectomy.20 A “blind” cholecystectomy based on
symptoms without CCK-CS evidence has been reported with
a >90% satisfaction rate. That many patients with sus-
pected FGBD are not helped by cholecystectomy is shown by
the significant number who present afterward with “post-
cholecystectomy pain,” and are considered for another
contentious diagnosis, sphincter of Oddi dysfunction (SOD).
Conclusion. Current evidence indicates that cholecys-
tectomy can provide symptom relief in many patients with
acalculous biliary pain, and GBEF is often low in these pa-
tients. However, more stringent studies are needed to
Figure 2. Evaluation of
biliary pain in patients with
intact GB. In patients with
biliary pain and negative
investigations (including
EUS), the decision to pro-
ceed to cholecystectomy
or dynamic imaging of the
gallbladder will depend on
the strength of the clinical
suspicion. CT, computed
tomography; EGD, esoph-
agogastroduodenoscopy;
MRI, magnetic resonance
imaging; RUQ, right upper
quadrant; US, ultrasound.
May 2016
establish which patients are likely to benefit (or not), and to
clarify the predictive value of the CCK-CS test.
One approach to managing these patients is shown in
Figure 2, but the need for more research is obvious.
Future Research. We need to know more about the
etiology of FGBD, better methods for making and excluding
the diagnosis, the natural history, and the role of different
treatments. More stringent prospective studies of chole-
cystectomy, with independent outcome assessments, are
required to provide a more evidence-based approach.
Functional Biliary Sphincter Disorder
Dysfunction of the biliary sphincter is commonly
considered in patients with biliary-type pains after chole-
cystectomy, when stones and other pathology are
excluded.1,22
Epidemiology
Many patients have persistent or recurrent pain after
cholecystectomy.23,24 The proportion is higher in patients
who have had elective rather than emergency surgery, in
patients without GB stones, and in those with less typical
symptoms.25
Diagnostic Criteria
The longstanding popular classification of 3 clinical
types of SOD1,22,26 seemed validated by the fact that the
likelihood of abnormal sphincter manometry, and relief by
sphincterotomy, appeared to correlate with the types.
However, most data came from cohort studies of poor
quality,27,28 and one showed no such correlation.29 Earlier
recommendations were that type I patients (with a dilated
bile duct and elevated liver enzymes) should undergo
biliary sphincterotomy without manometry, and that type II
(dilated duct or elevated liver enzymes) patients and type
III (no abnormalities) patients should be considered for
manometry-directed sphincterotomy.1
This classification is now outdated and should be
abandoned. Most patients with prior SOD type I have
organic stenosis rather than functional pathology; they
benefit from biliary sphincterotomy. The EPISOD (Evalu-
ating Predictors and Interventions in Sphincter of Oddi
Dysfunction) trial30 showed that patients with SOD type III
do not respond to sphincter ablation better than sham
intervention. We therefore now recommend using the term
suspected functional biliary sphincter disorder (suspected
FBSD) for patients with post-cholecystectomy pain and
some objective findings (the prior SOD type II). Further
research is needed to establish more precisely which clinical
features and investigations can best identify those who are
likely to respond (or not) to sphincter treatments.
E1b. Diagnostic Criteria for Functional Biliary Sphincter
of Oddi Disorder
1. Criteria for biliary pain
2. Elevated liver enzymes or dilated bile duct, but
not both
Gallbladder and Sphincter of Oddi Disorders 1423
3. Absence of bile duct stones or other structural
abnormalities
Supportive Criteria
1. Normal amylase/lipase
2. Abnormal sphincter of Oddi manometry
3. Hepatobiliary scintigraphy
Changes Since Rome III. Elevated liver enzymes or a
dilated bile duct (but not both) are now required, rather
than supportive, criteria. Normal amylase and/or lipase
have been moved to supportive criteria because they may
occur in some episodes of pain. We have added abnormal
biliary manometry as supportive because randomized trials
showed that it is predictive of response to biliary sphinc-
terotomy.31,32 Hepatobiliary scintigraphy is also included,
GALLBLADDER AND SOD
although its value is disputed.
Pathophysiology
Classical teaching is that aberrant sphincter physiology
leads to biliary pain by increased resistance to bile outflow
and subsequent rise in intrabiliary pressure. This concept is
intuitively appealing, leading to widespread acceptance,
especially by biliary endoscopists. However, both theoretical
and experimental evidence indicate a more complex
pathophysiology.
There is evidence that sphincter dynamics are altered
after cholecystectomy.33 Animal studies have shown a
cholecystosphincteric reflex with distention of the GB that
results in sphincter relaxation.34 Interruption of this reflex
could affect sphincter behavior by an altered response to
CCK, or because the loss of innervation unmasks the direct
contractile effects of CCK on smooth muscle. Abnormalities
in both basal pressure and responsiveness to CCK have also
been described in humans.35
The simple concept of SOD leading to obstruction and
biliary pain is now being challenged, as the EPISOD trial has
shown.30 One explanation for this syndrome stems from the
concept of nociceptive sensitization.36 Significant tissue
inflammation, such as cholecystitis, will activate nociceptive
neurons acutely and, if it persists, will also result in sensi-
tization and the gain in the entire pain pathway is increased.
In most patients with GB disease, cholecystectomy removes
the ongoing stimulus and the system reverts back to its
normal state. However, in a subset of patients, the “gain”
stays at a high level (Figure 1). In such patients, even minor
increases in biliary pressure (within the physiological
range) can trigger nociceptive activity and the sensation of
pain (allodynia).
A relevant related phenomenon is cross-sensitization.
Many viscera share sensory innervation. For example,
nearly half of the sensory neurons in the pancreas also
innervate the duodenum.37 Therefore, it is difficult to
distinguish pain resulting in one organ from that in another.
Persistent sensitization in one organ can lead to
 1424 Cotton et al
sensitization of the nociceptive pathway from an adjacent
organ. Thus, an entire region can be sensitized with inno-
cous stimuli (such as duodenal contraction after a meal)
leading to pain that was indistinguishable from that asso-
ciated with the initial insult. Evidence for this was provided
by a study in which patients with post-cholecystectomy pain
were found to found to have duodenal, but not rectal,
hyperalgesia.38 A strong case can be made for nociceptive
sensitization to be the principal cause of pain. Motor phe-
nomena, such as sphincter hypertension, might still be
relevant, but more as a marker for the syndrome rather than
the cause.
Exclusion of Organic Disease
The first task in patients with post-cholecystectomy pain
is to exclude organic causes. Possibilities include retained
stones or partial GB; postoperative complications (such as a
bile leak or duct stricture); other intra-abdominal disorders,
such as pancreatitis, fatty liver disease, peptic ulceration,
GALLBLADDER AND SOD
functional dyspepsia and irritable bowel syndrome;
musculoskeletal disorders; and other rare conditions. Non-
biliary findings are more likely when the symptoms are
atypical and longstanding, similar to those suffered preop-
eratively and without a period of relief postoperatively, and
when the GB did not contain stones.1,25,39
The initial diagnostic approach should consist of a
careful history and physical examination, followed by stan-
dard liver and pancreas blood tests, upper endoscopy, and
abdominal imaging. Although ultrasound or computed to-
mography scanning may be used initially, MRCP or EUS
provide more complete information. The report of a “dilated
bile duct” on any of these studies is difficult to interpret. It is
widely believed that the bile duct enlarges after cholecys-
tectomy. However, some studies have shown no change,
others only a slight increase in size; there is a gradual in-
crease with age.40–43 Regular narcotic use can cause biliary
dilation, although usually associated with normal liver en-
zymes.44 EUS is the best way to rule out duct stones and
pathology of the papilla.45,46
Noninvasive Testing
A major problem with assessing diagnostic tools in this
context is the lack of a gold standard. One could argue that
the only proof that the sphincter is (or was) the cause of the
pain is if patients are satisfied by the results of sphincter
ablation, albeit recognizing the often prolonged placebo ef-
fect of endoscopic retrograde cholangiopancreatography
(ERCP) intervention.30 There are very few studies with
objective blinded assessments and even fewer randomized
trials. Many tests are assessed by comparison with the re-
sults of manometry, whose validity is also uncertain. Thus,
arguments are often circular, and our comments on the
value of these various tests are not based on solid evidence.
Liver enzymes, which peak with attacks of pain, might be a
good sign of obstruction by spasm (or passage of stones),47
but confirmation is lacking. Another problem is that most
patients have intermittent pains, so that measurements
taken when pain-free are open to question.
Gastroenterology Vol. 150, No. 6
The drainage dynamics of the bile duct have been tested
after stimulation with a fatty meal or injection of CCK and
measuring any dilatation of the duct with abdominal or
endoscopic ultrasound. These techniques deserve further
evaluation, and there is potential for studying dynamic pa-
rameters with contrast agents during MRCP13 and
computed tomography scanning.14
Hepatobiliary scintigraphy. Hepatobiliary scintig-
raphy involves intravenous injection of a radionucleotide
and deriving time-activity curves for its excretion
throughout the hepatobiliary system. This technique has
been used to assess the rate of bile flow into the duodenum
and to look for any evidence of obstruction. Interpretation
of the literature is difficult due to the use of different test
protocols, diagnostic criteria, and categories of patients, and
whether the results are compared with manometry (usu-
ally) or the outcome of sphincterotomy. Various parameters
are used: time to peak activity, slope values, and hepatic
clearance at predefined time intervals, disappearance time
from the bile duct, duodenal appearance time, and the he-
patic hilum
duodenum transit time.48–51 One study in
asymptomatic post-cholecystectomy subjects showed sig-
nificant false-positive findings and intra-observer vari-
ability.52 The reported specificity of hepatobiliary
scintigraphy was at least 90% when manometry was used
as the reference standard, but the level of sensitivity is more
variable.53 Although hepatobiliary scintigraphy with hepatic
hilum
duodenum transit time was shown to be predictive
of the results of sphincterotomy in type I and II patients,54 it
is not widely used currently; further studies are needed.
Endoscopic retrograde cholangiopancreatography
and sphincter of Oddi manometry. ERCP should be
reserved for patients who need sphincter manometry or
endoscopic therapy, such as those with strong objective
evidence for biliary obstruction.
Manometry technique. ERCP allows measurement of
both the biliary and pancreatic sphincters, but the method is
imperfect. Recording periods are short and subject to
movement artifact. The effects of medications commonly
used for sedation and anesthesia have not been studied
sufficiently. Furthermore, reproducibility is in question.55
The assessable variables at SO manometry include the
basal sphincter pressure and the phasic wave amplitude,
duration, frequency, and propagation pattern. However,
only basal pressure has so far been shown to have clinical
significance.31,32 The standard upper limit of normal for
baseline biliary sphincter pressure is 35
40 mm Hg.
Normal pancreatic sphincter pressures are accepted as
similar to those of the bile duct, although reference data are
more limited.
In normal volunteers, pressures obtained from the bile
duct and pancreatic duct are similar.56 However, abnor-
malities may be confined to one side of the sphincter in up
to 50% of patients.57–59 For patients in whom the indication
for SO manometry is biliary pain and not idiopathic
pancreatitis, some authorities avoid pancreatic cannulation
entirely to reduce the frequency of pancreatitis. The value of
studying the pancreatic sphincter has been questioned,
given 2 recent studies that failed to show superiority for
May 2016
dual sphincterotomy over biliary alone in suspected biliary
sphincter dysfunction and in idiopathic recurrent
pancreatitis.30,60
Solid-state manometry catheters have also been used,
with results identical to those of the water-perfused sys-
tem.61 A technique using a sleeve device also showed
similar results, with the advantage of reducing movement
artifacts, but is not commercially available.62
Indications for manometry. Sphincter manometry
has been recommended in patients with suspected biliary
type II SOD because 3 randomized trials showed that biliary
manometry predicted the response to biliary sphincter-
otomy.31,32,63 However, in clinical practice, biliary sphinc-
terotomy is often performed empirically in those patients.
Because of the EPISOD trial findings, manometry is no
longer recommended in patients without objective findings
(prior type III SOD).30
Non-Manometric Endoscopic Retrograde
Cholangiopancreatography Diagnostic
Approaches
Trial placement of a pancreatic or biliary stent to predict
response to subsequent sphincterotomy has been proposed as
an alternative method for diagnosing SOD, but should be
avoided due to the very high risk of inducing pancreatitis.
Injection of Botulinum toxin has been shown to relax the
sphincter complex temporarily64,65 and no complications have
been reported. It is claimed to predict which patients would
benefit from sphincterotomy,65,66 but more data are needed.
Figure 3 suggests diagnostic pathways, based on current
limited evidence.
Figure 3. Post-
cholecystectomy biliary
pain. Patients with clear
evidence for biliary
obstruction should have a
biliary sphincterotomy; if
the evidence is less
convincing, further testing
with manometry or scin-
tigraphy may be helpful.
CT, computed tomo-
graphy; HB is hep-
atobiliary; US, ultrasound.
Gallbladder and Sphincter of Oddi Disorders 1425
Treatment
Current recommendations for management of patients
with suspected functional biliary sphincter disorder are
based on expert consensus, with inadequate evidence. Many
patients are disabled with pain and desperate for assistance.
The placebo effect of intervention is strong, with about one-
third of sham-treated patients claiming long-term benefit in
blinded randomized studies.30,31,32,63
Medical therapy. Because of the risks and un-
certainties involved in invasive approaches, it is important
to explore conservative management initially. Nifedipine,
phosphodiesterase type-5 inhibitors, trimebutine, hyoscine
butylbromide, octreotide, and nitric oxide have been shown
to reduce basal sphincter pressures in SOD and asymp-
tomatic volunteers during acute manometry.67,68 H2 an-
tagonists, gabexate mesilate, ulinastatin, and gastrokinetic
agents also showed inhibitory effects on sphincter motility.
Amitriptyline, as a neuromodulator, also has been used
along with simple analgesics. A trial of duloxetine had
GALLBLADDER AND SOD
encouraging results.69 A French group was able to avoid
sphincterotomy in 77% of patients with suspected SOD
using treatment with trimebutine and nitrates.70 None of
these drugs are specific to the SO and therefore may also
have positive effects in patients with nonbiliary dysfunc-
tional syndromes. Transcutaneous electrical nerve stimula-
tion71 and acupuncture72 also have been shown to reduce
SO pressures, but their long-term efficacy has not been
evaluated.
Endoscopic therapy: sphincterotomy. Consensus
opinion remains that patients with definite evidence for SO
obstruction (former biliary SOD type I) should be treated
with endoscopic sphincterotomy without manometry.1 The
 1426 Cotton et al
evidence base for biliary sphincterotomy in patients with
less objective clinical evidence (prior SOD type II) is not
strong; many studies have been retrospective, unblinded,
and have not used objective assessments.27,28 One large
study claimed success in about three-quarters of patients
simply because they did not return to the treatment site for
further intervention.73 The most convincing data come from
3 small randomized studies of suspected type II patients,
which showed that sphincterotomy was more effective than
a sham procedure in patients with elevated basal biliary
sphincter pressures.31,32,63 The EPISOD trial showed that
there is no justification to perform manometry or sphinc-
terotomy in patients with normal labs and imaging (prior
SOD type III patients).30 Outcomes were also poor in a
parallel observational study (EPISOD 2) of 72 similar pa-
tients who did not agree to randomization and underwent
manometry-directed sphincterotomies (Table 1). ERCP in
this context is clinically dangerous and has medicolegal
consequences when complications arise.
GALLBLADDER AND SOD
Better predictors of outcomes of sphincterotomy in pa-
tients with “suspected functional biliary sphincter disorder”
(prior SOD II) are needed. Freeman and colleagues29
showed that normal pancreatic manometry, delayed
gastric emptying, daily opioid use, and age younger than 40
years predicted poor outcomes. It has been reported that
patients are more likely to respond if their pain was not
continuous, if it was accompanied by nausea and vomiting,
and if there had been a pain-free interval of at least 1 year
after cholecystectomy.74 Future studies should re-examine
these items and a range of possible predictors, including
laboratory findings (fluctuating or not), the actual size of the
bile duct, and whether it is known to have enlarged since
surgery, the severity and pattern of the pain, the presence of
other functional disorders, psychosocial factors, the reason
for the cholecystectomy and response to it, as well as any
potential diagnostic methods as described here.
Endoscopic retrograde cholangiopancreatography
adverse events. ERCP in patients with SOD (with or
without manometry) is associated with a high risk of
pancreatitis. The rate is 10%
15%, even in expert hands
using pancreatic stent placement and/or rectal nonsteroidal
anti-inflammatory drugs.75,76 Sphincterotomy adds the risks
Table 1.Results of the EPISOD Randomized Trial and the
EPISOD 2 Observational Study
Pain relief,
Study Sphincter treatment n n (%)
EPISOD None (sham) 73 27 (37)
Any sphincterotomy 141 32 (23)
Biliary sphincterotomy without PSH 43 8 (19)
Biliary sphincterotomy with PSH 51 10 (20)
Dual sphincterotomy with PSH 47 14 (30)
EPISOD 2 Biliary sphincterotomy 21 5 (24)
Dual sphincterotomy 39 12 (31)
None 12 2 (17)
EPISOD, Evaluating Predictors and Interventions in Sphincter of
Oddi Dysfunction; PSH, pancreatic sphincter hypertension.
Gastroenterology Vol. 150, No. 6
of bleeding and retroduodenal perforation, which both
occur in about 1% of cases, and also a significant risk for
late restenosis, especially after pancreatic sphincterotomy.
Surgical therapy. Surgical sphincteroplasty can be
performed primarily or after failed endoscopic therapy. Case
series and one small randomized study (published in ab-
stract) suggest good outcomes in most patients,63,77–80 but
endoscopic intervention is currently preferred for primary
treatment.
Functional Biliary Sphincter Disorder in
Patients With an Intact Gallbladder
Very few studies have addressed the role of sphincter
dysfunction in patients with biliary-type pain in the presence
of the GB. Two small retrospective case series showed a lower
chance of clinical response to biliary sphincterotomy in pa-
tients with an intact GB than in those with prior cholecys-
tectomy.81,82 Response was more likely if the bile duct was
dilated. A third study reported that 43% had long-term pain
relief.83 More information is needed on how to manage these
patients. At this time, it is not appropriate for patients with
intact GBs (without stones) to undergo ERCP, manometry, or
sphincterotomy unless they are enrolled in a clinical trial.
Summary of Functional Biliary Sphincter Disorder
Post-cholecystectomy pain is a common complaint, the
cause of which often remains obscure after standard in-
vestigations. This is a clinical minefield, which patients and
physicians should enter only with extreme caution, espe-
cially when considering the use of ERCP and sphincter-
otomy, with or without sphincter manometry. The EPISOD
trial again showed the strength of the placebo effect of
intervention, which bedevils the assessment of all types of
treatment. Further stringent trials are needed.
Functional Pancreatic Sphincter
Dysfunction
The idea that dysfunction of the pancreatic sphincter can
cause pancreatic pain and pancreatitis is popular. It seems a
logical extension to the consensus that sphincter hyperten-
sion can cause biliary pain. Obstruction at the sphincter
causes pancreatitis in animal experiments, and in several
clinical situations, including tumors of the papilla, duct
stones, and by mucus plugs in intrapancreatic mucinous
neoplasm. In addition, opiates increase sphincter pressure
and have been implicated in attacks of pancreatitis.84
Finally, patients with unexplained attacks of pancreatitis
are often found to have elevated pancreatic sphincter
pressures.28,85–87
Proof that elevated sphincter pressures actually cause
pancreatitis would require demonstration of abnormal
sphincter activity, and resolution of the attacks after
sphincter ablation. Earlier small cohort studies suggested
benefit after endoscopic or surgical sphincterotomy with
recurrence in less than one-third of patients.28 More recent
studies suggest that pancreatitis recurs in about 50% of
patients with longer follow-up.88,89 A recent prospective
May 2016
study showed a 50% recurrence rate in 2 years after
sphincterotomy in patients with raised pressures.60 This did
show a 3.5 times greater likelihood of recurrent attacks in
patients with elevated pressures without treatment. How-
ever, there was no additional benefit of dual (pancreatic and
biliary) sphincterotomy over biliary sphincterotomy alone.
Whether these reports mean that sphincterotomy is bene-
ficial is difficult to interpret in the absence of controls.
It remains possible that the finding of sphincter abnor-
mality in these patients is an epiphenomenon, the result of
previous attacks, or due to an unexplained cause. The fact
that many patients eventually develop features of chronic
pancreatitis suggests that the underlying pathogenesis of
the disease is not altered.
Can Pancreatic Sphincter Dysfunction
Cause Pain Without Pancreatitis?
Historically, it was proposed that SOD can cause
pancreatic pain without definite evidence of pancreatitis
and, indeed, a categorization of pancreatic SOD types similar
to that used in suspected biliary SOD was suggested.28
Pancreatic pressures higher than the accepted norm are
found in many patients with unexplained pain (including
those in the EPISOD study). Many such patients have un-
dergone sphincterotomies, but proof of benefit is lacking.85
Diagnosis and Criteria for Functional
Pancreatic Sphincter Disorder
Given the uncertainty about the role of pancreatic SOD,
efforts to provide useful guides to investigation and treat-
ment are currently speculative. Pancreatic SOD may be
considered in patients with documented acute recurrent
pancreatitis, after a comprehensive review of known etiol-
ogies and search for structural abnormalities, and with
elevated pancreatic pressures on manometry.
E2. Diagnostic Criteria for Pancreatic Sphincter
of Oddi DisorderAll of the following:
1. Documented recurrent episodes of pancreatitis
(typical pain with amylase or lipase >3 times
normal and/or imaging evidence of acute
pancreatitis)
2. Other etiologies of pancreatitis excluded
3. Negative endoscopic ultrasound
4. Abnormal sphincter manometry
Alternative diagnostic tests. Measuring the size of
the pancreatic duct by MRCP or EUS before and after an
intravenous injection of secretin has been used to demon-
strate sphincter dysfunction. One report suggests that the
results do not correlate with sphincter manometry, but may
predict the outcome of sphincterotomy in patients with
otherwise unexplained pancreatitis.90 This test deserves
further assessment. Injection of Botulinum toxin into the
Gallbladder and Sphincter of Oddi Disorders 1427
sphincter and temporary stenting have been used in this
context, but have not been validated.91
Treatment
Patients with recurrent acute pancreatitis that remains
unexplained after detailed investigation should be reassured
that the attacks may stop spontaneously and if they recur,
they usually follow the same course and are rarely life
threatening. They should be counseled to avoid factors that
may precipitate attacks (eg, alcohol, opiates). While certain
medications (such as antispasmodics and calcium channel
blockers) are known to relax the sphincter, there have been no
trials of their use.
In earlier days, cholecystectomy was often recom-
mended after 2 unexplained attacks of pancreatitis,
assuming that small stones or microlithisasis were respon-
sible.92 That approach seems less acceptable now that these
are easier to exclude with modern imaging. Others have
GALLBLADDER AND SOD
approached the problem of microlithiasis with biliary
sphincterotomy, or treatment with ursodeoxycholic acid,
but current data are unconvincing.
Pancreatic sphincterotomy would be the logical treatment
if the sphincter dysfunction is indeed causative. Historically,
complete division of the both sphincters was done by an open
transduodenal approach. Case series of patients who have
undergone this procedure have claimed resolution of episodic
pancreatitis in the majority of patients.93,94 The pancreatic
sphincterotomies performed endoscopically are much
smaller, and repeat manometry studies in patients with
recurrent problems often show them to be incomplete.60,89
Manometry has not been repeated in patients without
recurrent symptoms, so it is not clear whether treatment has
failed because of inadequacy of the sphincterotomy, or an
incorrect diagnosis. Stenosis of the pancreatic orifice is not
uncommon after pancreatic sphincterotomy, and repeat ERCP
treatment rarely resolves the problem. Endoscopic biliary
sphincterotomy is known to reduce pancreatic sphincter
pressures in many cases, and the recent prospective trial
showed no benefit of adding pancreatic sphincterotomy.60
At the present time, practitioners and patients should
approach invasive treatments in this context with consid-
erable caution, recognizing the short and long-term risks,
and the marginal evidence for benefit. Additional stringent
trials are required.
Functional Pancreatic Sphincter Dysfunction
and Chronic Pancreatitis
Elevated pancreatic sphincter pressure has been
described in 50%
87% of patients with chronic pancrea-
titis of many etiologies.94,95 Whether it plays a role in the
pathogenesis or progression of chronic pancreatitis is not
known. Endoscopic pancreatic sphincterotomy was re-
ported to improve pain scores in short-term uncontrolled
studies in 60%
65% of chronic pancreatitis patients with
pancreatic SOD,95 but long-term data are not available. The
role of endoscopic treatment (in the absence of stones or
strictures) remains unclear.
 1428 Cotton et al
Summary of Functional Pancreatic
Sphincter Dysfunction
There is no proven role for ERCP with manometry in pa-
tients with suspected pancreatic pain without evidence for
pancreatitis. Patients with a single episode of unexplained
acute pancreatitis should not undertake the risks of ERCP
because a second episode may never happen, or may be long
delayed. Similarly, there is currently no clear role for treating
SOD in patients with chronic pancreatitis. The optimal
approach for patients with unexplained recurrent acute
pancreatitis needs clarification by stringent studies with long
follow-up. Currently, it appears reasonable to consider ERCP
with sphincterotomy when manometry is abnormal. Biliary
sphincterotomy alone appears as effective as dual sphincter-
otomy, and likely lowers the short and long-term risks. Pa-
tients should understand the significant risks and uncertain
benefits.
GALLBLADDER AND SOD
Conclusions
Our understanding of functional gall bladder and
sphincter disorders is far from complete, and our current
treatment recommendations are not firmly evidence-based.
The need for more stringent prospective research is obvious.
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. Visit the online version of
Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.033.
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Reprint requests
Address requests for reprints to: Peter B. Cotton, MD, FRCP, FRCS, Digestive
Disease Center, Medical University of South Carolina, 25 Courtenay Drive,
ART, Charleston, SC, 29425-2900. e-mail: Cottonp@musc.edu; fax: (843)
876-4718.
Conflicts of interest
The authors disclose no conflicts.
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 Gastroenterology 2016;150:1430–1442

Anorectal Disorders
Satish S. C. Rao,1 Adil E. Bharucha,2 Giuseppe Chiarioni,3,4 Richelle Felt-Bersma,5
Charles Knowles,6 Allison Malcolm,7 and Arnold Wald8
1
Division of Gastroenterology and Hepatology, Augusta University, Augusta, Georgia; 2Department of Gastroenterology and
Hepatology, Mayo College of Medicine, Rochester, Minnesota; 3Division of Gastroenterology of the University of Verona,
Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; 4Division of Gastroenterology and Hepatology and UNC
Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;
5
Department of Gastroenterology/Hepatology, VU Medical Center, Amsterdam, The Netherlands; 6National Centre for Bowel
Research and Surgical Innovation, Blizard Institute, Queen Mary University of London, London, United Kingdom; 7Division of
Gastroenterology, Royal North Shore Hospital, and University of Sydney, Sydney, Australia; 8Division of Gastroenterology,
University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

This report defines criteria and reviews the epidemiology,
pathophysiology, and management of the following com-
mon anorectal disorders: fecal incontinence (FI), func-
tional anorectal pain, and functional defecation disorders.
FI is defined as the recurrent uncontrolled passage of fecal
material for at least 3 months. The clinical features of FI
are useful for guiding diagnostic testing and therapy.
Anorectal manometry and imaging are useful for evalu-
ANORECTAL
questionnaires and bowel diaries are correlated,5 some
patients may not accurately recall bowel symptoms6; hence,
symptom diaries may be more reliable.
In this report, we examine the prevalence and patho-
physiology of anorectal disorders, listed in Table 1, and
provide recommendations for diagnostic evaluation and
management. These supplement practice guidelines rec-
ommended by the American Gastroenterological Associa-

ating anal and pelvic floor structure and function. Educa-
tion, antidiarrheals, and biofeedback therapy are the
mainstay of management; surgery may be useful in re-
fractory cases. Functional anorectal pain syndromes are
defined by clinical features and categorized into 3 sub-
types. In proctalgia fugax, the pain is typically fleeting and
lasts for seconds to minutes. In levator ani syndrome and
unspecified anorectal pain, the pain lasts more than 30
minutes, but in levator ani syndrome there is puborectalis
tenderness. Functional defecation disorders are defined by
‡2 symptoms of chronic constipation or irritable bowel
syndrome with constipation, and with ‡2 features of
impaired evacuation, that is, abnormal evacuation pattern
on manometry, abnormal balloon expulsion test, or
impaired rectal evacuation by imaging. It includes 2 sub-
types: dyssynergic defecation and inadequate defecatory
propulsion. Pelvic floor biofeedback therapy is effective for
treating levator ani syndrome and defecatory disorders.
Keywords: Anorectal Disorders; Fecal Incontinence; Con-
stipation; Dyssynergic Defecation; Levator Ani Syndrome;
Anorectal Pain; Biofeedback Therapy.
tion7 and American College of Gastroenterology.8 We will
not address anorectal symptoms secondary to a neurologic
or systemic disorder. The revised diagnostic criteria
include a minimum duration of symptoms that were
selected arbitrarily to avoid the inclusion of self-limited
conditions.
F1. Fecal Incontinence
Definition
Fecal incontinence (FI) is defined as the recurrent un-
controlled passage of fecal material for at least 3 months.
We recognize that fecal staining of underwear may reflect
poor hygiene, prolapsing hemorrhoids, or rectal prolapse
rather than true FI, but for practical purposes it is included
in the definition of FI. Clear mucus secretion must be
excluded by careful questioning. Flatus incontinence is
often included in the definition of anal incontinence but not
in the current diagnosis of FI because it is difficult to define
when isolated passage of flatus is abnormal. FI is often
multifactorial and occurs in conditions that cause diarrhea,
impair colorectal storage capacity, and/or weaken the
pelvic floor (Table 2). FI is considered abnormal after

A
toilet training has been achieved, generally around 4 years
norectal disorders are defined by specific symptoms
of age.9
and, in the case of functional disorders of defecation,
also with abnormal diagnostic tests. Our understanding of
these disorders continues to evolve with the availability of
newer techniques to characterize anorectal structure and
function.1–3 Consequently, the distinction between “organic” Abbreviations used in this paper: ARM, anorectal manometry; CI, confi-
and “functional” anorectal disorders may be difficult in dence interval; DRE, digital rectal examination; EMG, electromyography;
FDD, functional defecation disorder; FI, fecal incontinence; IBS, irritable
individual patient.1–3 bowel syndrome; MRI, magnetic resonance imaging; OR, odds ratio.
Anorectal disorders, such as fecal incontinence, are Most current article
usually defined by specific symptoms, but functional disor-
© 2016 by the AGA Institute
ders of defecation require symptoms and anorectal physi- 0016-5085/$36.00
ological testing.4 While bowel symptoms recorded by http://dx.doi.org/10.1053/j.gastro.2016.02.009
May 2016
Table 1.Functional Anorectal Disorders
F. Functional anorectal disorders
F1. Fecal incontinence
F2. Functional anorectal pain
F2a. Levator ani syndrome
F2b. Unspecifed functional anorectal pain
F2c. Proctalgia fugax
F3. Functional defecation disorders
F3a. Dyssynergic defecation
F3b. Inadequate defecatory propulsion
Epidemiology
Prevalence. Several large community-based stud-
ies10–17 have suggested that FI is common, with a preva-
lence ranging from 7% to 15% in community-dwelling
women, 18% to 33% in hospitals, and 50% to 70% in
nursing homes.18,19 The prevalence is either compara-
ble16,20 or lower in men than women.21,22 Some11,13,17,23 but
not all16,24 studies reported a lower prevalence in African-
American than white women, but similar prevalence
across races in men.24 Interestingly, the majority of patients
seen in clinical practice are women.
Variations in the prevalence of FI among studies may
reflect differences in survey methods, screening questions,
reference time frame10,16,25 (1 year or past month), and
definition of incontinence. Two studies evaluated the
incidence of FI.23,26 In a community study (65 years and
older), the incidence of FI at 4 years was 17%, with 6%
having FI at least monthly.23 In a follow-up community
study (50 years and older), the incidence of FI was
7.0%.26
Table 2.Common Causes of Fecal Incontinence
Anal sphincter weakness
Traumatic: obstetric, surgical (eg, hemorrhoidectomy, internal
sphincterotomy, fistulectomy)
Nontraumatic: scleroderma, idiopathic internal sphincter
degeneration
Neuropathy
Peripheral (eg, pudendal) or generalized (eg, diabetes mellitus)
Pelvic floor disorders
Rectal prolapse, descending perineum syndrome
Disorders affecting rectal capacity and/or sensationa
Inflammatory conditions: radiation proctitis, Crohn’s disease,
ulcerative colitis
Anorectal surgery (pouch, anterior resection)
Rectal hyposensitivity
Rectal hypersensitivity
Central nervous system disorders
Dementia, stroke, brain tumors, multiple sclerosis, spinal cord
lesions
Psychiatric diseases, behavioral disorders
Bowel disturbances
Irritable bowel syndrome, post-cholecystectomy diarrhea
Constipation and fecal retention with overflow
a
These conditions may also be associated with diarrhea.
Functional Anorectal Disorders 1431
Impact on quality of life and psychosocial
factors. Persons with FI report that poor bowel control
restricts their social life; other issues pertain to toilet
location, hygiene/odor issues, coping strategies, fear,
physical activities, embarrassment, and unpredictability of
bowel habits.27 Co-existent psychological problems may
include anxiety and depression,28,29 poor self-esteem, and
problems with sexual relationships.30 Quality of life issues
can be evaluated by generic or disease-specific in-
struments, such as the Rockwood Fecal Incontinence
Quality of Life Scale, modified Manchester Health Ques-
tionnaire, Fecal Incontinence and Constipation Assessment
Quality of Life scale. FI symptoms can also be
assessed by Pelvic Organ Prolapse/Incontinence Sexual
Questionnaire
IUGA (International Urogynecology
Association).31–34 There is a significant correlation be-
tween symptom severity and QOL in FI.31,35 FI was asso-
ciated with increased mortality in some, but not all
studies.36–38 but whether it is due to FI per se or condi-
tions associated with FI (age and comorbidity) is
unknown.16
Etiology and risk factors for fecal incontinence. The
etiology of incontinence is often multifactorial. Therefore, it
is more appropriate to focus on associated conditions,
especially when they precede the onset of FI, and on risk
ANORECTAL
factors for FI. In community surveys, bowel disturbances,
especially diarrhea and rectal urgency, and the burden of
chronic illness were more important and independent risk
factors for FI than obstetric-related pelvic floor injury (eg,
forceps use, complicated episiotomy).2,16,26,39–41 In a
community-based cohort of 176 randomly selected women
with FI and 176 without FI, the independent risk factors for
FI were diarrhea (odds ratio [OR] ¼ 53; 95% confidence
interval [CI]: 6.1
471), cholecystectomy (OR ¼ 4.2l 95% CI:
1.2
15), current smokers (OR ¼ 4.7; 95% CI: 1.4
15),
rectocele (OR ¼ 4.9; 95% CI: 1.3
19), stress urinary in-
continence (OR ¼ 3.1; 95% CI: 1.4
6.5), and body mass
index (per unit, OR ¼ 1.1; 95% CI: 1.004
1.1).41 Smoking,
external sphincter atrophy, and obesity are also risk fac-
tors for FI.2,11,13,17,41 Other conditions associated with FI
include advanced age, disease burden (comorbidity count,
diabetes), anal sphincter trauma (obstetrical injury, prior
surgery), and decreased physical activity.11,16,17,42,43
Several diseases that affect anorectal sensorimotor dys-
functions and/or alter bowel habits are also associated
with FI in clinical practice (Table 2). Some of these con-
ditions do not emerge as risk factors in community
studies, possibly because their prevalence is relatively low.
Consistent with the findings of community-based studies,
the vast majority of women with FI who consult a
physician might not have a neurologic or inflammatory
disorder, but rather have bowel disturbances, typically
diarrhea, often associated with a history of obstetric risk
factors. However, neurologic deficit can only be identified
with neurophysiological tests, and these are not widely
available.
The incidence of FI after vaginal delivery was 8% in a
recent series.44 This may reflect improvements in obstet-
rical practices, including decreased use of instrumented
 1432 Rao et al
vaginal delivery (eg, forceps), less frequent and more
selective use of episiotomy, and increased use of cesar-
ean sections, although a Cochrane review showed no
demonstrable difference between cesarean sections and
vaginal deliveries.45 Third-degree (ie, involving the
external anal sphincter) and fourth-degree lacerations
(ie, extending through the external and internal anal
sphincters) are strong risk factors for anal and fecal
incontinence.46 A prospective National Institutes of
Health trial identified a nearly 2-fold increased OR of FI
for women with sphincter injury during childbirth
compared with a control group.47 The risk is highest for
instrument-assisted deliveries, with increased odds of
1.5 for anal incontinence and a higher risk with forceps
than vacuum extraction.48 Among women in the com-
munity, the median age of onset of FI is in the 7th
decade, that is, many decades after vaginal delivery11
and, therefore, how obstetric injury predisposes to FI
is unclear.
Anorectal surgery for fistula, fissures, or hemor-
rhoidectomy and anorectal carcinoma can damage the
sphincters.49 Impaired rectal compliance, as can occur with
proctitis or after creation of a pouch, and fecal impaction
with overflow diarrhea, can all cause FI.50–52
F1. Diagnostic Criteriaa for Fecal Incontinence
ANORECTAL
1. Recurrent uncontrolled passage of fecal material
in an individual with a developmental age of at
least 4 years
a
Criteria fulfilled for the last 3 months. For research
studies, consider onset of symptoms for at least 6
months previously with 2
4 episodes of FI over 4
weeks.
Gastroenterology Vol. 150, No. 6
Justification for Changes in Diagnostic Criteria
The earlier definition of functional fecal incontinence
was cumbersome, did not facilitate management, and was
seldom used in clinical practice or research studies. There-
fore, we recommend the generic term fecal incontinence.
We recognize that newer sensitive diagnostic tools (eg, anal
ultrasonography, pelvic magnetic resonance imaging [MRI],
and high resolution/3-dimenstional high-definition anorectal
pressure topography) often reveal disturbances of anorectal
structure and/or function in a majority of patients with FI, but
their relationship to symptoms is unclear, especially as some
have more dysfunction(s) than others. Therefore, it can be
challenging to attribute symptoms with confidence to an
organic or functional cause and more studies are needed.
Pathophysiology
Physiological factors. Continence is maintained by
several mechanisms, including anatomical factors (endo-
vascular cushions, integrity of anal sphincter, and pubor-
ectalis muscle), rectoanal sensation, rectal compliance,
neuronal innervation, stool consistency, mobility, and psy-
chological factors (Figure 1).53
Anorectal and pelvic floor musculature. Anal sphincter
weakness is the most frequently identified abnormality in FI.
Among older women, approximately 40% had reduced anal
resting pressure and 80% reduced squeeze pressure.54 In-
ternal anal sphincter dysfunction is characterized by exag-
gerated spontaneous relaxation of the internal anal sphincter
(sampling reflex)55 or decreased resting pressure.54,55 The
latter is associated with structural disturbances, that is, de-
fects (after obstetric injury) and/or thinning (scleroderma,
advanced age). This is best visualized by ultrasonography.
Among postpartum women, the severity of FI was greater in
women with internal anal sphincter defects.56
Figure 1. Anatomy of the
anal canal and rectum,
which displays the key
physiologic mechanisms
for continence and
defecation.
May 2016
External anal sphincter weakness can result from one
or more of the following factors: sphincter damage, neu-
ropathy, myopathy, or reduced corticospinal input. In
addition to the anal sphincters, the levator ani muscles also
contribute to the pelvic barrier.57 One study suggested that
the reduced inward traction exerted by the puborectalis in
patients with FI correlated more closely with symptoms
than did squeeze pressures, and improved after biofeedback
therapy.58 Whereas the anal sphincters and endovascular
cushions seal the anal canal, the levator ani and puborectalis
maintain continence of solid stool by a flap-valve
action.59–62 Patients with excessive perineal descent have
a more obtuse anorectal angle, suggesting that the flap valve
that normally maintains continence when intra-abdominal
pressure increases is impaired.57
FI in men who generally have fecal soiling or leakage
rather than gross incontinence may be associated with
normal sphincteric function63–67; iatrogenic anal injury (eg,
after perianal procedures); or dyssynergic defecation,68
wherein high anal resting pressure entraps feces during
defecation and subsequently expels them69; radiation ther-
apy70; or isolated weakness of the internal anal sphincter.
Rectal compliance and rectoanal sensation. Stool is
often transferred into the rectum by colonic high-amplitude
propagated contractions, which tend to occur after awak-
ening or meals.71 Rectal distention by stool is associated
with several processes that serve to preserve continence
or, if appropriate, proceed to defecation. Rectal distention
induces reflex relaxation of the internal anal sphincter and
is perceived as a sensation of rectal fullness, as if the
rectum were uncomfortably full of flatus or feces. If defe-
cation is inconvenient, the desire to defecate prompts
voluntary contraction of the external sphincter and
puborectalis muscle72; this sensation wanes, together with
the sense of urgency, as the rectum accommodates to hold
more stool.
The sphincter pressures alone do not always distinguish
continent from incontinent subjects. Reduced rectal sensa-
tion allows stool to enter the anal canal and perhaps leak
before the external sphincter contracts.55,72,73 Decreased
rectal sensitivity (rectal hyposensitivity) and increased
rectal compliance can also contribute to fecal retention by
decreasing the frequency and intensity of the urge (and
hence the motivation) to defecate. Conversely, fecal reten-
tion may reduce rectal sensation, perhaps by altering rectal
tone and viscoelastic properties, or by affecting afferent
nerve pathways.74
Rectal hypersensitivity, perhaps a marker of concomi-
tant irritable bowel syndrome (IBS),55,75 may be associated
with reduced rectal compliance and repetitive rectal con-
tractions during rectal distention.54,76 Rectal capacity is
also reduced in women with FI and associated with the
symptom of urgency.54,77 In addition, rectal hypersensi-
tivity cannot be entirely explained by disturbances in rectal
compliance. Anal sphincter relaxation may occur during, or
independent of, rectal distention, or along with colonic
high-amplitude propagated contractions, which enables the
anal lining to periodically “sample” rectal contents and
ascertain whether rectal contents are gas, liquid, or
Functional Anorectal Disorders 1433
stool.74,78 Sampling occurred less frequently in incontinent
patients, perhaps depriving them of sensory information.74
In addition to anorectal dysfunctions, continence can also
be affected by disturbances of stool consistency and/or
delivery, impaired mental faculties, and mobility. These
observations confirm that FI is a heterogeneous disorder
and that patients often exhibit more than one deficit
(Table 2).
Clinical Evaluation
History. It is essential to develop a rapport with FI
patients and, with tact and skill, evaluate its severity,
awareness for stooling, and conditions that predispose,
including the type (solid, liquid, and/or gas), quantity, and
frequency. Staining, soiling, and seepage reflect the nature
and severity of FI.20 Soiling indicates leakage that is more
extensive than staining of underwear and can be specified
further (ie, soiling of underwear or furnishing/bedding).
Seepage refers to leakage of small amounts of stool.
Characterization of bowel habit is important and the
Bristol Stool Form Scale and bowel diaries can be useful.79
Constipation with fecal impaction is a significant risk in
nursing homes.36,80 Factors that cause or exacerbate incon-
tinence via loose stools (eg, laxatives, artificial sweeteners)
and anorectal surgical procedures (eg, lateral sphincter-
ANORECTAL
otomy) or other mechanisms (eg, smoking, obesity) should
be considered. Conversely, agents that cause constipation
may predispose to fecal retention and overflow. Recognizing
the timing of incontinence (eg, whether predominantly dur-
ing or after events such as meals, bowel movements, exercise,
or at night) can provide clues to etiology and management.40
History taking should also include consideration of condi-
tions that are a secondary cause of FI, such as multiple
sclerosis, diabetic neuropathy, or scleroderma.
Urge vs passive FI can provide clues to the pathophysi-
ology. Incontinence for solid stool suggests more severe
sphincter weakness than liquid stool alone.81 Patients with
urge incontinence have a sensation of the desire to defecate
before leakage, but cannot reach the toilet on time.
Conversely, patients with passive incontinence have dimin-
ished or no awareness of the desire to defecate before the
incontinent episode. Patients with urge incontinence often
have reduced squeeze pressures82 and/or squeeze dura-
tion,83 reduced rectal capacity, and increased perception of
rectal balloon distention,54,84 whereas patients with passive
incontinence often have lower resting pressures.82,83
Several FI instruments—Wexner (Cleveland Clinic),
Vaizey (St Marks), Rockwood, Fecal Incontinence and Con-
stipation Assessment, and the bowel version of the Inter-
national Consultation of Incontinence questionnaire—are
currently used in clinical studies to rate the severity of
FI10,31,35,85–87 and are validated instruments. Currently,
success in therapeutic trials is typically defined as a 50%
reduction in the number of episodes of FI or days per
week,88 although a patient’s perspective may differ and
more meaningful outcome measures are required.89,90
Physical examination including digital rectal
evaluation. A multisystem and abdominal examination
 1434 Rao et al
and focused neurologic examination is often necessary in FI
patients with neurologic symptoms.
A digital rectal examination (DRE) should be conducted
in the left lateral position and before enemas or laxatives
are given. Inspection may reveal scars from previous sur-
gery or obstetric injury or a patulous sphincter or perianal
fecal soiling or dermatitis. An absent anocutaneous reflex in
response to gentle stroking of the perianal region suggests
nerve impairment. After inspection, anorectal digital
palpation should be conducted. This may reveal external
anal sphincter and/or puborectalis weakness or defects,91
stool impaction, and presence of dyssynergia during simu-
lated defecation. A meticulous DRE performed by an expe-
rienced examiner had a positive predictive value of 67% and
81% for identifying low resting and squeeze pressures,
respectively.92
Diagnostic testing. Testing should be tailored to the
patient’s clinical problem, severity, possible etiology, impact
on quality of life, and response to medical management.
Endoscopy. Endoscopic assessment of the rectosigmoid
mucosa or full colonoscopy with biopsies may be considered
in patients with diarrhea or recent change in bowel habit.
Manometry evaluation. Anorectal manometry (ARM)
assesses continence and defecatory mechanisms by
determining:
ANORECTAL
1. resting anal pressure, which is predominantly (ie,
approximately 70%) attributable to internal anal
sphincter function;
2. squeeze pressure: the strength and duration of
voluntary external anal sphincter contraction and
puborectalis contraction;
3. presence of an internal anal sphincter inhibitory
reflex;
4. threshold volume of rectal distention required to
elicit the first sensation of distention, a sustained
feeling of urgency to defecate, and the maximum
tolerable volume;
5. whether attempted defecation is accompanied by
increased intra-abdominal pressure and relaxation of
the pelvic floor muscles (normal), or by paradoxical
contraction of the pelvic floor muscles, which may be
relevant to symptoms; and
6. rectal compliance can be evaluated by assessing the
pressure
volume relationship during stepwise
distention of a latex balloon, but it is preferable to do
so with an infinitely compliant polyethylene balloon
and a barostat.
The methods used for ARM, including solid-state probe,
high-resolution ARM, and 3-dimensional high-definition
ARM systems, and its measurements and interpretation
are detailed elsewhere.93–95
Anal endosonography. Anal endosonography identifies
anal sphincter thinning and/or defects that are often clini-
cally unrecognized and may be amenable to surgical
repair.96,97 Endosonography reliably identifies anatomic
Gastroenterology Vol. 150, No. 6
defects or thinning of the internal sphincter, whereas
interpretation of external sphincter images may pose tech-
nical challenges. In contrast, 3-dimensional endosonography
can measure the length and volume of the external anal
sphincter and atrophy.98 Endoanal MRI,99,100 and vaginal
ultrasound can provide additional information.101
Defecography. Defecography is useful only for selected
patients with FI, particularly before surgery, to identify or
confirm structural alterations of the pelvic floor.
Pelvic magnetic resonance imaging. MRI is the only
imaging modality that can visualize both anal sphincter
anatomy and global pelvic floor motion (ie, anterior, middle,
and posterior compartments) in real time without radiation
exposure.102 Endosonography is the first choice for anal
sphincter imaging in FI because it is widely available and
the internal sphincter is visualized more clearly. MRI is
more useful for identifying external sphincter atrophy and a
patulous anal canal, which is a marker of not only anal
sphincter injury, but disturbances beyond sphincter
injury, such as damage to the anal cushions or anal
denervation.54,103
Neurophysiologic tests. Neurophysiological tests can
characterize disturbances in the motor and sensory inner-
vation of the anorectum and pelvic floor muscles. These
tests include pudendal nerve terminal motor latencies,
electromyography (EMG), rectoanal sensory tests, and mo-
tor evoked potentials. There are several methodological
limitations to pudendal nerve terminal motor latencies, and
the utility of this measurement has been questioned.7 Nee-
dle EMG can identify normal, neurogenic, or muscle
injury.57,104 Recently, prolonged rectal and anal motor
evoked potentials have been shown in a majority of FI pa-
tients, suggesting that neurophysiologic dysfunction plays
an important role.105
Treatment
Management of FI must be tailored toward correction of
clinical manifestations.
Bowel habit modification with dietary or phar-
macological interventions. Loose stools are a major risk
factor for FI.2,40 Correction of reversible factors like laxa-
tives or other medications can help. Dietary trials (eg, low
lactose or low fructose) in selected patients can normalize
stool form. Among fiber supplements, only psyllium but
not gum arabic or carboxymethylcellulose, improved FI
compared with placebo.106 Loperamide given at an
adequate dose (ie, 2
4 mg, 30 minutes before meals) can
improve stool consistency and increase internal sphincter
tone, thereby reducing incontinence.107 Diphenoxylate,
combined with atropine, is an alternative to loperamide,
but there may be anticholinergic side effects.108 In an open-
label study of 18 patients, amitriptyline (20 mg daily),
which has anticholinergic effects, improved FI in most
patients.109
Patients with constipation, fecal impaction, and over-
flow incontinence often benefit from a program to increase
emptying of the colorectum by various means. For example,
a regimen consisting of a daily osmotic laxative (lactulose
10 mL twice daily) plus a weekly enema was useful in the
May 2016
majority of elderly patients with FI, including those with
dementia.110 However, loosening the stool may aggravate
FI. Other measures aimed at improving rectal emptying,
such as the use of suppositories or enemas, fiber supple-
mentation, oral laxatives, and correction of any abnormal
toileting behavior, or positioning and biofeedback may be
helpful.111
Rectal cleansing and anal plug devices. In patients
who fail bowel modification and biofeedback therapy, pe-
riodic rectal cleansing is a practical solution. It should be
considered particularly in patients with neurogenic bowel
dysfunction.112–115 Plug devices may also be useful in some
patients with seepage.115
Biofeedback therapy. Biofeedback is based on the
principle of operant conditioning or instrumental
learning.116 One randomized controlled trial showed that
biofeedback therapy is superior to Kegel exercises.117
Surgical approaches. Anal sphincter repair, although
well established, does not appear to be effective in the long-
term.118 Sacral nerve stimulation and anal submucosal in-
jection of dextranomer in stabilized hyaluronic acid [NASHA
Dx]), a bulking agent, are both approved by the US Food and
Drug Administration for the treatment of FI. In the pivotal
US multicenter study of sacral nerve stimulation, at 5-year
follow-up, 76 of 120 (63%) patients were available, of
whom, 36% reported complete continence and 89% were
deemed a therapeutic success.119 However, this and nearly
all other studies with sacral nerve stimulation have been
uncontrolled. In a crossover study of 34 patients, the
number of episodes of FI declined by 90% during stimula-
tion vs 76% without stimulation.120
In the pivotal trial of NASHA Dx (206 patients), the
proportion of patients achieving a 50% FI episode reduction
was higher for NASHA Dx (52%) than sham injections
(31%), this response was sustained up to 3 years in some
patients.121,122
F2. Functional Anorectal Pain
Three types of functional anorectal pain disorders have
been described: proctalgia fugax, levator ani syndrome, and
unspecified. They are primarily distinguished on the basis of
the duration of pain and the presence or absence of ano-
rectal tenderness. Despite some differences, there is signif-
icant overlap among these conditions.123
F2a. Levator Ani Syndrome
Definition. In levator ani syndrome, the pain is often
described as a vague, dull ache or pressure sensation high in
the rectum that is often worse with sitting than with
standing or lying down. Physical examination may reveal
spasm of levator ani muscles and tenderness on palpation,
more often on the left than right side, or of the pelvic floor
or vagina.124
Epidemiology. In one survey, the prevalence of ano-
rectal pain due to all causes and symptoms of levator ani
syndrome elicited by questionnaire were 11.6% and 6.6%,
respectively.125
Functional Anorectal Disorders 1435
F2a. Diagnostic criteriaa for Levator Ani Syndrome.
Must include all of the following:
1. Chronic or recurrent rectal pain or aching
2. Episodes last 30 minutes or longer
3. Tenderness during traction on the puborectalis
4. Exclusion of other causes of rectal pain, such as
inflammatory bowel disease, intramuscular ab-
scess and fissure, thrombosed hemorrhoids,
prostatitis, coccygodynia, and major structural al-
terations of the pelvic floor.
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis.
F2b. Diagnostic Criteria for Unspecified Functional
Anorectal Pain
Symptom criteria for chronic levator ani syndrome but
no tenderness during posterior traction on the pubor-
ectalis muscle
ANORECTAL
Justification for Changes in Diagnostic Criteria
The previous classification included chronic proctalgia
that was subcategorized into levator ani syndrome, un-
specified anorectal pain, and proctalgia fugax. Because
chronic proctalgia includes many other conditions, it has
been deleted, but the 3 subentities are retained. There are
very limited published data on the duration of pain, but we
believed the revised duration may facilitate better distinc-
tion between these entities. Reflecting the limited spatial
discrimination of visceral pain in humans, the location of
pain in proctalgia fugax has been revised to “rectum”
instead of “anal canal or lower rectum.”
Pathophysiology. Physiological factors. Levator ani
syndrome is hypothesized to result from spasm of pelvic
floor muscles and elevated anal resting pressures.123 How-
ever, a recent randomized controlled study found features
of dyssynergic defecation and a majority (85%) had levator
muscle tenderness. The dyssynergia reversed after suc-
cessful biofeedback, suggesting that rectoanal incoordina-
tion may be a pathophysiological explanation for levator ani
syndrome.126
Clinical evaluation. Diagnosis is based primarily on
the presence of characteristic symptoms and physical ex-
amination findings (see definition). Evaluation often in-
cludes sigmoidoscopy, ultrasonography, and pelvic imaging
to exclude alternative diseases.
Treatment. Treatments include electrogalvanic stimu-
lation; biofeedback training; muscle relaxants, such as
methocarbamol, diazepam, and cyclobenzaprine; digital
massage of the levator ani muscles; and sitz baths. However,
only 2 randomized controlled trials have been reported. In
one, 157 patients with chronic proctalgia received either
electrical stimulation or digital massage of the levator ani
 1436 Rao et al
and warm sitz baths or pelvic floor biofeedback plus psy-
chological counseling.126 Among patients who reported
tenderness on palpation, the intent-to-treat analysis showed
that 87% reported adequate relief of rectal pain after
biofeedback, compared with 45% for electrical stimulation
and 22% for massage. This improvement was maintained 12
months later. In another randomized controlled trial, 12
patients were randomized to anal sphincter injections of
either botulinum A toxin or placebo administered at an in-
terval of 3 months; botulinum toxin injections were similar
to placebo injections.127
F2c. Proctalgia Fugax
Definition. Proctalgia fugax is defined as sudden, se-
vere pain in the rectal area, lasting for a few seconds to
several minutes (rarely up to 30 minutes), and then dis-
appearing completely.128,129 Pain is localized to the rectum
in 90% of cases.130 Attacks are infrequent, typically occur-
ring fewer than 5 times per year in 51% of patients.130 The
pain has been described as cramping, gnawing, aching, or
stabbing and may range from uncomfortable to unbear-
able.129 Almost 50% of patients had to interrupt their
normal activities during an attack.131 The symptoms may
awaken the patient from sleep.
Epidemiology. The prevalence of proctalgia fugax
ANORECTAL
has ranged from 8% to 18% with no difference between
the sexes.125,128 Symptoms rarely begin before puberty,
but there have been cases reported in 7-year old
children.128,129
F2c. Diagnostic Criteriaa for Proctalgia Fugax
Must include all of the following:
1. Recurrent episodes of pain localized to the rectum
and unrelated to defecation
2. Episodes last from seconds to minutes, with a
maximum duration of 30 minutes
3. There is no anorectal pain between episodes.
4. Exclusion of other causes of rectal pain, such as
inflammatory bowel disease, intramuscular ab-
scess and fissure, thrombosed hemorrhoids,
prostatitis, coccygodynia, and major structural al-
terations of the pelvic floor.
a
For research purposes, criteria must be fulfilled for 3
months with symptom onset at least 6 months before
diagnosis.
Pathophysiology. Physiological factors. The short
duration and sporadic, infrequent nature of this disorder
have made the identification of physiological mechanisms
difficult, but abnormal smooth muscle contractions may be
responsible for the pain.132–134 Two studies cited families in
which a hereditary form of proctalgia fugax was found to be
associated with hypertrophy of the internal anal sphincter
and comorbid constipation.135,136 Attacks of proctalgia
fugax are often precipitated by stressful life events or
Gastroenterology Vol. 150, No. 6
anxiety.137 In an uncontrolled unblinded study, a majority of
patients were perfectionistic, anxious, and/or
hypochondriacal.138
Clinical evaluation. Diagnosis is based on the pres-
ence of characteristic symptoms as described and exclusion
of anorectal and pelvic pathophysiology.
Treatment. For most patients, the episodes are so
brief that remedial treatment is impractical and preven-
tion is not feasible, and because it is harmless, treatment
will normally consist of reassurance and explanation.
However, patients with frequent symptoms will require
treatment. A randomized controlled trial showed that
inhalation of salbutamol was more effective than placebo
for shortening the duration of episodes of proctalgia
for patients in whom episodes lasted 20 minutes or
longer.139
F3. Functional Defecation Disorders
Definition
Chronic constipation is commonly classified as either
slow colonic transit or outlet dysfunction, although some
patients may have neither and others fulfill criteria for
both. A large subset of outlet dysfunction has a functional
defecation disorder (FDD), which is characterized by
paradoxical contraction or inadequate relaxation of the
pelvic floor muscles during attempted defecation and/or
inadequate propulsive forces during attempted defeca-
tion. These disorders are frequently associated with
symptoms such as excessive straining, feeling of incom-
plete evacuation, and digital facilitation of bowel move-
ments.140 However, symptoms (eg, digital disimpaction,
anal pain) do not consistently distinguish patients with
FDDs from those without.141–143 Thus, the criteria for
FDDs must rely on both symptoms and physiological
testing.
Several investigators have described the association of
paradoxical anal contraction with constipation and have
described dyssynergia patterns.144,145 Likewise, studies
have shown inadequate propulsive forces as identified by
decreased or absent intrarectal pressure during attempted
defecation.141,142,145–148 These patients are clinically indis-
tinguishable from patients with dyssynergic defecation.
Recently, a large controlled study showed that dyssynergic
defecation, inadequate propulsive forces, and a hybrid of
both disturbances were uncorrelated, suggesting that the
pathophysiology of dyssynergic defecation and inadequate
propulsive forces are distinct.142 Also, these patterns are
observed in asymptomatic controls,94,141,149,150 and by
themselves they have limited utility for discriminating be-
tween health and defecatory disorders. Hence, FDDs are
best identified by a combination of dyssynergic patterns
during attempted defecation and other findings (see diag-
nostic criteria).
Epidemiology
The prevalence of FDDs in the general population is
unknown because the diagnosis requires laboratory testing.
May 2016
At tertiary referral centers, the prevalence of dyssynergic
defecation among patients with chronic constipation has
ranged widely, from 20% to 81%.151–155 However, the
prevalence of dyssynergia may have been overestimated
due to the high false-positive rates seen in some
studies.156,157 In one tertiary care center, the prevalence of
dyssynergia was 3 times higher in women than men, but
was similar in younger and older individuals.140
F3. Diagnostic Criteriaa for Functional Defecation
Disorders
1. The patient must satisfy diagnostic criteria for
functional constipation and/or irritable bowel
syndrome with constipation
2. During repeated attempts to defecate, there must
be features of impaired evacuation, as demon-
strated by 2 of the following 3 tests:
a. Abnormal balloon expulsion test
b. Abnormal anorectal evacuation pattern with
manometry or anal surface EMG
c. Impaired rectal evacuation by imaging
Subcategories F3a and F3b apply to patients who satisfy
criteria for FDD
F3a. Diagnostic Criteria for Inadequate Defecatory
Propulsion
Inadequate propulsive forces as measured with
manometry with or without inappropriate contraction of
the anal sphincter and/or pelvic floor musclesb
F3b. Diagnostic Criteria for Dyssynergic Defecation
Inappropriate contraction of the pelvic floor as
measured with anal surface EMG or manometry
with adequate propulsive forces during attempted
defecation b
a
Criteria fulfilled for the last 3 months with symptom
onset at least 6 months before diagnosis.
b
These criteria are defined by age- and sex-appropriate
normal values for the technique.
Justification for Changes in Diagnostic Criteria
In the previous classification, only patients with func-
tional constipation, but not constipation-predominant IBS,
were eligible to be diagnosed with a defecatory disorder.
Since then, an association between IBS and pelvic floor
dysfunction has been recognized,158,159 and patients with
dyssynergic defecation can be effectively treated with
biofeedback therapy irrespective of coexistent IBS.160
Hence, the Rome IV criteria have been revised to include
patients with constipation-predominant or mixed IBS. The
criteria for “inadequate propulsive forces” and “inappro-
priate contraction of the anal sphincter and/or pelvic floor
Functional Anorectal Disorders 1437
muscles” are no longer specified because they vary among
different techniques.141,142,161
Clinical Evaluation
A detailed assessment of bowel symptoms (eg, pro-
longed or excessive straining, feeling of incomplete evacu-
ation after defecation, digital facilitation of defecation) and a
meticulous DRE often raise suspicion for an FDD. Bowel
diaries avoid the limitation of recall bias inherent to ques-
tionnaires and an interview. In a single study, the DRE has a
sensitivity of 75% and specificity of 87% for detecting
dyssynergia,162 which is associated with contraction or
failure to relax the puborectalis and/or anal sphincter
muscle and reduced perineal descent when patients try to
expel the examining finger.
Physiologic studies should be considered if there is
insufficient response to conservative treatment, for
example, education regarding normal bowel habits,
increased dietary fiber and liquids, and elimination of
medications with constipating side effects whenever
possible. These studies should include balloon expulsion
test, anorectal manometry, and if necessary, defecography-
imaging to aid in diagnosis of FDD. There is no single
“gold standard” diagnostic test to diagnose FDD and limited
ANORECTAL
agreement among various tests.
Balloon expulsion test. Rectal expulsion can be
evaluated by asking patients to expel balloons filled with
water or air from the rectum.143,146,163 The time required to
expel the balloon depends on the method used and ranges
from 1 minute to expel a 50-mL balloon filled with wa-
ter145,164,165 to 2 minutes.148 It is recommended that the
patient sit on a commode chair behind a privacy screen.148
The balloon expulsion test is a useful screening test for FDD,
but it does not define the mechanism of disordered defe-
cation. Because the balloon may not mimic the patients’
stool, a normal balloon expulsion study does not always
exclude a defecation disorder.141
Manometric assessment. Traditionally, ARM has
been considered essential for diagnosis of FDDs. This
assessment includes measurement of intrarectal pressures
during attempted defecation, and measurement of anal
pressures and/or EMG activity during attempted defecation.
However, given the overlap of findings in asymptomatic
people and patients with FDD, the precise criteria and utility
of manometry for diagnosing defecatory disorders is in
evolution. Also, body position and manometry systems may
influence findings.
A normal pattern is characterized by increased intra-
rectal pressure associated with anal relaxation. A study
of 100 patients with a 6-sensor, solid-state manometry
system identified 4 patterns of FDD.141 Two patterns,
types I and III, describe dyssynergic defecation. Type I
pattern is characterized by increased intrarectal pressure
(45 mm Hg) and increased anal pressure reflecting
contraction of the anal sphincter. Type III pattern is
characterized by increased intrarectal pressure (45 mm
Hg) with absent or insufficient (<20%) relaxation of
the anal sphincter. Inadequate propulsion (intrarectal
 1438 Rao et al
pressure <45 mm Hg) may be associated with paradoxical
contraction (type II pattern) or insufficient relaxation
(<20%) of anal sphincter (type IV pattern). During testing
1 month later, the abnormal patterns were reproducible
in 51 of 53 patients.141 Levels of inter-observer agreement
for identifying these patterns was substantial for types I
and IV dyssynergia, moderate for normal defecation
pattern, and fair for types II and III dyssynergia.161 A
study using high-resolution manometry in 62 healthy
women and 295 women with chronic constipation iden-
tified 3 phenotypes (high anal, low rectal, and hybrid) that
discriminated among patients with normal and abnormal
balloon expulsion time with 75% sensitivity and 75%
specificity.165
Defecography. Defecography is a radiologic technique
used to evaluate the rectum and pelvic floor during
attempted defecation.3,166 This test can detect structural
abnormalities (rectocele, enterocele, intussusception, rectal
prolapse, and megarectum) and assess functional parame-
ters (anorectal angle at rest and during straining, perineal
descent, anal diameter, indentation of the puborectalis, de-
gree of rectal emptying).
The diagnostic value of defecography is unclear,7 but is
still employed when ARM and balloon expulsion test are
equivocal, or for patients who are unable to evacuate a
ANORECTAL
balloon, but who relax the pelvic floor normally during
simulated defecation. In several European countries, defe-
cography is the primary modality for identifying FDD.
Magnetic resonance defecography images anorectal
motion and rectal evacuation in real time. Advantages
include better resolution of soft tissue surrounding the
rectum, improved ability to visualize anal sphincter and
levator ani muscles, and lack of radiation. MRI is particu-
larly useful in patients with normal balloon expulsion to
identify structural lesions and disordered defecation, and
to guide surgical therapy, for example for rectoceles and
cystoceles.102,167
Radio-opaque marker test of whole gut transit
time. By itself, slow colonic transit is not diagnostic of a
primary colonic motility disorder because slow transit
constipation exists independent of, or co-exists with, FDDs
and up to two-thirds of patients with a defecation disorder
also have delayed colonic transit.141,168,169 In one study,
colonic transit improved after biofeedback therapy for
outlet dysfunction, which suggests that outlet dysfunction
was responsible for delayed colonic transit.168 Colonic
transit time can be measured by obtaining abdominal ra-
diographs after patients ingest radio-opaque markers,170 a
wireless motility capsule,171–173 or by scintigraphy. The
wireless motility capsule and scintigraphy can also measure
gastric emptying and small intestinal transit, which may also
be delayed in constipated patients.174
Utility of anorectal testing for functional defeca-
tion disorders. The role of diagnostic testing was eval-
uated by assessing anorectal manometry, balloon
expulsion test, defecography, and colonic transit in 100
consecutive patients with symptoms of difficult defeca-
tion.141 In this group, anal manometry and balloon
Gastroenterology Vol. 150, No. 6
expulsion were normal in 30%. Among 70 patients with
abnormal manometry, balloon expulsion was abnormal in
42 patients (60%) indicative of FDD. Among 28 patients
with abnormal manometry and normal balloon expulsion,
defecography showed features of dyssynergic defecation
in 7 patients (25%). Because a considerable proportion
of healthy people exhibit dyssynergia when tested with
high-resolution manometry, the utility of high-resolution
manometry for identifying DD is unclear.142,161 Based on
these results, abnormal findings with 2 of 3 tests
(ie, anorectal manometry, balloon expulsion test, and
defecography) are required to confirm the diagnosis of
FDD.
Pathophysiology
FDDs are probably acquired but subliminal behav-
ioral disorders, particularly in patients who learn to
relax the external anal sphincter and puborectalis
muscles appropriately when provided with biofeedback
training.
Anxiety and/or psychological stress may also
contribute to the development of dyssynergic defecation
by increasing skeletal muscle tension,175 and one study
found that patients with dyssynergic defecation had
higher scores for anxiety, depression, paranoid ideation,
hostility, and obsessive compulsiveness than those pa-
tients with slow transit constipation.176 Psychological
distress seem to have a negative impact on the outcome
of biofeedback therapy.177 Uncontrolled studies have re-
ported sexual abuse in 22% of women with FDD, and
40% of women with functional lower gut disorders,
including FDD.140,178
Treatment
Historically, 2 types of pelvic floor training involving
behavioral modification have been advocated: biofeedback
training in which pressure sensors or EMG placed inside the
anus and rectum provide feedback to the patient on muscle
activity179 and simulated defecation in which the patient
practices evacuating an artificial stool surrogate.179,180
Simulated defecation has been combined with diaphrag-
matic muscle training by some investigators.179,181 Recent
randomized controlled trials have used multicomponent
biofeedback treatment,182 which includes the following four
steps (Table 3):
1. Patient education: Explain to patients that they
inadvertently squeeze or fail to relax their anus when
they are straining.
2. Enhance push effort: Teach the patients to effectively
push, when straining, by appropriately increasing the
intra-abdominal pressure; use feedback from rectal
sensor regarding abdominal and diaphragmatic push
effort to expel stool.
3. Train to relax pelvic floor muscles: Teach patients
to relax their pelvic floor muscles when straining.
This skill can be taught by providing visual
May 2016 Functional Anorectal Disorders 1439

Table 3.Summary of Randomized Controlled Trials of Biofeedback Therapy for functional defecation disorder

Variable Chiarioni et al184 Rao et al183 Chiarioni et al168 Heymen et al186 Rao et al185

Trial design EMG Biofeedback Biofeedback EMG biofeedback EMG biofeedback Biofeedback
vs PEG 14.6 g (manometry for slow transit vs diazepam 5 (manometry
pressure) vs vs dyssynergia mg vs placebo pressure) vs
standard standard therapy
treatment vs
sham
biofeedback
Subjects and 109 (104 women) 77 (69 women) 52 (49 women) 84 (71 women) 52 ¼ short-term
randomization 54 biofeedback 1:1:1 distribution 34 dyssynergia 30 biofeedback therapy
and 55 polyethylene Standard: diet, 12 slow transit 30 diazepam 26 ¼ long-term
intervention(s) glycol exercise, 6 mixed 24 placebo study
laxatives 12 ¼ biofeedback
Sham: progressive 13 ¼ standard
muscle therapy
relaxation with Standard: diet,
anorectal probe exercise,
laxatives
(titrated)
Duration and no. of 6 mo, 1 y, 3 mo, every other 1-6-12-24 mo 6 every other week, 1y
biofeedback 5 weekly, 30-min week, 1 h, 5 weekly 30-min 1-h sessions 6 active therapy
sessions training sessions maximum of 6 training sessions and
performed by sessions over 3 sessions, 3 reinforcement
physician mo, performed performed by sessions at 3-mo
investigator by biofeedback physician intervals
nurse therapist investigator

ANORECTAL
Primary outcomes Global improvement Presence of Symptom Global symptom No. of CSBMs
of symptoms dyssynergia improvement relief Secondary
Worse ¼ 0 Balloon expulsion None ¼ 1 outcome;
No improvement time Mild ¼ 2 Presence of
¼1 No. of CSBMs Fair ¼ 3 dyssynergia
Mild ¼ 2 Global satisfaction Major ¼ 4 Balloon expulsion
Fair ¼ 3 time
Major improvement Global satisfaction
¼4
Dyssynergia 79.6% reported Dyssynergia 71% with 70% improved with No. of CSBMs/wk
corrected or major corrected at 3 dyssynergia and biofeedback increased
symptoms improvement at months in 79% 8% with slow compared to significantly in
improved 6 and 12 mo with biofeedback transit alone 38% with biofeedback;
81.5% reported vs 4% sham and reported fair placebo P < .001
persistent major 6% in standard improvement in and 30% with Dyssynergia pattern
improvement at group; symptoms both diazepam; normalized;
24 mo CSBM ¼ at short and P < .01 P < .0010
biofeedback long-term Balloon expulsion
group vs sham follow-up improved;
or Standard; intervals P < .001
P < .05 Colonic transit
normalized;
P < .01

CSBM, complete spontaneous bowel movement; PEG, polyethylene glycol.

feedback regarding anal canal pressure or EMG ac-
tivity (Figure 2).
4. Practice simulated defecation: Educate patient to
practice defecation and expulsion of a lubricated,
inflated balloon while the therapist assists by gently
pulling on the catheter.
Several randomized controlled trials have demon-
strated that biofeedback is safe and effective treat-
ment for dyssynergic defecation (Table 3). Biofeedback
therapy was more effective than sham feedback, pelvic
floor exercises, laxatives, and muscle relaxant drugs,
both on a short- and long-term basis without side
effects.116–117,183–185 Biofeedback therapy is to be re-
garded as first-choice treatment for FDD whenever
dedicated expertise is available. Biofeedback therapy is
not effective for constipated patients without FDD.116
Whether biofeedback is as effective for altered defeca-
tory propulsion as it is for dyssynergic defecation is not
known.
 1440 Rao et al Gastroenterology Vol. 150, No. 6

Figure 2. Effect of
biofeedback therapy on
dyssynergia in 1 patient
before and after treatment.
Panel A shows baseline
intrarectal and anal
sphincter pressures. There
is inadequate propulsion
and paradoxical anal
contraction. Panel B shows
that after learning dia-
phragmatic breathing
technique, the pushing
effort has improved but
patient still shows para-
doxical contraction. Panel
C shows coordinated
relaxation, with an increase
in intrarectal pressure and
relaxation of the anal
sphincter. Adapted from
Rao, with permission.187

Recommendations for Future Research
1. Multicenter studies of normal physiology of defecation
and fecal continence using newer diagnostic modalities in
ANORECTAL
2. Bharucha AE, Fletcher JG, Melton LJ 3rd, et al. Obstetric
trauma, pelvic floor injury and fecal incontinence: a
population-based case-control study. Am J Gastro-
enterol 2012;107:902–911.

large groups of subjects stratified for age, sex, and parity.
2. Define the role of rectal contraction and sensation in
disordered defecation, especially to understand dyssy-
nergic defecation vs inadequate propulsion.
3. Evaluate interaction(s) between stool consistency,
sphincter weakness, sphincter defects, rectal sensation
and compliance, and neurogenic sphincter injury in FI.
4. Randomized, blinded controlled study of biofeedback
treatment for dyssynergic defecation, especially to
examine its generalizability for FDD.
5. Examine the natural history, duration, and phenotype of
anorectal pain syndromes and perform randomized
studies of drugs, biofeedback, and other treatments for
levator ani syndrome.
6. Randomized controlled trials of bowel management,
biofeedback, sacral nerve stimulation, anal bulking
agents and sphincteroplasty in FI, including mechanistic
understanding and well-designed outcome measures.
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. Visit the online version of
Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.009.
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Reprint requests
Address requests for reprints to: Satish SC Rao, MD, PhD, FRCP (LON),
Augusta University, Division of Gastroenterology and Hepatology, AD 2238,
Digestive Health Center 1481 Laney-Walker Blvd, Augusta, Georgia 30912.
e-mail: srao@gru.edu; fax: (706) 721-0331; office: 706-721-2238.
Conflicts of interest
The authors disclose the following: AEB is an inventor of the portable anorectal
manometry catheter that has been licensed to Medspira Inc; AEB and Mayo
Clinic have contractual rights to receive royalties from the licensing of this
technology. GC is an advisory board member and speaker for Shire Italia
and Takeda Italia. The remaining authors disclose no conflicts.
Funding
SSCR is supported in part by grant National Institutes of Health, 5
R21DK104127-02. AEB was supported in part by grant R01 DK78924 from
the National Institutes of Health, US Department of Health and Human
Services.
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Childhood Functional Gastrointestinal Disorders:
Neonate/Toddler
Marc A. Benninga,1,* Samuel Nurko,2,* Christophe Faure,3 Paul E. Hyman,4
Ian St. James Roberts,5 and Neil L. Schechter6
1
Pediatric Gastroenterology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands;
2
Center for Motility and Functional Gastrointestinal Disorders, Boston Children’s Hospital, Boston, Massachusetts;
3
Pediatric Gastroenterology, Sainte-Justine Hospital, Montreal, Quebec, Canada; 4Pediatric Gastroenterology, Children’s
Hospital, New Orleans, Louisiana; 5Thomas Coram Research Unit, University College London Institute of Education, University
College London, London, UK; 6Pediatric Pain Center, Boston Children’s Hospital, Boston, Massachusetts
In 2006, a consensus concerning functional gastrointes-
tinal intestinal disorders in infants and toddlers was
described. At that time, little evidence regarding epidemi-
ology, pathophysiology, diagnostic workup, treatment
strategies, and follow-up was available. Consequently, the
criteria for the clinical entities were more experience
based than evidence based. In the past decade, new in-
sights have been gained about the different functional
gastrointestinal intestinal disorders in these age groups.
Based on those, further revisions have been made to the
criteria. The description of infant colic has been expanded
to include criteria for the general pediatrician and specific
criteria for researchers. The greatest change was the
addition of a paragraph regarding the neurobiology of pain
in infants and toddlers, including the understanding of the
neurodevelopment of nociception and of the wide array of
factors that can impact the pain experience.
Keywords: Neonate; Toddler; Regurgitation; Colic; Constipation.
I nfant and toddler functional gastrointestinal disorders
(FGIDs) include a variable combination of often age-
dependent, chronic, or recurrent symptoms not explained
by structural or biochemical abnormalities. Functional
symptoms during childhood sometimes accompany normal
development (eg, infant regurgitation), or they can arise
from maladaptive behavioral responses to internal or
external stimuli (eg, retention of feces in the rectum often
results from an experience with painful defecation). The
clinical expression of an FGID varies with age, and depends
on an individual’s stage of development, particularly with
regard to physiologic, autonomic, affective, and intellectual
development. As the child gains the verbal skills necessary
to report pain, it is then possible to diagnose pain-
predominant FGIDs.
Through the first years, children cannot accurately
report symptoms such as nausea or pain. The infant and
preschool child cannot discriminate between emotional
and physical distress. Therefore, clinicians depend on the
reports and interpretations of the parents, who know
their child best, and the observations of the clinician,
who is trained to differentiate between health and
illness.
Gastroenterology 2016;150:1443–1455
The decision to seek medical care for symptoms arises
from a caretaker’s concern for the child. The threshold for
concern varies with previous experiences and expectations,
coping style, and perception of illness. For this reason, the
office visit is not only about the child’s symptom, but also
about the family’s fears. The clinician must not only make a
diagnosis, but also recognize the impact of the symptom on
the family’s emotions and ability to function. Therefore, any
intervention plan must attend to both the child and the
family. Effective management depends on securing a ther-
apeutic alliance with the parents.
Childhood FGIDs are not dangerous when the symptoms
and caregiver’s concerns are addressed and contained.
NEONATE/TODDLER
Conversely, failed diagnosis and inappropriate treatments of
functional symptoms may be the cause of needless physical
and emotional suffering. Disability from a functional symp-
tom is related to maladaptive coping with the symptom.
In severe cases, well-meaning clinicians inadvertently
co-create unnecessarily complex and costly solutions, as
well as ongoing emotional stress that promotes disability.1
This article provides a description, assessment, and
analysis of each FGID that affects the neonate/toddler age
group (Table 1). Figure 1 shows the age of presentation of
FGIDs in the pediatric age group, and Table 2 shows a
summary of the prevalence of FGIDs in this age group, as well
as their pathophysiology and treatment. We will then review
the developmental neurobiology of the pain response, as well
as the assessment of pain in infants and toddlers.
I. Functional Gastrointestinal Disorders
G1. Infant Regurgitation
Reflux refers to retrograde involuntary movement of
gastric contents in and out of the stomach, and is often
*Authors share co-first authorship.
Abbreviations used in this paper: CVS, cyclic vomiting syndrome; FC,
functional constipation; FGID, functional gastrointestintal disorder; GERD,
gastroesophageal reflux disease; NASPGHAN, North American Society of
Pediatric Gastroenterology Hepatology and Nutrition.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.016
 1444 Benninga and Nurko et al
Table 1.G. Functional Gastrointestinal Disorders in Neonates
and Toddlers
G1. Infant regurgitation
G2. Infant rumination syndrome
G3. Cyclic vomiting syndrome
G4. Infant colic
G5. Functional diarrhea
G6. Infant dyschezia
G7. Functional constipation
referred as gastroesophageal reflux.2 When the reflux is
high enough to be visualized it is called regurgitation.
Regurgitation of stomach contents into the esophagus,
mouth, and/or nose is common in infants and is within
the expected range of behaviors in healthy infants. In-
fant regurgitation is the most common FGID in the first
year of life.3 Recognition of infant regurgitation avoids
unnecessary doctor visits and unnecessary in-
vestigations and therapy for gastroesophageal reflux
disease (GERD).2 Infant regurgitation is distinguished
from vomiting, which is defined by a central nervous
system reflex involving both autonomic and skeletal
muscles in which gastric contents are forcefully
expelled through the mouth because of coordinated
movements of the small bowel, stomach, esophagus,
and diaphragm. Regurgitation is also different from
rumination, in which previously swallowed food is
NEONATE/TODDLER
returned to the pharynx and mouth, chewed, and
swallowed again. When the regurgitation of gastric
contents causes complications or contributes to tissue
damage or inflammation (eg, esophagitis, obstructive
apnea, reactive airway disease, pulmonary aspiration,
feeding and swallowing difficulties, or failure to thrive),
it is called GERD.2
Gastroenterology Vol. 150, No. 6
G1. Diagnostic Criteria for Infant Regurgitation
Must include both of the following in otherwise healthy
infants 3 weeks to 12 months of age:
1. Regurgitation 2 or more times per day for 3 or
more weeks
2. No retching, hematemesis, aspiration, apnea,
failure to thrive, feeding or swallowing difficulties,
or abnormal posturing
Rationale for change in diagnostic criteria. There
are minor changes from Rome III. Recently, a position paper
by the North American Society of Pediatric Gastroenterology
Hepatology and Nutrition (NASPGHAN) and the European
Society of Pediatric Gastroenterology Hepatology and
Nutrition added “bothersome symptoms” as one criterion to
differentiate infant regurgitation from GERD.3 The challenge
with that definition is that quantitative methods to define
“troublesome” are missing. Infants cannot communicate if
they are bothered. Variations in clinician and parent in-
terpretations of troublesome have resulted in unnecessary
evaluation and treatment of many infants with regurgita-
tion, not GERD. There is a lack of correlation between
crying, irritability, and GER.4 GER is not a common cause of
unexplained crying, irritability, or distressed behavior in
otherwise healthy infants.2 Therefore, we have elected to
leave “troublesome” symptoms out of the criteria.
Clinical evaluation. Daily regurgitation is more com-
mon in young infants than in older infants and children, and
is found in higher rates in neonates.5 A recent study of 1447
mothers throughout the United States showed a prevalence
of infant regurgitation of 26% using Rome III criteria.3
Regurgitation occurs more than once a day in 41%
67%
of healthy 4-month-old infants.2,6
Figure 1. Age of presen-
tation of FGIDs in pediatric
patients. The bars show
each diagnosis. Symp-
toms might begin earlier,
as there is a time require-
ment to fulfill diagnostic
criteria. IBS, irritable bowel
syndrome; FD, functional
dyspepsia.
 May 2016
Table 2.Prevalence, Pathophysiology, and Treatment of Functional Gastrointestinal Disorders in Neonates and Toddlers

Disorder Age Prevalence, % Pathophysiology Treatment Outcome

Infant regurgitation 3 wk to 12 mo 41
67 (peak at 4 mo Small esophageal volume, Education, smaller feedings feeding Resolves in 90% by 12 mo of age
of age) overfeeding, infant positioning thickening, positioning
Infant rumination syndrome 3
8 mo 1.9 Emotional and sensory Behavioral interventions, improved Recovery with nurturing
deprivation nurturing
Cyclic vomiting syndrome Wide range 3.4 Activation of the emetic reflex and Prevention of triggers, prophylactic Usually resolves as child gets
the HPA axis medications, abortive medications, older but may continue or
supportive measures change to abdominal migraine
or migraine headache
Infant colic Early infancy to 5
19 Results from normal Reassurance Resolves by 5 mo of age
5 mo developmental process No evidence that pharmacologic
Normal variations in development interventions are useful
and temperament account for There is inadequate evidence whether
differences in crying elimination of cow’s milk protein,
Influence of parental perceptions probiotics, or herbal interventions
provide viable and effective
treatments
These approaches remain problematic
and controversial
Functional diarrhea 6
60 mo 6
7 Dietary and motility abnormalities; Education, dietary changes Usually resolves by 60 mo of age
increased mucosal secretion?
Infant dyschezia Birth to 9 mo 2.4 Uncoordinated defecation Education and reassurance, avoidance Resolves in most cases by 9 mo
dynamics of anal stimulations and laxatives of age

Childhood FGIDs: Neonate/Toddler 1445

Functional constipation Birth to 3
27 Results from painful defecation Education, behavioral interventions, Successful long-term treatment in
adulthood associated with withholding laxatives 80% after first year, and
increases over time

HPA, hypothalamic
pituitary
adrenal.

NEONATE/TODDLER
 1446 Benninga and Nurko et al
Although regurgitation can occur at any age, the peak is
around 4 months of age, with tapering beginning at 6
months and then declining in frequency until 12
15
months.5
History and physical examination may provide evidence
of disease outside the GI tract, including metabolic, infectious,
and neurologic conditions associated with vomiting. Prema-
turity, developmental delay, and congenital abnormalities of
the oropharynx, chest, lungs, central nervous system, heart,
or GI tract are considered risk factors for GERD.2 Evidence of
failure to thrive, hematemesis, occult blood in the stool,
anemia, food refusal, and swallowing difficulties, should
prompt an evaluation for GERD.2 Assessment to exclude an
upper GI anatomical abnormality, such as malrotation or a
gastric outlet obstruction, should be done if regurgitation
persists past the first year of life, if it started early in the
neonatal period, or it is associated with bilious vomiting,
dehydration, or other complications.
Treatment. The natural history of infant regurgitation
is one of spontaneous improvement.6 Therefore, treatment
goals are to provide effective reassurance and symptom
relief while avoiding complications. Improving the
caregiver
child interaction is often aided by relieving the
caregiver’s fears about the condition of the infant, identi-
fying sources of physical and emotional distress, and making
plans to eliminate them. Management does not require
medical interventions. There are multiple randomized trials
showing a lack of benefit to the use of proton pump in-
hibitors in infants with regurgitation or those suspected of
NEONATE/TODDLER
having GERD, mostly based on regurgitation and bother-
some symptoms.4,7 In addition, proton pump inhibitor
treatment can be associated with adverse effects, mainly
respiratory and GI infections.7 Conservative measures
include positioning after meals and thickened feedings.
Thickened feedings and antiregurgitation formulas can
decrease regurgitation in healthy infants.8,9 While frequent
smaller-volume feedings are sometimes recommended,2
there is little direct evidence to support the efficacy of this
approach. Postprandial left-sided and prone position
reduces regurgitation.10 Sleeping in prone and lateral
position can increase the risk of sudden infant death
syndrome. Therefore, the American Academy of Pediatrics
recommends sleeping in the supine position.11
G2. Rumination Syndrome
Rumination is the habitual regurgitation of stomach
contents into the mouth for the purpose of self-stimulation.12
Rumination has the following clinical presentations: infant
rumination syndrome, rumination in neurologically
impaired children and adults, and rumination in healthy
older children and adults.12 The latter 2 presentations are
not discussed in this supplement.
G2. Diagnostic Criteria for Rumination Syndrome
Must include all of the following for at least 2 months:
1. Repetitive contractions of the abdominal muscles,
diaphragm, and tongue
Gastroenterology Vol. 150, No. 6
2. Effortless regurgitation of gastric contents, which
are either expelled from the mouth or rechewed
and reswallowed
3. Three or more of the following:
a. Onset between 3 and 8 months
b. Does not respond to management for gastro-
esophageal reflux disease and regurgitation
c. Unaccompanied by signs of distress
d. Does not occur during sleep and when the
infant is interacting with individuals in the
environment
Rationale for change in diagnostic criteria. There
have been no major changes from the Rome III criteria.
However, given the difficulty for infants to communicate the
presence of nausea, that word has been eliminated. The
duration was also shortened to 2 months to be consistent
with the rumination criteria for the older age groups.
Clinical evaluation. Infant rumination syndrome is
rare, and has received little attention in the literature. A
recent questionnaire based study of 1447 mothers showed a
prevalence of 1.9%.3 Rumination historically has been
considered a self-stimulatory behavior that arises in the
context of longstanding social deprivation. In the limited
published literature, maternal behavior may appear to be
neglectful or slavishly attentive, but there is no enjoyment in
holding the baby or sensitivity to the infant’s needs for
comfort and satisfaction.12
Observing the ruminative act is essential for diagnosis.
However, such observations require time, patience, and
stealth because rumination can cease as soon as the infant
notices the observer. No tests are necessary for the diag-
nosis of infant rumination syndrome.
Treatment. Historically, infant rumination syndrome
responded to empathetic and responsive nurturing.
Excessive and continuous loss of previously swallowed
food may cause progressive malnutrition. Behavioral ther-
apy is useful in eliminating rumination in highly motivated
adults or children with neurologic impairment. There is no
information on whether those techniques are useful in in-
fant rumination syndrome. The most humane, develop-
mentally appropriate, and comprehensive management
aims at reversing the baby’s weight loss by eliminating its
need for ruminative behavior. Treatment aims at helping the
caregivers address their feelings toward the infant and to
improve their ability to recognize and respond to the in-
fant’s physical and emotional needs.13
G3. Cyclic Vomiting Syndrome
Although data on clinical course in infants and toddlers
are sparse, epidemiologic studies clearly report that cyclic
vomiting syndrome (CVS) can occur before 3 years of
age.14,15 A study from the United States found a prevalence
of CVS of 0.2%
1.0% in children and of 3.4% in toddlers
May 2016
using the Rome III diagnostic criteria.3 CVS occurs from
infancy to midlife, and is most common between 2 and 7
years.16 In a study in Ireland reporting 41 cases, the median
age at onset of symptoms was 4 years, with 46% of affected
children having an onset of symptoms at the age of 3 years
or younger.14 The poor recognition of the disorder leads to a
timespan between the onset of symptoms and the diagnosis
ranging between 1.1 to 3.4 years.14
G3. Diagnostic Criteria for Cyclic Vomiting Syndrome
Must include all of the following:
1. Two or more periods of unremitting paroxysmal
vomiting with or without retching, lasting hours to
days within a 6-month period
2. Episodes are stereotypical in each patient
3. Episodes are separated by weeks to months with
return to baseline health between episodes of
vomiting
Rationale for change in diagnostic criteria. The
Rome IV committee reviewed the Rome III guidelines,
NASPGHAN Cyclic Vomiting Syndrome Consensus State-
ment17 and International Headache Society18 criteria for
CVS and the validation and epidemiologic data derived from
their utilization. We found no studies designed for the
validation of the CVS guidelines after the publication of the
NASPGHAN and International Headache Society guidelines.
Those guidelines require a minimum of 5 attacks of intense
nausea and vomiting in any interval for a child to be
considered to have a diagnosis of CVS. The NASPGHAN
consensus statement considered the Rome III minimum of 2
recurrent episodes for a child to be diagnosed with CVS as
lacking specificity. However, 5 recent studies using Rome III
criteria conducted in infants, toddlers, children, and ado-
lescents failed to report a significantly higher prevalence of
CVS than reported previously, as would be expected if the
lack of specificity was important.19–22 The consistency of the
epidemiologic data using the Rome III criteria and the
narrow range of prevalence of CVS found in 4 studies
(range, 0.2%
3.4%) using the Rome III criteria stands in
contrast with the lack of epidemiologic data using the
NASPGHAN criteria or the International Headache Society
criteria. The committee agreed that, based on the important
impact for the child’s quality of life and family disruption
derived from each CVS attack, early diagnosis is important.
Therefore, the committee maintained 2 as the minimum
number of episodes required. Given the difficulty for infants
to communicate the presence of nausea, that word has been
eliminated from the criteria.
Clinical evaluation. CVS is characterized by stereo-
typical and repeated episodes of vomiting lasting from
hours to days with intervening periods of return to baseline
health.17 The frequency of episodes in a series of 71 patients
ranged from 1 to 70 per year and averaged 12 per year.16
Attacks may be sporadic or occur at fairly regular
intervals. Typically, episodes begin at the same time of day,
Childhood FGIDs: Neonate/Toddler 1447
most commonly during late night or in the early morning.
The duration of episodes tends to be the same in each
patient over time.16 Once vomiting begins, it reaches its
highest intensity during the first hours. The frequency of
vomiting tends to diminish thereafter, although nausea
continues until the episode ends. Episodes usually end as
rapidly as they begin and are marked by prompt recovery of
well being, provided the patient has not incurred major
deficits of fluids and electrolytes.
Signs and symptoms that might accompany cyclic vom-
iting include pallor, weakness, increased salivation,
abdominal pain, intolerance to noise, light and/or odors,
headache, loose stools, fever, tachycardia, hypertension, skin
blotching, and leukocytosis.17
Patients with CVS frequently have a maternal history of
migraine headaches and commonly progress to migraine
headaches themselves. The matrilineal history of migraines
suggests a mitochondrial dysfunction. Individuals related
through the maternal line carry an identical mitochondrial
DNA sequence. In addition to genetic factors, psychosocial
factors have also been associated with CVS in children.
Episodes of CVS may be triggered by excitement, stress, or
anticipatory anxiety. A high prevalence of internalizing
psychiatric disorders (especially anxiety disorders) was
found in children with CVS and their caregivers.23
There are no tests to diagnose CVS. The working team
agreed with the clinical evaluation proposed in the NASP-
GHAN guidelines of CVS for children 2
18 years of age.17
There is a higher likelihood of neurologic and metabolic
NEONATE/TODDLER
diseases explaining the vomiting episodes in children with
early onset of symptoms. Evaluation depends on the phy-
sician’s confidence in making a symptom-based diagnosis
and the likelihood of identifying an underlying condition.
The differential diagnosis of CVS includes GI, neurologic,
urologic, metabolic, and endocrine conditions having similar
presentations during at least part of their courses.24 The
NASPGHAN guideline recommends a basic metabolic profile
(electrolytes, glucose, blood urea nitrogen, creatinine) in all
patients before the administration of intravenous fluids,
and upper GI series to exclude malrotation and anatomic
obstructions. Because serious underlying metabolic and
anatomic disorders must be considered in toddlers, the
occurrence of CVS under the age of 2 years should prompt
metabolic or neurologic and anatomical testing.
Treatment. Treatment goals are to reduce the fre-
quency and severity of episodes, and establish a protocol for
rescue therapy in home and hospital settings. Prevention is
the goal in patients whose episodes are frequent, severe,
and prolonged. Conditions that trigger episodes may be
identified, and avoided and treated.17 Prophylactic daily
treatment with cyproheptadine or pizotifen in children
younger than 5 years are the first-line drugs, but amitrip-
tyline or propranolol have also been used. Erythromycin,
which improves gastric emptying, as well as phenobarbital,
have also been reported to be effective in the prevention of
the attacks.25 These medications succeed in reducing the
frequency of, or eliminating, episodes in many children.17
Early in the episode it might be helpful to begin an oral
acid-inhibiting drug agent to protect esophageal mucosa and
 1448 Benninga and Nurko et al
dental enamel, and lorazepam for its anxiolytic, sedative,
and antiemetic effects. Intravenous fluids, electrolytes, and
H2
histamine receptor antagonists or proton pump in-
hibitors are administered until the episode is over. Com-
plications arising during cyclic vomiting episodes include
water and electrolyte deficits, hematemesis mostly due to
prolapse gastropathy, peptic esophagitis and/or Mallory-
Weiss tears, deficits in intracellular potassium and magne-
sium, hypertension, and inappropriate secretion of antidi-
uretic hormone.
G4. Infant Colic
Understanding infant colic requires an appreciation of the
development of the infant, the dyadic relationship with the
caregiver, and the family and social milieu in which they
exist.26 Infant colic has been described as a behavioral syn-
drome in 1- to 4-month-old infants involving long periods of
crying and hard-to-soothe behavior. The crying bouts occur
without obvious cause so that their unexplained nature is one
of the main reasons for caregivers’ concerns.27 Prolonged
crying is more likely to occur in the afternoon or evening and
tends to resolve by 3 to 4 months of age or, in the case of
babies born prematurely, 3 to 4 months after term.28 On
average, crying peaks at about 4
6 weeks and then steadily
diminishes by 12 weeks.29 Most cases of colic probably
represent the upper end of the normal developmental “crying
curve” of healthy infants and there is no proof that the crying
in such cases is caused by pain in the abdomen or any other
NEONATE/TODDLER
part of the infant’s body. Nevertheless, caregivers often
assume that the cause of crying is abdominal pain of GI
origin. Despite the lack of proof that infant colic is caused by a
functional GI disturbance, infants with colic are often referred
to pediatric gastroenterologists. Familiarity with infant colic
is therefore necessary to help families and to avoid diagnostic
and therapeutic misadventures.
G4. Diagnostic Criteria for Infant Colic
For clinical purposes, must include all of the following:
1. An infant who is <5 months of age when the
symptoms start and stop
2. Recurrent and prolonged periods of infant crying,
fussing, or irritability reported by caregivers that
occur without obvious cause and cannot be pre-
vented or resolved by caregivers
3. No evidence of infant failure to thrive, fever, or
illness
“Fussing” refers to intermittent distressed vocalization
and has been defined as “[behavior] that is not quite
crying but not awake and content either.” Infants often
fluctuate between crying and fussing, so that the 2
symptoms are difficult to distinguish in practice.
For clinical research purposes, a diagnosis of infant colic
must meet the preceding diagnostic criteria and also
include both of the following:
Gastroenterology Vol. 150, No. 6
1. Caregiver reports infant has cried or fussed for
3 or more hours per day during 3 or more days in
7 days in a telephone or face-to-face screening
interview with a researcher or clinician
2. Total 24-hour crying plus fussing in the selected
group of infants is confirmed to be 3 hours or
more when measured by at least one prospec-
tively kept, 24-hour behavior diary
Rationale for change in diagnostic criteria. The
Rome III report included a version of the Wessel et al’s “rule
of threes” criteria, which stipulated that colic crying had to
start and stop suddenly and occur for 3 or more hours/day
for at least 3 days in a week.30 Recent research has found
that these criteria fail to meet the requirements for an
effective clinical diagnostic scheme31 because:
1. They are arbitrary. There is no evidence that infants
who cry more than 3 hours per day are different from
infants who cry 2 hours and 50 minutes per day.32
2. They are culturally dependent. Infants in some cul-
tures cry more than in others.33
3. They are impractical to use. Caregivers are often
reluctant to keep behavior diaries for 7 days.
4. The rule of threes focuses on crying amount, but the
amount of crying has been found to distress care-
givers less than its prolonged, hard-to-soothe, and
unexplained nature.34 The duration of unsoothable
crying bouts was most strongly associated with
caregiver reports of daily frustration, more so than
the amounts infants cried.34
5. Few studies have assessed whether colic crying bouts
start suddenly or sound abnormal, but the available
evidence does not support this.35,36
Ultimately, criteria and methods that allow the infant
behaviors involved in colic to be measured objectively are
highly desirable.
Clinical evaluation. About 20% of infants are
reported by caregivers to have the prolonged periods of
crying known as colic.37 However, the prevalence of infant
colic is influenced by caregivers’ perceptions of the intensity
and duration of crying bouts,37,38 the method by which data
on crying are collected, the well being of the caregivers,39
and culturally influenced infant care practices.33
In a study of all afebrile infants presented to a pediatric
hospital over a year because of crying, irritability, colic,
screaming, or fussiness, just 12 of 237 (5.1%) were found to
have a serious underlying organic etiology.40 Most of the
infants with organic disease were visibly unwell on clinical
examination and tests for urinary tract infections were
recommended in such cases. Behaviors associated with colic
(eg, prolonged crying, unsoothable crying, facial expressions
appearing to show pain, abdominal distension, increased
gas, flushing, and legs over the abdomen) are not diagnostic
May 2016
clues indicative of pain or organic disease, but they do help
to explain caregivers’ concerns.30,41
Time-limited therapeutic trials have been recommended
to confirm possible etiologies of prolonged crying: elimina-
tion of cow’s milk from the breastfeeding mother’s diet or
switching to a protein-hydrolysate formula if the infant is
formula fed.42 Elimination of cow’s milk from the mother’s
diet remains controversial because there are no data on how
often this is successfully implemented. Despite widespread
use of treatments for gastroesophageal reflux to reduce in-
fant crying, there is no evidence that GERD causes infants to
cry, or and there is evidence that treatments for reflux are
ineffective in reducing crying.43
The satiated infant’s response to nonanalgesic, non-
nutritive soothing maneuvers, such as rhythmic rocking and
patting 1 to 3 times per second in a quiet, nonalerting envi-
ronment, may quiet the baby who might nevertheless resume
crying as soon as it is put down.44 Demonstration that a
common maneuver of this kind quiets the infant supports a
diagnosis of colic as well as providing caregiver reassurance.
Treatment. In >90% of cases, treatment consists not of
“curing the colic,” but of helping the caregivers get through
this challenging period in their baby’s development.45 Clini-
cians need to evaluate caregiver vulnerabilities, such as
depression and lack of social support, and to provide
continuing availability to the family.30,46 Making an assess-
ment of the infant’s crying at the referral point can help to
reassure caregivers and provide useful diagnostic informa-
tion, particularly when this is combined with a discussion of
normal babies’ crying patterns. Prospectively kept logs of
crying and other behavior, such as the Baby’s Day Diary, are
the most accurate and validated tools.47 Questionnaire as-
sessments, such as the Crying Patterns Questionnaire, are
more subjective but easier for caregivers to complete with
clinician support and sufficiently accurate for screening
purposes.48,49 These assessments can be obtained free of
charge for clinical use from the original authors.32,50
There is recent evidence from several randomized
controlled trials that particular probiotic supplements (eg,
Lactobacillus reuteri DSM 17938) can reduce infant crying
relative to controls.51,52 However, no benefits were found in
a recent large-scale fully blinded trial47 and a systematic
review of this evidence found an equal number of trials in
which probiotic supplements had not ameliorated crying.53
If attempts to control a baby’s crying are unsuccessful,
anxiety and frustration may develop, leading to caregiver
exhaustion.54,55 This may be more likely when the caregiver
relationship is unsupportive.56 This stressful state can
impair the caregiver’s ability to soothe the infant and cause
doubts about their competence as a caregiver.56 The
emergence of adversarial or alienated feelings toward the
unsoothable infant lowers the threshold for “shaken baby
syndrome” and other forms of abuse.34 Infant colic may then
present as a clinical emergency.
G5. Functional Diarrhea
Population-based studies show that the defecation fre-
quency declines with age from a mean of 3.0 per day at 4
Childhood FGIDs: Neonate/Toddler 1449
weeks to 1.3 per day at 4 years.57,58 Defecation frequency is
higher in breastfed infants compared with formula-fed in-
fants, but there is no difference in stool frequency between
preterm and term-born infants.58–60 Breastfed infants usu-
ally have softer stools than formula-fed infants and they are
more often yellow in color.61 Approximately 97% of 1- to 4-
year-old children pass stool 3 times daily to once every
other day.60,62 Many children are ready to start toilet
training at the age of 21 to 36 months. Initiation of toilet
training before the age of 27 months does not lead to earlier
completion of toilet training, but it is also not associated
with constipation, stool withholding, or stool toileting
refusal.63
Functional diarrhea is defined by the daily painless
recurrent passage of 3 or more large unformed stools for 4
or more weeks with onset in infancy or preschool years.
There is no evidence of failure to thrive if the diet has
adequate calories. The child appears unperturbed by the
loose stools and the symptom resolves spontaneously by
school age. Functional diarrhea has been called chronic
nonspecific diarrhea, or toddler’s diarrhea previously.
G5. Diagnostic Criteria for Functional Diarrhea
Must include all of the following:
1. Daily painless, recurrent passage of 4 or more
large, unformed stools
2. Symptoms last more than 4 weeks
NEONATE/TODDLER
3. Onset between 6 and 60 months of age
4. No failure to thrive if caloric intake is adequate
Rationale for change in diagnostic criteria. In a US
survey, 11.7% of the children (mean age 1.4 years; range,
0.4
3 years) were reported by their caregivers as having 3
stools per day. Twenty-seven percent of the children had
very soft stools, 4.5% had watery stools, 1.5% had undi-
gested food in the stools, and 22.1% started after 6 months
of age.3 Based on these data, the committee decided to
increase the number of stools from 3 to 4 stools per day.
Furthermore, about 25% of mothers reported that their
young children pass stools when asleep, so this criterion is
no longer required because of its low specificity.
Clinical evaluation. Functional diarrhea is the leading
cause of chronic diarrhea in an otherwise well child.
According to the Rome III criteria, 2.4% of infants <1 year
and 6.4% of toddlers aged 1
3 years presented with
functional diarrhea.3
Small intestinal transport is not defective in children
with functional diarrhea. Water and electrolyte secretion
and glucose absorption are normal and steatorrhea is
absent.64 Nutritional factors are reported to play key roles
in the pathogenesis of toddler’s diarrhea. Overfeeding,
excessive fruit juice consumption, excessive carbohydrate
(fructose) ingestion with low fat intake, and excessive sorbitol
intake have been reported in children with functional
diarrhea.65,66 In patients with functional diarrhea, food fails
 1450 Benninga and Nurko et al
to interrupt the fasting migrating motor complex (MMC), so
there is a lack of postprandial motility in the small
intestine.67
The evaluation of children with chronic diarrhea in-
cludes identifying factors that may cause or exacerbate
diarrhea, such as past enteric infections, laxatives, antibi-
otics, or diet. In toddlers with functional diarrhea, typical
stools contain mucus and/or visible undigested food. Often
stools become less solid with each bowel movement during
the day. The physical examination focuses on height, weight,
and signs of malnutrition, diaper rash, and fecal impaction.
In children fulfilling the criteria for functional diarrhea, a
malabsorption syndrome would be unexpected. Chronic
diarrhea as the sole symptom in a thriving child makes
cystic fibrosis and celiac disease unlikely.
Treatment. No medical interventions are necessary, but
an evaluation of fruit juices and fructose intake with subse-
quent dietary advice to normalize and balance the child’s diet
is recommended. Furthermore, effective reassurance of the
caregivers is of paramount importance. A daily diet and
defecation diary helps to reassure caregivers that specific
dietary items are not responsible for the symptom. Many
families accept effective reassurance readily. The morbidity
associated with functional diarrhea may be related to the
caloric deprivation caused by the misuse of elimination
diets.68 This can be related to an anxious caregiver’s inability
to accept the functional diarrhea diagnosis, or a clinician’s
attempt to assuage the caregiver’s anxiety.
NEONATE/TODDLER
G6. Infant Dyschezia
Infants with dyschezia strain for many minutes, scream,
cry, and turn red or purple in the face with each effort to
defecate. The symptoms usually persist for 10
20 minutes.
Stool passes several times daily. In the majority of infants,
the symptoms begin in the first months of life, and resolve
spontaneously in the majority of children after 3
4 weeks.
G6. Diagnostic Criteria for Infant Dyschezia
Must include in an infant <9 months of age:
1. At least 10 minutes of straining and crying before
successful or unsuccessful passage of soft stools
2. No other health problems
Justification for changes in diagnostic criteria. The
age that infant dyschezia can still be present has been
changed from 6 to 9 months based on a recent prospective
study.69 The unsuccessful attempt to defecate was added to
the criteria based on this study, which found that caregivers
reported other defecation-related symptoms, especially
extreme reddening of the face and straining without
subsequent defecation.
Clinical evaluation. A population based study in the
Netherlands showed that at the age of 1 and 3 months,
dyschezia was present in 3.9% and 0.9% of the infants,
respectively. At the age of 9 months, the symptoms of
Gastroenterology Vol. 150, No. 6
another 0.9% were consistent with a diagnosis of dysche-
zia.69 A recent questionnaire-based study of 1447 mothers
showed a prevalence of 2.4% in the first year of life.3
Failure to coordinate increased intra-abdominal pres-
sure with relaxation of the pelvic floor results in infant
dyschezia.30 The examiner performs a history including diet;
conducts a physical examination, including rectal examina-
tion, to exclude anorectal abnormalities; and charts the
infant’s growth.
Treatment. The child’s caregivers require effective
reassurance to address their concerns that their child is in
pain and that there is no pathologic disease process that
requires intervention in their infant.
Parents usually accept the explanation that the child
needs to learn to relax the pelvic floor at the same time as
bearing down. To encourage the infant’s defecation learning,
the caregivers are advised to avoid rectal stimulation, which
produces artificial sensory experiences that might be
noxious, or that might condition the child to wait for stim-
ulation before defecating. Laxatives are unnecessary.
G7. Functional Constipation
Functional constipation (FC) is often the result of
repeated attempts of voluntary withholding of feces by a
child who tries to avoid unpleasant defecation because of
fears associated with evacuation.70 Withholding behavior
leads to stool retention that leads the colon to absorb more
water, creating hard stools. In the first years of life, an
acute episode of constipation due to a change in diet may
lead to the passage of dry and hard stools, which may
cause painful defecation. In toddlers, the onset of con-
stipation may coincide with toilet training, when excessive
caregiver pressure to maintain bowel control and/or
inappropriate techniques, such as the use of regular toilets
that do not allow sufficient leg support, can lead to stool
withholding.
G7. Diagnostic Criteria for Functional Constipation
Must include 1 month of at least 2 of the following in
infants up to 4 years of age:
1. 2 or fewer defecations per week
2. History of excessive stool retention
3. History of painful or hard bowel movements
4. History of large-diameter stools
5. Presence of a large fecal mass in the rectum
In toilet-trained children, the following additional
criteria may be used:
6. At least 1 episode/week of incontinence after the
acquisition of toileting skills
7. History of large-diameter stools that may obstruct
the toilet
May 2016
Rationale for change in diagnostic criteria. The
change in criteria to differentiate between toilet-trained or
not toilet-trained children is based on data suggesting
that the majority of toddlers younger than 2.5 years are
not toilet trained.63,71 In addition, recognition of fecal
incontinence in infants and toddlers wearing diapers is
unreliable.
Clinical evaluation. The prevalence of constipation in
the first year of life is 2.9% and increases to 10.1% in the
second year of life, with no difference between boys and
girls.72,73 A cohort study from Brazil reported a constipation
prevalence of 27% at the age of 24 months.74
The presentation of functional constipation (FC) in in-
fants and toddlers varies. Only a minority of infants with FC
defecates <3 times/week and exhibit bloody stools.75 These
infants have hard stools >90% of the time and almost half
of them may exhibit pain during defecation, stool with-
holding behavior, and rectal impaction. Eighty-six percent of
the toddlers with FC have either 2 bowel movements weekly
or hard, painful bowel movements and at least one of the
other Rome III criteria for functional constipation.76 Fecal
incontinence more than once per week is the most common
symptom found in these children.
FC is a clinical diagnosis that can be made on the basis of
a typical history and physical examination. Withholding
behavior may lead to the passage of large stools, which can
cause anal fissures, especially in the first 2 years. The
painful evacuation of a fecal mass often leads a terrified
child to try to avoid further bowel movements. Blood in the
stools alarms caregivers, but does not cause clinically
important blood loss. Fecal incontinence (involuntary pas-
sage of fecal material) can occur in toddlers who accumulate
a large rectal fecal mass. Loose stool that accumulates
around the fecal mass may be involuntary extruded as the
infant passes gas. Physical examination provides reassur-
ance to the clinician and caregivers that there is no disease.
The physical examination includes assessing the size of the
rectal fecal mass, which is judged for height above the pelvic
brim with bimanual palpation on either side of the rectus
sheath. When the history is typical for FC, the perineum
should be inspected, but a digital rectal examination may
not be necessary until a treatment trial fails, there is un-
certainty in the diagnosis, or there is suspicion of an
anatomic problem.
The differential diagnosis of constipation in infancy in-
cludes anatomic obstructions, Hirschsprung’s disease, spinal
problems, and other metabolic and neuroenteric abnor-
malities. More than 90% of healthy term infants and <10%
of infants with Hirschsprung’s disease pass their first
meconium before 24 hours of life.58,77 Therefore, a rectal
suction biopsy is necessary in an infant with delayed pas-
sage of meconium by 24 hours who has accompanying
symptoms (vomiting, food refusal, abdominal distension,
fever, failure to thrive, blood in stool) to rule out Hirsch-
sprung’s disease.78 Another rare defecation disorder is in-
ternal anal sphincter achalasia, but in contrast to
Hirschsprung’s disease, ganglion cells are present in rectal
suction biopsies but the rectoanal inhibitory reflex is
absent.79
Childhood FGIDs: Neonate/Toddler 1451
Treatment. In infants, symptoms improve with early
intervention. The shorter time that the symptoms persist,
the higher likelihood of treatment success.80 Education for
caregivers and the child is the first step in treatment.70 The
child and family appreciate a clinician who thoroughly as-
sesses the history and physical examination, then explains
the evolution of the problem, the absence of worrisome
disease, and safe and effective management. The clinician
addresses the myths and fears by sharing information: The
child has FC, one of the most common problems in pediat-
rics; FC is not dangerous and it resolves when the child
gains confidence and trusts that defecation will not cause
pain; for toddlers, toilet training will not proceed smoothly
until the child’s fear of painful defecation resolves; care-
givers who are anxious must understand that coercive toilet
training tactics are likely to backfire into a struggle for
control.
Recently, evidence-based recommendations for the
treatment of FC have been made by the European Society of
Pediatric Gastroenterology Hepatology and Nutrition/
NASPGHAN.70 Treatments that soften stools and assure
painless defecation are an important part of the treatment.
To date, however, large well-designed randomized clinical
trials evaluating the effect of any dietary supplement or
laxative in infants and toddlers with FC are still lacking. The
key to effective maintenance is assuring painless defecation
until the child is comfortable and acquisition of toilet
learning is complete. For the maintenance phase of treat-
ment, stool softeners are continued for months to years.
NEONATE/TODDLER
There is limited published information on the treatment
of infant constipation with probiotics.81,82
Inconsistent data exist about the role of cow’s milk
protein allergy in FC. Iacono et al83 were the first to show
that 78% of children affected by constipation and cow’s milk
protein allergy improved after cow’s milk protein elimina-
tion diet. In contrast, others were not able to confirm this
association in patients affected by chronic constipation.84
However, a history of cow’s milk allergy in the first year
of life was associated with FC in childhood (odds ratio ¼
1.57; 95% confidence interval: 1.04
2.36).85 The recent
published guideline on FC suggests consideration of a 2- to
4-week trial of hypoallergenic formula in those infants and
toddlers in whom laxative treatment failed.70
Most experts favor a daily nonstimulant laxative, such as
polyethylene glycol, lactulose, or milk of magnesia, which
slowly softens the mass until the child chooses to pass it
days or weeks later.70 The goal of stool softening is to
assure painless defecation until FC resolves. For preschool
children, behavior modification utilizing rewards for suc-
cesses in toilet learning is often helpful. A child can earn
“stars” for a chart with each successful defecatory effort.
II. Neurobiology of Pain in Infants
and Toddlers
Because pain is a complex symptom often associated
with FGIDs, an understanding of the neurodevelopment
of nociception and of the wide array of factors that may
impact the pain experience, and an appreciation for pain
 1452 Benninga and Nurko et al
assessment in infants and toddlers is important for the
clinician addressing functional pain in children. The model
that most individuals use to understand pain is that of acute
pain in which the pain functions as a signal of anatomic or
biochemical pathology. The underlying assumption is that if
the pathology is addressed, the pain will dissipate. This
model is simplistic because it does not account for the
various elements that contribute to the interpretation and
response to nociceptive information. The acute pain model
is inappropriate in addressing functional pain, in which the
pain does not serve a warning function, but is itself the
illness (Figure 2).
Development of Nociceptive and Pain Pathways
Data from neonatal animals and human infants suggest
that preterm infants have nociceptive systems in place at
birth.86 Cutaneous innervation is already present at 8 weeks
of gestational age, afferent synapses to the spinal cord by 10
weeks, and lamination in the spinal cord by 15 weeks. By 20
weeks, there is reflex motor withdrawal to a noxious stim-
ulus. Thalamo-cortical projections are present by 24 weeks
and somatosensory evoked potentials after cutaneous
stimulation are present by 29 weeks gestational age. Noci-
ceptive circuitry is functional by 30 weeks gestation. Recent
work measuring cortical hemodynamic activity in the
somatosensory cortex suggests that by 24 weeks, the impact
of a noxious stimulus is identifiable in the brain.87 Infants
have a lower pain threshold that increases with age and, as a
NEONATE/TODDLER
result, they may respond to routine handling, such as diaper
changes, similarly to invasive procedures. Additionally, they
lack descending inhibitory control, a key element in modu-
lating the pain experience, and therefore lack the ability to
put the pain experience in perspective. It appears, therefore,
that not only are preterm and term infants capable of
Gastroenterology Vol. 150, No. 6
cortical level pain processing, but they may experience
painful stimuli differently and more intensely then others.88
The fact that infants experience pain is evident in their
immediate response to noxious stimuli. Preterm and term
infants display measurable physiologic responses, such as
increased heart rate, respiratory rate, blood pressure, and
decreased oxygen saturation. They produce cortisol and
stress hormones in response to pain. They also display
distinct behavioral responses to noxious stimuli, such as
specific facial expressions and patterns of movement.89
Another important consideration is the long-term impact
of pain in the newborn and its relationship to the subse-
quent development of altered pain perception, particularly
as it relates to functional abdominal pain. Infants and tod-
dlers exposed to painful events, such as early surgery, may
be predisposed to visceral hyperalgesia.90,91 There are a
number of studies that have examined the impact of early
painful procedures/neonatal intensive care unit admission
on the subsequent development of chronic abdominal pain.
It appears that pyloric stenosis or allergic colitis may pre-
dispose infants to development of chronic abdominal pain.92
In addition to physical trauma, Barreau et al,93
attempting to identify the impact of emotional trauma,
demonstrated that neonatal maternal deprivation in rodents
triggered changes in the colonic epithelial barrier and
mucosal immunity.
Pain Assessment in Infants and Toddlers
In adults and older children who are intellectually
intact, self-report of pain is the gold standard. Typically, a
numeric rating scale in which pain can be quantified is
used.94 This addresses pain intensity only, and not the
quality of the pain, but is often the cornerstone of clinical
pain care. For children aged between 3 and 8 years,
Figure 2. Proposed path-
ophysiology of functional
pain. From von Baeyer and
Champion,95 adapted with
permission.
May 2016
modifications of the numeric rating scale are often used.
These are typically cartoon faces of individuals in pain.
They require the child to have the intellectual sophisticat-
ion to appreciate differences in size and apply them to
internal sensations.
Infants and most toddlers do not have that capability,
however. Although caregivers may play a vital role in
conveying their perception of the child’s level of discomfort,
it is helpful as well to have techniques that may allow us
proxies for direct verbal reporting from the child. A number
of techniques have been developed to serve in that capacity.
These include evaluation of various behaviors associated
with pain (facial action, body movement, cry, consolability)
and physiological indicators (heart rate, blood pressure,
oxygen saturation, galvanic skin response measurements).
Individually, these markers lack specificity, but a number of
composite measures that link together various elements
have become the standard of care in managing acute pain in
infants and young children.
More recently, investigators have used near infrared
spectroscopy and somatosensory evoked potentials in an
attempt to intuit a “pain signature.” Slater et al87 compared
the results of a behavioral pain assessment (Preterm Infant
Pain Profile) with near-infrared spectroscopy in a group of
preterm babies undergoing heel stick. They reported that
almost one-third of the babies demonstrated evidence of a
cortical hemodynamic response without evidence of a
behavioral response. As a result, they suggested that the
typically used instruments to clinically assess newborn pain
may be inaccurate.
Even more complicated than the assessment of acute pain
in newborns is the measurement of chronic pain in which
many of the expected behaviors may not be present. Currently,
however, there is no instrument available for infants and
toddlers to assess chronic pain. The challenges around chronic
pain assessment in young children further complicate our
attempt to identify and categorize pain-predominant func-
tional disorders in this vulnerable population.
Recommendations for Future Research
1. Epidemiological cross-cultural studies are needed to
ascertain the impact on quality of life, and medical
consultation across cultures.
2. Pathophysiology in the majority of FGIDs in young chil-
dren is still poorly understood and multicenter pro-
spective genetic, metabolic, and neurophysiologic
characterizations of large numbers of patients are
needed.
3. Among key questions for research is what the primary
outcome measures should be for trials that seek to
resolve it.
4. Validated measures, especially for infant crying and pain
assessment, are needed. These will help to clarify the
relationship between colic and pain and to distinguish
the specific infant behaviors underlying caregiver’s per-
ceptions of infant colic.
Childhood FGIDs: Neonate/Toddler 1453
5. Prospective studies are needed to show the efficacy of
different diets in infants and toddlers with FGIDs.
6. Studies to show that anticipatory guidance and efforts to
intervene at the pediatrician office will have an impact
are required.
7. Recent limited information has suggested that there is a
possibility that other, not as well-defined, functional GI
problems in neonates and toddlers may need to be
considered, particularly those related to feeding
disorders.
Supplementary Material
Note: The first 50 references associated with this article
are available below in print. The remaining references
accompanying this article are available online only with the
electronic version of the article. Visit the online version of
Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.016.
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NEONATE/TODDLER
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 Gastroenterology 2016;150:1456–1468

Childhood Functional Gastrointestinal Disorders: Child/

Adolescent
Jeffrey S. Hyams,1,* Carlo Di Lorenzo,2,* Miguel Saps,2 Robert J. Shulman,3
Annamaria Staiano,4 and Miranda van Tilburg5
1
Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children’s Medical Center, Hartford,
Connecticut; 2Division of Digestive Diseases, Hepatology, and Nutrition, Nationwide Children’s Hospital, Columbus,
Ohio; 3Baylor College of Medicine, Children’s Nutrition Research Center, Texas Children’s Hospital, Houston, Texas;
4
Department of Translational Science, Section of Pediatrics, University of Naples, Federico II, Naples, Italy; and
5
Department of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina

Characterization of childhood and adolescent functional
gastrointestinal disorders (FGIDs) has evolved during the 2-
decade long Rome process now culminating in Rome IV. The
era of diagnosing an FGID only when organic disease has
been excluded is waning, as we now have evidence to sup-
port symptom-based diagnosis. In child/adolescent Rome
IV, we extend this concept by removing the dictum that
there was “no evidence for organic disease” in all defini-
tions and replacing it with “after appropriate medical
evaluation the symptoms cannot be attributed to another
medical condition.” This change allows the clinician to
perform selective or no testing to support a positive diag-
nosis of an FGID. We also point out that FGIDs can coexist
with other medical conditions that themselves result in
GI symptoms (eg, inflammatory bowel disease). In Rome IV,
functional nausea and functional vomiting are now
described. Rome III’s “abdominal pain related functional
CHILD/ADOLESCENT
Rome III criteria emphasized that there should be “no evi-
dence” for organic disease, which may have prompted a
focus on testing.1 In Rome IV, the phrase “no evidence of an
inflammatory, anatomic, metabolic, or neoplastic process
that explain the subject’s symptoms” has been removed
from diagnostic criteria. Instead, we include “after appro-
priate medical evaluation, the symptoms cannot be attrib-
uted to another medical condition.” This change permits
selective or no testing to support a positive diagnosis of an
FGID. We also point out that FGIDs can coexist with other
medical conditions.2,3 Similarly, different FGIDs frequently
coexist in the same patient. We have described 2 new dis-
orders, functional nausea and functional vomiting. We
changed “abdominal pain related functional gastrointestinal
disorders” to “functional abdominal pain disorders” (FAPD)
and have derived a new term, functional abdominal
pain—not otherwise specified (FAP-NOS) to describe chil-

gastrointestinal disorders” has been changed to “functional

abdominal pain disorders” and we have derived a new term,
functional abdominal painLnot otherwise specified, to
describe children who do not fit a specific disorder, such as
irritable bowel, functional dyspepsia, or abdominal
migraine. Rome IV FGID definitions should enhance clarity
for both clinicians and researchers.
Keywords: Children; Adolescents; Abdominal Pain; Nausea;
Vomiting; Functional Disorders.
dren who do not fit a specific disorder, such as irritable
bowel, functional dyspepsia, or abdominal migraine. Minor
modifications have been made to several other FGID.
H1. Functional Nausea and Vomiting
Disorders
H1a. Cyclic Vomiting Syndrome
Epidemiology. Data suggest a community prevalence
of 0.2% 1.0% for cyclic vomiting syndrome (CVS) using
Rome III criteria.4 Median age of symptom onset varies
from 3.5 to 7 years, but CVS occurs from infancy to
adulthood, with 46% having symptom start at 3 years of

T he Rome criteria provide symptom-based guide-

lines by which child and adolescent functional
gastrointestinal disorders (FGID) can be diagnosed. Pre-
age or before.5

vious Rome III criteria were based mostly on consensus,

as research in child/adolescent FGIDs was still largely
lacking. An expanded evidence base from the last 10 years
provides the basis for many of the recommendations of
the child/adolescent committee for Rome IV. For disor-
ders still lacking scientific data, the committee used clin-
ical experience and consensus among the committee
members.
The Rome IV functional gastrointestinal disorders
(FGID) for children and adolescents are shown in Table 1.
*Authors share co-first authorship.
Abbreviations used in this paper: CVS, cyclic vomiting syndrome; EGD,
esophagogastroduodenoscopy; FAPD, functional abdominal pain disor-
der; FD, functional dyspepsia; FGID, functional gastrointestinal disorder;
IBS, irritable bowel syndrome; NFI, nonretentive fecal incontinence; NOS,
not otherwise specified.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.015
May 2016
Table 1.Functional Gastrointestinal Disorders: Children and
Adolescents
H1. Functional nausea and vomiting disorders
H1a. Cyclic vomiting syndrome
H1b. Functional nausea and functional vomiting
H1c. Rumination syndrome
H1d. Aerophagia
H2. Functional abdominal pain disorders
H2a. Functional dyspepsia
H2b. Irritable bowel syndrome
H2c. Abdominal migraine
H2d. Functional abdominal pain not otherwise specified
H3. Functional defecation disorders
H3a. Functional constipation
H3b. Nonretentive fecal incontinence
H1a. Diagnostic Criteria for Cyclic Vomiting Syndrome
Must include all of the following:
1. The occurrence of 2 or more periods of intense,
unremitting nausea and paroxysmal vomiting,
lasting hours to days within a 6-month period.
2. Episodes are stereotypical in each patient
3. Episodes are separated by weeks to months with
return to baseline health between episodes.
4. After appropriate medical evaluation, the symp-
toms cannot be attributed to another condition.
If abdominal pain and vomiting are present, the pre-
dominant or more consistent symptom should be consid-
ered for the primary diagnosis. If the predominant feature is
abdominal pain, then abdominal migraine should be
considered.
Rationale for changes in diagnostic criteria. Rome
IV criteria require that the attacks be stereotypical for the
individual patient, occur within a 6-month period, that
criteria for another FGID not be fulfilled, and that the pri-
mary and most severe symptom be vomiting rather than
abdominal pain. The committee has changed the statement
“return to usual state of health lasting weeks to months” to
“episodes are separated by weeks to months with return to
baseline health between episodes.” This change was made
because “usual state of health” could have been mis-
interpreted as being asymptomatic between episodes and
did not allow the coexistence of mild GI symptoms at
baseline.
Clinical evaluation. The committee endorses the
clinical evaluation proposed in the North American Society
for Pediatric Gastroenterology, Hepatology, and Nutrition
CVS guidelines for children 2 to18 years of age.6 There is a
higher likelihood of underlying neurometabolic diseases in
children with early onset of symptoms and metabolic
FGIDs in Children and Adolescents 1457
testing should be carried out during the vomiting episode
and before administration of intravenous fluids to maxi-
mize detection of abnormalities. Chronic use of cannabis
can be associated with repeated episodes of severe vom-
iting, nausea, and abdominal pain (cannabinoid hyper-
emesis syndrome) and should be considered in adolescent
patients. Compulsive long hot water bath or shower
(frequently lasting several hours) resulting in temporary
symptom relief is common in cannabinoid hyperemesis
syndrome.
Treatment. The committee endorses the therapeutic
approach recommended in the North American Society for
Pediatric Gastroenterology, Hepatology and Nutrition CVS
guidelines.6 The guidelines recommend cyproheptadine in
children <5 years of age and amitriptyline in children >5
years. Second-line treatment includes prophylaxis with
propranolol for children of all ages. Some patients with CVS
may require combinations of drugs or complementary
treatments, such as acupuncture and/or cognitive-
behavioral therapy to help control their symptoms.7 Mito-
chondrial cofactors co-enzyme Q10 and L-carnitine have
been used as adjunctive therapy in some patients.8 Abortive
treatment is based on a combination of hydration and drug
administration.
H1b. Functional Nausea and Functional Vomiting
Epidemiology. There are no pediatric data on the
prevalence of isolated nausea, isolated vomiting, or a com-
bination of both in the literature.
H1b. Diagnostic Criteriaa for Functional Nausea and
Functional Vomiting
CHILD/ADOLESCENT
H1b1. Functional Nausea
Must include all of the following fulfilled for the last 2
months:
1. Bothersome nausea as the predominant symptom,
occurring at least twice per week, and generally
not related to meals
2. Not consistently associated with vomiting
3. After appropriate evaluation, the nausea cannot be
fully explained by another medical condition
H1b2. Functional Vomiting
Must include all of the following:
1. On average, 1 or more episodes of vomiting per
week
2. Absence of self-induced vomiting or criteria for an
eating disorder or rumination
3. After appropriate evaluation, the vomiting cannot
be fully explained by another medical condition
a
Criteria fulfilled for at least 2 months before diagnosis.
 1458 Hyams et al
Rationale for adoption of diagnostic entities. Based
on clinical experience, especially in children with anxiety or
depression, functional nausea and functional vomiting are
now included in Rome IV. Some patients have nausea alone,
some have vomiting alone, and some have nausea and
vomiting. We believe that the absence of concomitant pain in
these disorders suggests they should not be included as part
of functional dyspepsia.
Pathophysiologic considerations. Some patients
with these disorders also experience autonomic symptoms,
such as sweating, dizziness, pallor, and tachycardia. Postural
orthostatic tachycardia syndrome may include nausea and
vomiting as part of its symptom complex,9 and should be
distinguished from functional nausea and functional vom-
iting. Some children only experience nausea early in the
morning, and observe that when they “sleep late,” that is,
past the usual time when they would experience nausea, the
nausea does not occur.
Clinical evaluation. We have established functional
nausea and functional vomiting as separate entities, but
patients with chronic nausea commonly report mild vom-
iting with varying frequency. The presence of severe vom-
iting in addition to nausea presents a different situation in
which central nervous system disease, GI anatomic abnor-
malities (eg, malrotation), gastroparesis, and intestinal
pseudo-obstruction should be excluded. Biochemical testing
may include measurement of serum electrolytes, calcium,
cortisol, and thyroid hormone levels. Intestinal obstruction
and motility disorders (eg, gastroparesis, intestinal pseudo-
obstruction) should be considered and excluded in the
presence of recurrent vomiting. A relationship between
functional nausea or vomiting and delayed gastric emptying
in children is not clearly established. We did not consider a
normal upper GI endoscopy a requirement for a diagnosis of
CHILD/ADOLESCENT
functional nausea without vomiting. Psychological evalua-
tion is important in children with functional nausea or
functional vomiting.
Treatment. There are no published data on the
treatment of isolated functional nausea and isolated func-
tional vomiting (with or without nausea) in children.
Mental health intervention should be offered first in those
patients with obvious psychological comorbidities. Cogni-
tive behavioral therapy and hypnotherapy have been used
in patients with severe nausea due to chemotherapy10 and
may be helpful in this condition as well. Cyproheptadine
has been used in children with functional dyspepsia
with nausea.11 Gastric electrical stimulation has been
used to treat intractable dyspepsia (including nausea) in
children and may be effective even in the absence of
gastroparesis.12
H1c. Rumination Syndrome
Epidemiology. Prevalence in adolescents and children
is largely unknown. A limitation is that regurgitation and
rumination often occur in secret without parents being
aware. This may explain why rumination defined by Rome
III could not be identified based on parental report in a large
community-based study in the United States.13 Rumination
Gastroenterology Vol. 150, No. 6
can occur at any age, but some patient groups, such as
adolescent girls, seem to be at higher risk.
H1c. Diagnostic Criteriaa for Rumination Syndrome
Must include all of the following:
1. Repeated regurgitation and rechewing or expul-
sion of food that:
a. Begins soon after ingestion of a meal
b. Does not occur during sleep
2. Not preceded by retching
3. After appropriate evaluation, the symptoms
cannot be fully explained by another medical
condition. An eating disorder must be ruled out
a
Criteria fulfilled for at least 2 months before diagnosis.
Rationale for changes in criteria. The name
“adolescent rumination syndrome” is now “rumination
syndrome” because children who are younger may also
suffer from this condition. The elimination of “painless”
from the description of the regurgitation is justified by the
fact that often patients have another FAPD and by the fact
that the act of regurgitation is often triggered by a sensation
of discomfort (pressure, pain, burning) in the abdomen that
is relieved by regurgitation. We eliminated the requirement
that symptoms do not respond to gastroesophageal reflux
disease treatment, as it is not compulsory to treat for
gastroesophageal reflux disease before diagnosis of rumi-
nation. We added the need to rule out an eating disorder.
Finally, we have eliminated the need for the act of rumi-
nation to “occur at least once per week” because patients
with this condition usually have symptoms after each meal.
Pathophysiologic features. The act of rumination is
caused by an increase in intragastric pressure due to the
contraction of the abdominal muscles and is associated with
opening of the lower esophageal sphincter, leading to the
return of gastric content into the esophagus. When gastro-
jejunal manometry is used to aid in the diagnosis, the in-
crease in intragastric or intra-abdominal pressure can be
recognized as a simultaneous increase in pressure (“r”
waves) across multiple areas of the upper gut. These pres-
sure waves are thought to be the result of the contraction of
the skeletal abdominal muscles. Fasting and postprandial
motility is usually normal. It also has been suggested that
when abdominal pressure increases, the gastroesophageal
junction is displaced into the thorax, and it is this anatomic
change rather than relaxation of the lower esophageal
sphincter that explains the mechanism of voluntary regur-
gitation occurring during rumination syndrome.14
Psychological features. There is often a triggering
event before the onset of the symptoms of rumination. An
intercurrent infectious process may cause vomiting and
nausea, which do not disappear once the infection has
resolved. On other occasions, a traumatic psychosocial event
may be recognized at the onset of symptoms. Psychiatric
May 2016
disturbances can include depression, anxiety disorder,
obsessive compulsive disorder, post-traumatic stress dis-
order, adjustment disorder, developmental delays, and
attention deficit-hyperactivity disorder.15
Clinical evaluation. Effortless repetitive regurgitation,
reswallowing, and/or spitting within minutes of starting a
meal define rumination. Other common complaints include
abdominal pain, bloating, nausea, heartburn, and several
somatic symptoms, such as headaches, dizziness, and
sleeping difficulties. Differential diagnosis includes gastro-
esophageal reflux, gastroparesis, achalasia, bulimia nervosa,
and other functional or anatomical gastric and small intes-
tinal diseases, but in none of these entities does the regur-
gitation occur immediately after eating. One study suggested
that high-resolution esophageal manometry can identify
subgroups with distinct mechanisms of disease that respond
to specific management strategies.16
Treatment. A thorough understanding of rumination
syndrome and a clear motivation to overcome it are critical
in achieving successful treatment. Because rumination syn-
drome can be conceptualized in terms of a learned habit,
treatment often has used strategies successful in the man-
agement of habit disorders. A successful novel inpatient
interdisciplinary approach that involved pediatric psychol-
ogy, pediatric gastroenterology, clinical nutrition, child life,
therapeutic recreation, and massage therapy has been re-
ported in adolescents with this condition.17
H1d. Aerophagia
Epidemiology. In a large US population study using
Rome III criteria, aerophagia was found in 4.2% of children
by parental report of symptoms.13 A large school-based,
cross-sectional study conducted in Sri Lanka used Rome
III criteria and reported a prevalence of 7.5%.18 Aerophagia
seems to be particularly common in patients with neuro-
cognitive disabilities.
H1d. Diagnostic Criteriaa for Aerophagia
Must include all of the following:
1. Excessive air swallowing
2. Abdominal distention due to intraluminal air
which increases during the day
3. Repetitive belching and/or increased flatus
4. After appropriate evaluation, the symptoms
cannot be fully explained by another medical
condition.
a
Criteria must be fulfilled for at least 2 months before
diagnosis
Rationale for changes in diagnostic criteria. We
have added “excessive” to the air swallowing and “increases
during the day” to abdominal distention. All 3 criteria are
now required to meet the diagnosis. Aerophagia has been
deleted as a diagnosis in the adult Rome IV classification as
FGIDs in Children and Adolescents 1459
it was believed to largely represent a mechanism for
supragastric or gastric belching, as well as abdominal
bloating or distention rather than a specific disorder. In
contrast, the pediatric committee believes that aerophagia is
a well-recognized condition in pediatrics.
Pathophysiologic features. When air swallowing is
excessive, gas fills the GI lumen, resulting in excessive
belching, abdominal distention, flatus, and pain, presumably
as a consequence of luminal distention. A subgroup of
children seems unable to belch and, in those patients,
symptoms of distention and pain may be more severe. A
higher percentage of children with aerophagia were found
to be exposed to stressful events compared with controls,18
and anxiety can be a cause for excessive air swallowing.
Clinical evaluation
Aerophagia may be confused with gastroparesis or other
motility disorders, such as chronic intestinal pseudo-
obstruction. Bacterial overgrowth and malabsorption
(particularly celiac disease and disaccharidase deficiency)
are other etiologies of abdominal distention and excessive
flatus. In older children, large amounts of air can be swal-
lowed while chewing gum or drinking very quickly.
Intestinal-related (abdominal pain, nausea, and early
satiety) and extraintestinal symptoms (headache, sleeping
difficulty, and lightheadedness) were found to be common
among affected children.18
Treatment. There are no controlled studies in children
to guide therapy, which remains largely supportive and may
include behavioral therapy, psychotherapy, and
benzodiazepines.
H2. Functional Abdominal Pain
CHILD/ADOLESCENT
Disorders
We have now changed “abdominal pain related functional
gastrointestinal disorders” to “functional abdominal pain
disorders.” We found that the term functional abdominal pain
often was used to refer to any of the abdominal pain related
FGIDs (eg, FAP, irritable bowel syndrome [IBS], and func-
tional dyspepsia [FD]).19 This inconsistent use of the term
functional abdominal pain was considered a major problem
by the Rome IV committee. The committee believes it is
important to distinguish between different types of FAPD for
clinical and research purposes. For those children not
meeting criteria for IBS, FD, or abdominal migraine, we now
use the term functional abdominal pain not otherwise spec-
ified (NOS). Studies demonstrate that there can be overlap of
more than 1 FAPD in an individual patient.13 For clinical
purposes, we recognize that FAP will still be used; however,
for research purposes, FAP NOS, although potentially
cumbersome, will hopefully improve specificity in identifying
different disorders.
H2a. Functional Dyspepsia
Epidemiology. A US nationwide survey of 949 mothers
revealed that 1.4% of their children had pain or discomfort
in the upper abdomen at least once weekly, but only 0.2%
 1460 Hyams et al
met the Rome III pediatric criteria for FD.13 In a community-
based study in the northeast United States, 5% 10% of
otherwise healthy adolescents reported dyspeptic
symptoms.20
H2a. Diagnostic Criteriaa for Functional Dyspepsia
Must include 1 or more of the following bothersome
symptoms at least 4 days per month:
1. Postprandial fullness
2. Early satiation
3. Epigastric pain or burning not associated with
defecation
4. After appropriate evaluation, the symptoms
cannot be fully explained by another medical
condition.
a
Criteria fulfilled for at least 2 months before diagnosis.
Within FD, the following subtypes are now adopted:
1. Postprandial distress syndrome includes bother-
some postprandial fullness or early satiation that
prevents finishing a regular meal. Supportive fea-
tures include upper abdominal bloating, post-
prandial nausea, or excessive belching
2. Epigastric pain syndrome, which includes all of
the following: bothersome (severe enough to
interfere with normal activities) pain or burning
localized to the epigastrium. The pain is not
generalized or localized to other abdominal or
chest regions and is not relieved by defecation or
passage of flatus. Supportive criteria can include
CHILD/ADOLESCENT
(a) burning quality of the pain but without a ret-
rosternal component and (b) the pain commonly
induced or relieved by ingestion of a meal but may
occur while fasting.
Rationale for changes in diagnostic criteria. With
recognition of dyspepsia subtypes, we have eliminated the
requirement of pain to fulfill the criteria for FD. There is now
evidence for dyspepsia subtypes in children. A study of 100
children identified by Rome II pediatric criteria as having FD
were questioned for evidence of adult Rome III features of FD
and 29% met criteria for postprandial distress syndrome,
24% for epigastric pain syndrome, 26% met criteria for both,
and 21% fit neither.21 These adult Rome III subtypes related
better to differences in mast cell densities and scores on
psychological subscales than found with Rome II subtypes
(ulcer-like, dysmotility-like).21 Nocturnal pain that awakens
the individual from sleep was associated with higher
duodenal mast cell density, whereas bloating was associated
with lower levels of antral inflammation and higher self-
reports of anxiety and somatization. Early satiation and
postprandial fullness were associated with higher levels of
depression and self-reported anxiety. Postprandial distress
Gastroenterology Vol. 150, No. 6
syndrome phenotype differs from functional nausea as
nausea in the latter disorder can occur at any time and is
often not related to meals.
Pathophysiologic features. FD is a heterogeneous
disorder likely associated with different underlying patho-
physiologic disturbances associated with specific symptom
patterns. Hypotheses include abnormalities of gastric motor
function, visceral hypersensitivity due to central or pe-
ripheral sensitization, low-grade inflammation, and genetic
predisposition.22 Impaired gastric accommodation, as
determined by a decreased ability of the stomach to relax in
response to a meal, has been demonstrated.23 Using elec-
trogastrogram and gastric emptying studies, 50% of pedi-
atric patients with FD had abnormal electrogastrogram and
47% slow gastric emptying.24 FD developed in 24% of
children as a sequela of an acute bacterial, but not viral,
gastroenteritis.25,26 Eosinophils and mast cells within the
gastric lamina propria were increased in number in children
with atopy and FD and degranulated rapidly after cow’s
milk challenge.27 Using a barostat, several investigators
have demonstrated that FD patients have lower sensory
thresholds to balloon distention of the proximal stomach
than healthy volunteers.28 There is no evidence in children
that Helicobacter pylori gastritis causes dyspeptic symptoms
in the absence of duodenal ulcer.
Clinical evaluation. The role of esophagogas-
troduodenoscopy (EGD) in pediatric FD is unclear. One pe-
diatric study suggested that duration of symptoms of <1
year and vomiting were risk factors for mucosal inflamma-
tion.29 A prospective study evaluated Rome III criteria and
alarm features in 290 children (aged 4 18 years) under-
going EGD for chronic abdominal pain. EGD was thought to
be diagnostic in 109 (38%), with gastroesophageal reflux
and eosinophilic esophagitis being the most common find-
ings.30 A report from an expert panel asked to evaluate the
need for EGD in different case scenarios of children with
dyspeptic symptoms suggested EGD was indicated in
dyspeptic children with a family history of peptic ulcer
Table 2.Potential Alarm Features in Children With Chronic
Abdominal Paina
Family history of inflammatory bowel disease, celiac disease, or
peptic ulcer disease
Persistent right upper or right lower quadrant pain
Dysphagia
Odynophagia
Persistent vomiting
Gastrointestinal blood loss
Nocturnal diarrhea
Arthritis
Perirectal disease
Involuntary weight loss
Deceleration of linear growth
Delayed puberty
Unexplained fever
a
Clinical judgment should be exercised, putting what might
be considered an alarm sign into the whole context of the
history and physical examination.
May 2016
disease or H pylori infection, children older than 10 years of
age, when symptoms persist for >6 months, and if symp-
toms are severe enough to affect activities of daily living,
including sleep.31 The Rome IV pediatric committee does
not believe there is compelling evidence to require an EGD
in order to make a diagnosis of FD, but recognizes that local
practice patterns and social considerations may influence
the decision. See Table 2 for alarm features suggesting
further diagnostic testing.
Treatment. There are no adequately sized, double-
blind, placebo-controlled pediatric studies of FD treatment.
Foods aggravating symptoms (eg, caffeine containing, spicy,
fatty) and nonsteroidal anti-inflammatory agents should be
avoided. Psychological factors that can contribute to the
severity of the problem should be addressed. Acid blockade
with histamine receptor antagonists and proton pump in-
hibitors can be offered for pain predominant symptoms.32 If
cure of FD is defined as complete symptomatic relief after 4
weeks of treatment, omeprazole is superior to ranitidine,
famotidine, and cimetidine.33 Although convincing data are
lacking, low-dose tricyclic antidepressant therapy with
agents such as amitriptyline and imipramine is often
considered in difficult cases. Nausea, bloating, and early
satiety are more difficult to treat, and prokinetics such as
cisapride and domperidone can be offered where available.
A retrospective, open-label study suggested that cyprohep-
tadine is safe and effective for treating dyspeptic symptoms
in children.11 Gastric electrical stimulation seems to be a
promising option for pediatric patients with FD refractory to
medical treatment.34
H2b. Irritable Bowel Syndrome
Epidemiology. School-based studies in Colombia and
Sri Lanka found a prevalence of IBS of 4.9% and 5.4%,
respectively.4,35 IBS prevalence in children across the
United States based on parental report ranges from 1.2% to
2.9%.13,36
Figure 1. Pathophysiology
of functional abdominal
pain disorders. Visceral
hyperalgesia leading to
disability is shown as the
final outcome of sensi-
tizing medical factors that
are superimposed on a
background of genetic
predisposition and early
life events.
FGIDs in Children and Adolescents 1461
H2b. Diagnostic Criteriaa for Irritable Bowel Syndrome
Must include all of the following:
1. Abdominal pain at least 4 days per month asso-
ciated with one or more of the following:
a. Related to defecation
b. A change in frequency of stool
c. A change in form (appearance) of stool
2. In children with constipation, the pain does not
resolve with resolution of the constipation (chil-
dren in whom the pain resolves have functional
constipation, not irritable bowel syndrome)
3. After appropriate evaluation, the symptoms
cannot be fully explained by another medical
condition
a
Criteria fulfilled for at least 2 months before diagnosis.
Pediatric IBS can be divided into subtypes analogous to
adults reflecting the predominant stool pattern (IBS with
constipation, IBS with diarrhea, IBS with constipation and
diarrhea, and unspecified IBS).37
Rationale for changes in diagnostic criteria. The
term discomfort was removed from Rome III criteria, as it is
not clear whether the distinction between pain and
discomfort is quantitative or qualitative. The difference be-
tween functional constipation and IBS with constipation has
been clarified. As many as 75% of children with constipation
report pain,38 and studies have shown IBS patients often
CHILD/ADOLESCENT
receive a diagnosis of functional constipation.39 The com-
mittee recommends that patients with constipation and
abdominal pain initially be treated for constipation only. If
abdominal pain resolves with constipation treatment, the
 1462 Hyams et al
patient has functional constipation. If pain does not resolve
with appropriate constipation treatment alone, the patient
likely has IBS with constipation. IBS subtypes, analogous to
those described in adults, are now included in Rome IV.
While the evidence base for IBS subtypes in children is
limited, the committee thought that establishing the concept
of subtypes in children might be useful for research
purposes.
Pathophysiologic features. IBS is considered a dis-
order of the brain gut axis (Figure 1). Symptoms (eg,
diarrhea vs constipation, pain severity, psychosocial
distress) in an individual patient reflect which components
of the brain gut axis are affected and to what degree. Some
children with IBS have rectal but not gastric hyperalgesia,
with the opposite present in some children with FAP-
NOS.40,41 Visceral hypersensitivity may relate to the child’s
psychological distress (anxiety, depression, impulsiveness,
anger).42 Increased mucosal proinflammatory cytokines
have been demonstrated and may be induced as a conse-
quence of an acute infectious gastroenteritis (postinfectious
IBS).25 Alterations in gut microbiome have been demon-
strated, although it is not clear if these changes are the cause
or result of IBS and its symptoms.43,44 Increased self-
reported stress, anxiety, depression, and emotional prob-
lems may be seen in children with IBS.45,46 Noxious early
life events (eg, surgery) have been associated with a higher
risk for developing FAPDs in childhood, including IBS.47
Clinical evaluation. A careful history and physical
examination may suggest functional constipation rather
than IBS. Similarly, in the case of possible IBS with diarrhea,
infection, celiac disease, carbohydrate malabsorption, and,
less commonly, inflammatory bowel disease, warrant
particular focus. Celiac disease can rarely present with
constipation as well and warrants evaluation in children
CHILD/ADOLESCENT
with IBS with constipation. The greater the number of alarm
symptoms present, the greater the likelihood of an organic
disease (Table 2). Determination of fecal calprotectin is
increasingly being utilized as a noninvasive screen for in-
testinal mucosal inflammation and appears to be superior to
standard testing such as C-reactive protein.48
Treatment. There are very few double-blind, ran-
domized treatment trials in pediatric patients with IBS. Most
randomized pediatric studies have lumped all FAPDs
together. There are data supporting the utility of pro-
biotics.49,50 One small prospective, double-blind trial in
children reported efficacy of peppermint oil in reducing pain
severity.51 A recent, double-blind cross-over trial in children
with IBS (all subtypes) suggested efficacy of an elimination
diet reducing intake of fermentable oligosaccharides, di-
saccharides, monosaccharides, and polyols.52 Behavioral
treatments, as described in the section on FAP-NOS, also can
be recommended for pediatric IBS. The primary focus of
behavioral treatments should be on optimizing symptom
coping skills.
H2c. Abdominal Migraine
Epidemiology. The frequency of abdominal migraine
varies between 1% and 23%, depending on diagnostic
criteria used for diagnosis.4,13,36,53 Since the Rome II criteria
Gastroenterology Vol. 150, No. 6
were replaced by Rome III, its frequency of diagnosis in
children greatly increased. Rome III diagnostic criteria were
more inclusive and less specific than Rome II criteria. Rome
III criteria had a high positive predictive value (100%), but a
low negative predictive value (7.7%), which might have led
to other FAPDs being incorrectly diagnosed as abdominal
migraine.54
H2c. Diagnostic Criteriaa for Abdominal Migraine
Must include all of the following occurring at least twice:
1. Paroxysmal episodes of intense, acute peri-
umbilical, midline or diffuse abdominal pain last-
ing 1 hour or more (should be the most severe and
distressing symptom)
2. Episodes are separated by weeks to months.
3. The pain is incapacitating and interferes with
normal activities
4. Stereotypical pattern and symptoms in the indi-
vidual patient
5. The pain is associated with 2 or more of the
following:
a. Anorexia
b. Nausea
c. Vomiting
d. Headache
e. Photophobia
f. Pallor
6. After appropriate evaluation, the symptoms
cannot be fully explained by another medical
condition.
Criteria fulfilled for at least 6 months before diagnosis.
a
Rationale for changes in diagnostic criteria. The
committee believes that the prevalence data based on Rome
II criteria55 better represent the actual prevalence of
abdominal migraine. To be consistent with diagnostic
criteria for CVS, the committee decided to use the same
frequency and number of episodes, that is, 2 within 6
months. The committee modified the following components
of the major criteria: “periumbilical pain” is substituted for
“midline pain, periumbilical or diffuse abdominal pain” as
described in various publications56,57 and “Episodes are
separated by weeks to months” is substituted for “return to
baseline health,” as the latter phrase may not account for
baseline GI symptoms and could be confusing to parents. To
increase the specificity of diagnosis, the committee decided
to add “stereotypical pattern and symptoms in the individ-
ual patient.” The diagnosis does not exclude the presence of
other FAPDs for symptoms outside of the episodes. The
May 2016
committee stressed that the primary symptom should be
abdominal pain.
Pathophysiologic features. Abdominal migraine,
CVS, and migraine headache likely share pathophysiologic
mechanisms as well as being episodic, self-limited, and
stereotypical, and with symptom-free intervals between
attacks. Children with abdominal migraine and classic
migraine report similar triggers (eg, stress, fatigue, and
travel), associated symptoms (eg, anorexia, nausea, and
vomiting), and relieving factors (eg, rest and sleep).58 Both
abdominal migraine and CVS can evolve into migraine
headaches in adulthood. Increased activity of excitatory
amino acids has been found in patients with classic mi-
graines, possibly explaining the efficacy of certain medica-
tions that increase g-aminobutyric acid.59
Clinical evaluation. The association of nonspecific
prodromal symptoms, such as behavior or mood changes
(14%), photophobia and vasomotor symptoms similar to
those experienced by children with migraine headaches, and
a history of symptom relief with antimigraine therapy,
supports the diagnosis.57 Evaluation might require
excluding processes associated with severe episodic symp-
toms, such as intermittent small bowel or urologic
obstruction, recurrent pancreatitis, biliary tract disease, fa-
milial Mediterranean fever, metabolic disorders such as
porphyria, and psychiatric disorders.
Treatment. The treatment plan is determined by the
frequency, severity, and impact of the abdominal migraine
episodes on the child and family daily life. A double-blind,
placebo-controlled, crossover trial in 14 children found a
prophylactic benefit of oral pizotifen, a drug with anti-
serotonin and antihistamine effects.60 Prophylaxis with
drugs such as amitriptyline,61 propranolol, and cyprohep-
tadine62 has been successful.
H2d. Functional Abdominal Pain Not Otherwise
Specified Epidemiology
The term functional abdominal pain not otherwise
specified in Rome IV substitutes for the Rome III terms
functional abdominal pain and FAPS. A mean of 35% to 38%
of elementary school children report abdominal pain
weekly.4,35 Only about one-third of these children meet
Rome criteria for diagnosis of any FAPD. The prevalence of
FAP-NOS is 2.7% in Colombian4 and 4.4% in Sri Lankan
school-aged children according to Rome III criteria.35
Studies using parental report found a 1.2% prevalence of
FAP-NOS in the US community36,63 and 2% in German
school children.45
H2d. Diagnostic Criteriaa for Functional Abdominal
Pain NOS
Must be fulfilled at least 4 times per month and include
all of the following:
1. Episodic or continuous abdominal pain that does
not occur solely during physiologic events (eg,
eating, menses)
FGIDs in Children and Adolescents 1463
2. Insufficient criteria for irritable bowel syndrome,
functional dyspepsia, or abdominal migraine
3. After appropriate evaluation, the abdominal pain
cannot be fully explained by another medical
condition
a
Criteria fulfilled for at least 2 months before diagnosis.
Justification for Changes in Diagnostic Criteria
The frequency of abdominal pain required for a diag-
nosis is changed from weekly to 4 times/month to align
with the other FAPD criteria and allow inclusion of children
who would otherwise not qualify for a FAPD, but have been
found to be at risk for long-term negative consequences.36
The wording “that does not occur solely during physio-
logic events (eg, eating, menses)” has been added to
harmonize with the adult criteria and to reflect the obser-
vation that patients with FAPDs may have worsening
symptoms during physiologic events, such as eating and
menses, and also have pain at other times. The committee is
also dropping the FAPS category, given that loss of function
can accompany other Rome diagnoses, such as IBS.
Pathophysiology
Studies separating FAP-NOS from IBS suggest that chil-
dren with FAP-NOS in general do not have rectal hyper-
sensitivity, in contrast to children with IBS.40,41 It has been
reported that children with FAP-NOS have lower antral
contractions and slower emptying rates of a liquid meal
compared with healthy controls, but the clinical significance
CHILD/ADOLESCENT
of this finding is unclear.64 There is evidence for the asso-
ciation between psychological distress and chronic abdom-
inal pain in children and adolescents.45,65,66 Chronic
abdominal pain is associated with stressful life events, such
as parental divorce, hospitalization, bullying, and childhood
abuse.35,67,68 How a child and his/her family copes with
pain influences outcomes of FAPDs (Figure 2).
Clinical evaluation. Children with FAP-NOS
frequently report nonspecific and extraintestinal somatic
symptoms that do not necessarily require laboratory or
radiologic investigation. Often for parental reassurance,
limited diagnostic workup is performed. Special consider-
ation should be given to the presence of autonomic symp-
toms, in particular in children with postural orthostatic
tachycardia syndrome. See Table 2 for alarm features sug-
gesting additional diagnostic testing.
Treatment. Most treatment trials for FAPDs have
lumped all disorders together limiting generalizability.
Although adult trials have shown the efficacy of antispas-
modics, mebeverine was not significantly better than pla-
cebo in children.69 A small trial of amitriptyline found
benefits, while a large multicenter study did not.70,71 A
recent large trial of citalopram found a trend toward
effectiveness of citalopram compared to placebo in the
 1464 Hyams et al
Figure 2. The appraisal of any pain episode experienced by a child may have significant impact on the child’s ability to cope
effectively and accommodate to the pain, and consequently his or her normal function and development. In the presence of
risk factors or when protective factors are less effective, the child may develop a maladaptive response leading to a state of
chronic pain. From Walker et al,90 adapted with permission.
treatment of children with FAP.72 Clinicians, patients, and
parents should be aware of a black box warning issued by
the US Food and Drug Administration for an increased risk
of suicidal ideation in adolescents. Hypnotherapy73 and
cognitive behavioral therapy74 have provided short- and
CHILD/ADOLESCENT
long-term benefit in these patients.
H3. Functional Defecation Disorders
H3a. Functional Constipation
Epidemiology. A systematic review reported a mean
and median prevalence in children of 14% and 12%,
respectively.75 The wide range in reported prevalence may
be due to the use of different FC criteria and cultural in-
fluences. Peak incidence of constipation occurs at the time of
toilet training with no sex differences.76 Childhood FC is
distributed equally among different social classes with no
relationship to family size, ordinal position of the child in
the family, or parental age. Boys with constipation had
higher rates of fecal incontinence than girls.
H3a. Diagnostic Criteria for Functional Constipation
Must include 2 or more of the following occurring at
least once per week for a minimum of 1 month with
insufficient criteria for a diagnosis of irritable bowel
syndrome:
1. 2 or fewer defecations in the toilet per week in a
child of a developmental age of at least 4 years
Gastroenterology Vol. 150, No. 6
2. At least 1 episode of fecal incontinence per week
3. History of retentive posturing or excessive voli-
tional stool retention
4. History of painful or hard bowel movements
5. Presence of a large fecal mass in the rectum
6. History of large diameter stools that can obstruct
the toilet
After appropriate evaluation, the symptoms cannot be
fully explained by another medical condition.
Justification for change in diagnostic criteria. The
only change is the decrease from 2 months to 1 month in
the duration of symptoms needed to fulfill the criteria in
order to harmonize with the European and the North
American Societies for Pediatric Gastroenterology, Hep-
atology and Nutrition constipation guidelines, which sug-
gested that the 2-month interval listed in the Rome III
criteria for older children may unduly delay treatment in
some children. The shorter interval is now similar to the
time needed to fulfill the definition of FC in the neonate/
toddler group.
Pathophysiology. Because FC is equally common in
both sexes and children with diverse socioeconomic back-
grounds, dietary practices, and cultural influences,75 the
triggering event is most likely the universal instinct to
avoid defecation because of pain or social reasons (eg,
May 2016
school, travel). As a consequence of withholding, the colonic
mucosa absorbs water from the feces and the retained
stools become progressively more difficult to evacuate. This
process leads to a vicious cycle of stool retention in which
the rectum is increasingly distended, resulting in overflow
fecal incontinence, loss of rectal sensation, and ultimately,
loss of the normal urge to defecate. Increasing fecal accu-
mulation in the rectum also causes decreased motility in the
foregut, leading to anorexia, abdominal distention and pain.
Clinical evaluation. We endorse the consensus
guideline for the evaluation and treatment of the child with
FC published by the European and the North American So-
cieties for Pediatric Gastroenterology, Hepatology and
Nutrition.77 Some of the recommendations from the guide-
lines are listed here:
1. ROME criteria are recommended for the definition of
FC for all age groups
2. The diagnosis of FC is based on history and physical
examination
3. Alarm signs and symptoms and diagnostic clues
should be used to identify an underlying disease
responsible for the constipation (Table 3)
4. If only one Rome criterion is present and the diag-
nosis of FC is uncertain, a digital examination of the
anorectum is recommended to confirm the diagnosis
and exclude underlying medical conditions.
5. There is no role for the routine use of an abdominal
x-ray to diagnose FC
6. A plain abdominal radiograph may be used in a child
if fecal impaction is suspected but in whom physical
examination is unreliable/not possible
7. Routine allergy testing for cow’s milk allergy is not
recommended in children with constipation in the
absence of alarm symptoms
8. Laboratory testing to screen for hypothy-
roidism, celiac disease, and hypercalcemia is not
Table 3.Potential Alarm Features in Constipation
Passage of meconium >48 h in a term newborn
Constipation starting in the first month of life
Family history of Hirschsprung’s disease
Ribbon stools
Blood in the stools in the absence of anal fissures
Failure to thrive
Bilious vomiting
Severe abdominal distension
Abnormal thyroid gland
Abnormal position of the anus
Absent anal or cremasteric reflex
Decreased lower extremity strength/tone/reflex
Sacral dimple
Tuft of hair on spine
Gluteal cleft deviation
Anal scars
FGIDs in Children and Adolescents 1465
recommended in children with constipation in the
absence of alarm symptoms
9. The main indication to perform anorectal manom-
etry in the evaluation of intractable constipation is
to assess the presence of the rectoanal inhibitory
reflex
10. Rectal biopsy is the gold standard for diagnosing
Hirschsprung’s disease
11. A barium enema should not be used as an initial
diagnostic tool for the evaluation of FC
Treatment. A systematic review showed that only
50% of children referred to a tertiary care center and fol-
lowed for 6 to 12 months recovered and were taken off
laxatives successfully.78,79 Education is as important as
medical therapy and should include counseling families to
recognize withholding behaviors and to use behavioral in-
terventions, such as regular toileting, use of diaries to track
stooling, and reward systems for successful evacuations.80 A
normal fiber and fluid intake is recommended, while the
addition of prebiotics and probiotics to the regimen
currently does not seem to be supported by adequate
evidence.
The pharmacologic approach comprises 2 steps: rectal
or oral disimpaction for children who present with fecal
impaction81 and maintenance therapy to prevent reac-
cumulation of feces using a variety of agents. Polyethylene
glycol is first-line therapy for constipated children.77 In 3
recent Cochrane Reviews, polyethylene glycol was found
superior to lactulose, although the quality of the evidence
was poor due to sparse data, heterogeneity, and high risk of
bias in the studies analyzed.82–84
CHILD/ADOLESCENT
H3b. Nonretentive Fecal Incontinence
Epidemiology. Fecal incontinence is estimated to
affect 0.8% to 4.1% of children in Western societies.
H3b. Diagnostic Criteria for Nonretentive Fecal
Incontinence
At least a 1-month history of the following symptoms in
a child with a developmental age older than 4 years:
1. Defecation into places inappropriate to the socio-
cultural context
2. No evidence of fecal retention
3. After appropriate medical evaluation, the fecal
incontinence cannot be explained by another
medical condition
Justification for changes in diagnostic criteria. To
maintain consistency with FC, we have changed the duration
of symptoms required for diagnosis from 2 to 1 month.
Pathophysiology. Patients with nonretentive fecal in-
continence (NFI) have normal defecation frequencies and
colonic and anorectal motility parameters, differentiating
 1466 Hyams et al
this condition from FC. Total and segmental colonic transit
times are significantly prolonged in constipated children
compared with children with NFI.85 The diagnosis of NFI
should be based on clinical symptoms, such as normal
defecation frequency and absence of abdominal or rectal
palpable mass, in combination with normal transit marker
studies.86 NFI might be a manifestation of an emotional
disturbance in a school-aged child and represent impulsive
action triggered by unconscious anger. NFI has been
described as a result of sexual abuse in childhood.87
Clinical evaluation. In general, children with this
condition have complete evacuation of colonic contents, not
just staining of the underwear, in contrast to FC. Inquiry
should be made whether there is a coexisting history of
constipation, noting stool pattern (size and consistency of
stools, withholding, straining), age of onset, type and
amount of material evacuated, diet history, medications,
coexisting urinary symptoms, psychosocial comorbidity, and
family or personal stressors. Physical examination should
focus on growth parameters, abdominal examination
(distention, palpable stools), rectal examination (sacral
dimple, position of anus, sphincter tone, rectal vault size,
presence or absence of stool in rectum), and a thorough
neurologic examination.
Treatment. Parents need to understand that psycho-
logical disturbances, learning difficulties, and behavioral
problems are usually significant contributors to the defe-
catory symptoms. Victims of sexual abuse must be identified
and referred for appropriate counseling. The most suc-
cessful approach to management of NFI involves behavioral
therapy. Regular toilet training use with rewards and
diminishing toilet phobia contribute to lower distress,
restore normal bowel habits, and re-establish self-respect. It
has been observed that in NFI, biofeedback therapy does not
CHILD/ADOLESCENT
provide additional benefit compared with conventional
therapy, even when improvement of defecation dynamics is
obtained.88 A long-term follow-up study showed that after 2
years of intensive medical and behavioral treatment, only
29% of the children were completely free of fecal inconti-
nence. At 18 years of age, 15% of adolescents with NFI still
had the disorder.89 No prognostic factors for success were
identified.
Recommendations for Future Research
Common research needs that apply to all pediatric FGIDs
include:
 Cross-cultural epidemiological studies
 Natural history
 Studies of pathophysiology, eg, the microbiome brain
gut axis
 Earlier access for children into clinical treatment trials
of emerging medications
Specific needs that the committee recognizes include:
 CVS and abdominal migraine
Gastroenterology Vol. 150, No. 6
B Comparative effectiveness treatment trials
B Long-term studies to provide guidelines on optimal
timing of stopping prophylactic therapy.
 Functional nausea and functional vomiting
B Validation of the Rome IV criteria
 Rumination syndrome
B Establish effective treatment strategies for children
too young or not cognitively mature to successfully
engage in behavioral interventions.
 Aerophagia
B Define effective therapeutic strategies in children
with and without neurodevelopmental deficits
 IBS and FAP-NOS
B Uncover pathophysiologic differences between IBS
and FAP-NOS
B Define IBS subgroups by pathophysiology
B Elucidate the role of dietary factors and diet
modification
 FD
B Define FD subgroups in children
B Define the role of upper GI endoscopy
 FC
B Assess safety of long-term osmotic and stimulant
laxative use
B Determine the role of surgery in children who fail
aggressive medical treatment
 Functional NFI
B Clarify the role of medical and behavioral treatments
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. Visit the online version of
Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.015.
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46. Waters AM, Schilpzand E, Bell C, et al. Functional
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Reprint requests
Address requests for reprints to: Jeffrey S. Hyams, MD, Division of Digestive
Diseases, Hepatology and Nutrition, Connecticut Children’s Medical Center,
282 Washington Street, Hartford, Connecticut 06106. e-mail:
jhyams@connecticutchildrens.org.
Conflicts of interest
The authors disclose the following: Carlo Di Lorenzo (QOL Medical, IM
HealthScience, and Merck: consultant), Miguel Saps (QOL Medical, Nutricia,
Ardelyx, Quintiles, Forest, and IM HealthScience: consultant), Robert J.
Shulman (Gerson-Lehrman and Nutrinia: consultant; Mead Johnson: research
support), Annamaria Staiano (Aboca and Nestec: clinical support; Aboca, D.
M.G. Italy, and Sucampo AG: consultant; Angelini, Milté, Menarini, and
Valeas: speaker), Miranda van Tilburg (Takeda: research support). The
remaining authors disclose no conflicts.
May 2016
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 Gastroenterology 2016;150:1469–1480

Design of Treatment Trials for Functional Gastrointestinal

Disorders
E. Jan Irvine,1,2,* Jan Tack,3,* Michael D. Crowell,4 Kok Ann Gwee,5 Meiyun Ke,6
Max J. Schmulson,7 William E. Whitehead,8 and Brennan Spiegel9
1
Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 2Li Ka Shing Knowledge Institute and Department
of Medicine, St Michael’s Hospital, Toronto, Canada; 3Departments of Clinical and Experimental Medicine and
Gastroenterology, Translational Research Center for Gastrointestinal Disorders, University Hospital KU Leuven, Leuven,
Belgium; 4Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona; 5Yong Loo Lin School of Medicine,
National University of Singapore, Singapore; 6Peking Union Medical College Hospital, Center of FGID and MGID, Peking Union
Medical College and Chinese Academy of Medical Sciences, Beijing, China; 7Facultad de Medicina, Universidad Nacional
Autónoma de México, Laboratorio de Hígado, Páncreas y Motilidad, Unidad de Investigación en Medicina Experimental,
Hospital General de México, Mexico City, Mexico; 8University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and
9
Cedars-Sinai Health System, Cedars-Sinai Center for Outcomes Research and Education, Los Angeles, California

This article summarizes recent progress and regulatory
guidance on design of trials to assess the efficacy of new
therapies for functional gastrointestinal disorders (FGIDs).
The double-masked, placebo-controlled, parallel-group
design remains the accepted standard for evaluating
treatment efficacy. A control group is essential, and a
detailed description of the randomization process and
concealed allocation method must be included in the study
report. The control will most often be placebo, but for
therapeutic procedures and for behavioral treatment tri-
als, respectively, a sham procedure and control interven-
tion with similar expectation of benefit, but lacking the
treatment principle, are recommended. Investigators
should be aware of, and attempt to minimize, expectancy
effects (placebo, nocebo, precebo). The primary analysis
should be based on the proportion of patients in each
treatment arm who satisfy a treatment responder defini-
tion or a prespecified clinically meaningful change in a
patient-reported outcome measure. Data analysis should
(PRO) measurement have undergone major changes with
the dissemination of regulatory guidelines for PROs from
the US Food and Drug Administration (FDA) and the Euro-
pean Medicines Agency (EMA).1–3 Accumulating data also
provide new insights for measuring common FGID symp-
toms, such as abdominal pain, discomfort, diarrhea, urgency,
constipation, and bloating, among others. New information
about the placebo, “nocebo,” and “precebo” responses also
challenges researchers to consider the biases inherent in
FGID trials. In addition, advances in pragmatic clinical trial
(PCT) design offer new approaches to measuring the effec-
tiveness of FGID therapies in the context of everyday clinical
practice. This updated Rome IV chapter now addresses each
of these new trends, provides guidance for investigators
seeking to develop and conduct FGID clinical trials, and
emphasizes evolving concepts about how best to test the
risks and benefits among the full range of FGID treatments.

use the intention-to-treat principle. Reporting of results
should follow the Consolidated Standards for Reporting
Trials guidelines and include secondary outcome measures
to support or explain the primary outcome and an analysis
of harms data. Trials should be registered in a public
location before initiation and results should be published
regardless of outcome.
Keywords: Functional Gastrointestinal Disorders; Controlled
Trial; Patient-Reported Outcome Measure; Intention to Treat.
TREATMENT TRIALS
Identifying the Hypotheses
and Research Questions
The first task is to establish the hypothesis of the puta-
tive effect of the studied treatment, based on its expected
mechanism of action, which generates the specific research
question(s) for the proposed trial. As multiple factors
contribute to the pathogenesis of FGIDs, it is likely that no
single therapeutic approach will fully abolish all symptoms.
*Authors share co-first authorship.

Abbreviations used in this paper: BSFS, Bristol Stool Form Scale; CON-

C
linical trial design for functional gastrointestinal
disorders (FGIDs) is hampered by several factors,
including symptom variability between subjects or groups
and within subjects over time and the lack of specific bio-
markers. The Rome diagnostic criteria and design recom-
mendations are now routinely applied in clinical treatment
trials. Since the publication of the Rome III guidance, there
have been substantial advances in several aspects of clinical
trial design. The expectations for patient-reported outcome
SORT, Consolidated Standards for Reporting Trials; EMA, European
Medicines Agency; FDA, US Food and Drug Administration; FGID, func-
tional gastrointestinal disorder; HRQOL, health-related quality of life; IBS,
irritable bowel syndrome; IBS-C, irritable bowel syndrome with con-
stipation; IBS-D, irritable bowel syndrome with diarrhea; IBS-M, irritable
bowel syndrome with constipation and diarrhea; MCID, minimally clinical
important difference; PCT, pragmatic clinical trials; PRO, patient-reported
outcome; RCT, randomized controlled trial.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.010
 1470 Irvine and Tack et al
Table 1.Goals of a Treatment Trial
To ascertain the ability of the intervention to
Relieve symptoms or decrease symptom severity
Improve functional health status and health-related quality of life
Improve ability to cope with symptoms
Decrease use of health care resources
Avoid harm and be cost-effective
Most FGID intervention studies evaluate the impact of a
treatment on the items listed in Table 1, but specific goals
can vary widely. Investigators should prioritize their
research question(s) pertinent to the specific FGID, develop
a hypothesis based on available evidence, and design a
study that most effectively answers the research
question(s).
In general, the primary question will address whether
the study treatment improves FGID symptoms. Conse-
quently, the primary outcome measurement tools must
include reporting of the most important symptoms expected
to change with the proposed treatment. The secondary
questions are best determined by the particular disorder,
that is, its specific symptoms and the mechanism of action of
the treatment. Pathophysiological factors, while important
explanatory parameters, should be considered secondary
rather than primary end points.
Defining the Target Condition
Patient Population
A screening log of key variables is mandatory in order
for readers to judge the generalizability of the results. The
log should include demographic (eg, age, sex, and race) and
clinical variables (eg, disease severity, symptom duration,
prior treatments for the condition, and the use of concurrent
medications) for patients entered and excluded, with rea-
sons for exclusion. Explicit inclusion and exclusion criteria
TREATMENT TRIALS
are mandatory for all studies. Most treatment trials in FGIDs
have required a minimum severity level for specific symp-
toms thought to be typical of the condition. Balanced
consideration for the potential mechanism of action of the
drug must also be given when selecting the study
population.
It is advisable to include as broad a spectrum of patients
as possible, defined by the Rome- specific FGID criteria.
Restricting or modifying the study population must be
justified. The EMA requests that early drug development
programs include sufficient numbers of both men and
women to permit assessment of safety and efficacy for both
sexes. The FDA also supports engagement of subjects of
different racial backgrounds.2,3
Inclusion Criteria
The minimum screening for eligibility should be speci-
fied and should adhere to current guidelines. The Rome
classification of FGIDs is currently the most comprehensive
and well-established diagnostic system, and its use ensures
Gastroenterology Vol. 150, No. 6
a sufficient degree of standardization of study participants
across centers and cultural settings, and allows further
exploration for differences in treatment response.
Exclusion Criteria/Appropriate Rule Outs
Important confounding factors to consider for possible
exclusion criteria are psychological comorbidities, socio-
cultural perspectives, and biological variations. Psychologi-
cal comorbidities are often thought to be predictors of poor
response to treatment, but this has not been proven.4 Other
psychologically related influences include the placebo and
nocebo effects (see section on placebo and nocebo), and
future studies may wish to consider designs that could
measure the subject’s proneness to these effects.
Managing Functional Gastrointestinal Disorders
Overlap, Comorbidities, and Disease Modifiers
Overlap disorders, potential disease modifiers, and
important comorbidities that might affect treatment
response should be assessed and explored. The overlap of
FGIDs with other FGIDs and with somatic and psychiatric
disorders is a challenge for clinical trail design. First, the
accuracy of the FGID diagnosis may be questioned and it is
possible that a treatment might improve the symptoms of
one disorder while symptoms of the other worsen. Second,
the presence of a comorbidity may be associated with
increased symptom severity, greater impact on health-
related quality of life (HRQOL), and greater psychological
distress—all of which could modify the response to
treatment. Third, underlying motility or sensory disorders
in different parts of the GI tract may interact in ways that
could affect the response to specific treatments. The
committee recommends that, in most situations, patients
with overlapping conditions be included in the trial and
the presence of comorbid conditions should be
documented.
Role of Biomarkers in Defining
Study Population
Continuing research is needed to identify biomarkers
that attempt to elucidate disease mechanisms and may
facilitate assessment of efficacy of treatments in FGID
studies. A biomarker is an indicator of a physiological or
pathological state that can be objectively measured and
evaluated, in contrast to PROs, which are measured using
questionnaires that capture patient perceptions of their
illness.5 A valid and reliable biomarker should optimally
distinguish patients with a known clinical syndrome from
other conditions, and do so with a high degree of sensitivity
and specificity. It may also have predictive value, in that its
presence could potentially predict natural history and/or
response to specific therapies.5 While they are not suitable
as surrogate end points at this time, they can be used to
stratify patients. However, at present, very few biomarkers
have been identified that have sufficient sensitivity and
specificity.
May 2016 Design of Treatment Trials for FGIDs 1471

Clinical Trial Design Masking/Blinding Process

Unique Challenges for the Design of Treatment
Trials in Functional Gastrointestinal Disorders
There are several challenges to conducting FGID treat-
ment trials, including a high placebo response rate6;
symptoms that are intermittent and of fluctuating severity7;
a potential need for multimodal therapy, given the limited
efficacy of available treatments or multiple etiological
mechanisms affecting the disease process8; difficulty main-
taining masking of patients and investigators in trials of
behavioral interventions9; contamination from over-the-
counter treatments or medicines taken for other condi-
tions; the necessity of avoiding significant harms10 in
treating non life-threatening conditions; absence of bio-
markers both for diagnosing the disorder in question and
for evaluating the treatment response; and absence of
acceptable end points for many FGIDs. In addition, clinical
trials differ from clinical practice in several ways, including
the application of strict inclusion and exclusion criteria, the
use of a placebo group, application of a standardized
intervention, frequent follow-up visits with extensive data
recording, and the use of study coordinators.
The placebo response observed in clinical trials has been
attributed in part to the attention given to enrolled subjects,
including detailed explanation and reassurance, close
monitoring, and ready access to study coordinators, which
may in themselves produce a therapeutic effect. Bias,
defined as “systematic error” in estimating the treatment
effect, may enter a clinical trial at any stage, from design to
publication.11 The major sources of bias are listed in
Table 2.
Table 2.Major Sources of Bias in Clinical Trials
Bias type Comments
Investigator bias Conscious or unconscious,
It is mandatory to undertake the maximum masking
possible, determined by the type of intervention and study
design. It is recommended to evaluate and report whether
masking was successful. Masking of participants, in-
vestigators, and evaluators to treatment assignment is a key
feature of a successful controlled trial.12 Single masking is
when only the study subject/patient is unaware of the
treatment allocation. Double-masking (both patients and
research personnel) is necessary to ensure the highest val-
idity of the primary outcome measurement. Triple-masking
includes also masking monitors, data managers, statisti-
cians, and others who interpret outcome tests.13 In-
terventions involving procedures such as psychotherapy,
hypnotherapy, sphincterotomy, or drug trials in which the
active drug causes predictable side effects or rapid symp-
tom changes, are difficult to mask from patients or in-
vestigators. Possible solutions include using independent
assessors who are unaware of the intervention, or stan-
dardized interviewer-administered or self-administered
questionnaires.14 In addition, study investigators are
encouraged to ask both patient and interventionist at the
end of the trial whether they believe active treatment was
administered and to report these data.
Randomization
Investigators must include a detailed description of their
randomization process and concealed allocation method in
the report of the study. Randomization is the process of
assigning subjects to different treatment arms without bias,
which can be accomplished either by someone other than an
investigator preparing a numbered series of sealed enve-
lopes containing group assignments or use of a computer
program for random allocation.13,15 Critical recommenda-
tions to ensure randomized concealed treatment are the
randomization code is generated by a noninvestigator
(preferably a computer), randomization is done within
blocks of variable size (permuted block randomization) or

Patient expectancy (placebo)
Ascertainment bias
Self-selection for treatment
Changes in subject pool
Nonspecific effects
Doctor patient relationship
Regression to the mean
Publication bias
usually expressed through
decisions about eligibility
Especially a problem where end
points are subjective
Patients are more likely to
respond positively to
treatments they prefer and
seek out
Publicity or other factors may
influence the subject pool
over time
Especially important in
psychological interventions
Patients are usually enrolled when
most symptomatic and
inevitably improve
Authors are more likely to submit
trials with positive results and
journals are more likely to
publish them
TREATMENT TRIALS
sufficient size to minimize unmasking due to side effects in
previously exposed patients, the list of patient treatment
assignments should be available only to the medical officer
in charge of patient safety, and a record should be kept of
patients for whom the mask has been broken. When
reporting the trial, the randomization procedure should be
described explicitly.15 Stratified randomization is a variation
on randomization that is designed to assure balance on the
most important prognostic factors by using a separate
randomization sequence for each stratum (eg, male vs fe-
male or IBS with constipation [IBS-C] vs IBS with diarrhea ]
IBS-D])16.
Selecting a Control Group
A control group is required to establish the true efficacy
of a new treatment. As therapies of proven efficacy accu-
mulate, a comparison against an active available treatment
can be considered, but this requires higher patient numbers
to establish efficacy and may fail to show a statistically
significant difference.17,18 Control groups for therapeutic
 1472 Irvine and Tack et al
procedures are equally crucial. In behavioral treatment tri-
als, confirming that the control intervention produces a
similar expectation of benefit but does not act on the same
physiological or psychological principle is recommended. In
trials involving a therapeutic procedure, a sham group is
recommended when feasible.
Placebo, Nocebo, and Precebo Responses
Placebo. Placebo (from the Latin “to please”) is an
intervention that generates the expectation of benefit in the
patient but is believed to lack any specific effect to change a
particular disorder,19 or an intervention for which there is
no scientific theory explaining its action.20 When used along
with blinding, use of a placebo design may enable in-
vestigators to assess side effects of interventions more
readily and with less bias. Placebos can be administered as a
drug or as a procedural intervention.20 The placebo effect is
well characterized in FGID trials, especially in FD and IBS,
with response rates ranging from 6% 72%21,22 and
0% 84%, respectively.6 A meta-analysis suggested that the
placebo response is larger when a responder is defined by a
global improvement in IBS symptoms compared with
defining a responder by reduction in abdominal pain.23,24 A
more recent systematic review and meta-analysis found
higher placebo rates in European randomized controlled
trials (RCTs) compared with those conducted in other con-
tinents; in those that used physician-reported outcomes
compared with those that used a patient-reported end
point; and in RCTs using shorter duration of therapy.25 Also,
pooled placebo response rates were generally higher in
RCTs using clinical criteria to define the presence of IBS
compared with those using Rome criteria, trials using 3
times daily dosing, trials that assigned patients to placebo or
active therapy in a 1:1 ratio, trials of antispasmodics and
mixed 5-HT3 antagonists/5-HT4 agonists, and trials of
lower scientific quality.25
Nocebo. In contrast to placebo, nocebo (from the Latin
“I shall harm”)20 is the expectation of distress. The expec-
TREATMENT TRIALS
tation of side effects may increase the frequency with which
adverse effects are reported in both the active and control
arms of a drug study, and may increase the likelihood that
subjects will drop out of the trial.
Precebo. The term precebo was coined to describe the
effect that influences placebo even before the study be-
gins.26 The precebo effect refers to the potential for a drug
benefit during a clinical trial to be influenced by precon-
ceived notions or by communications about the trial con-
tained in advertisements and consent forms.
Baseline Observation vs Placebo Run-In
A period of prospective baseline measurement before
treatment is useful to evaluate patient eligibility. This also
limits recall and reporting biases and ensures that patients
are currently symptomatic. It allows comparison of patients
in the active and placebo groups, as well as evaluation of a
clinically important change in health status.
Older studies have used a placebo run-in period where
all patients received placebo for a specified period and their
Gastroenterology Vol. 150, No. 6
responses were assessed using the study outcome mea-
sures. Patients who significantly improved were excluded.
Although acceptable to regulatory agencies, placebo run-in
can underestimate the overall effect size.27
Choice of Study Design
The double-masked, randomized, placebo-controlled,
parallel-group trial is the gold standard for testing the ef-
ficacy of new treatments. Variations of this basic design
include different groups receiving different doses of the
active treatment (dose-ranging, in phase 2), more than one
control treatment, multiarm trials, a baseline period of no
treatment, and a washout period after treatment is
completed.
As there is no universally effective treatment for any
FGID, the standard approach is to test a new therapy against
placebo to prove its superiority. Occasionally, trials of
equivalence and noninferiority are performed where a new
therapy is more convenient or less expensive.18
Crossover designs have been popular in FGID treatment
trials.6 Subjects receive both treatments during distinct time
periods, usually separated by a washout phase, in random-
ized order, with the aim of comparing the treatments.
Theoretically, a crossover design can increase sensitivity to
detect change, allowing a smaller sample size for the desired
statistical power. However, there are down sides: patient
dropout and missing data have a greater impact than in a
parallel-group design, carryover effects that occur when the
first treatment influences the response to the second
treatment, and there is a higher risk of unmasking due to
side effects. Therefore, crossover trials seems most appli-
cable in physiological studies where end points are objec-
tively measured.
A factorial design is appropriate when evaluating com-
bination treatments, which may be desirable in patients
with severe FGID symptoms.28 This requires a control group
for each intervention. The withdrawal trial is an “enrich-
ment design” in which all subjects receive the active treat-
ment and, at a predefined time point, are classified as
responders or nonresponders. The latter are then excluded
and responders are randomly assigned to continue with
treatment or placebo. The efficacy assessment is based only
on the second part of the trial. Potential carryover effects
from active treatment are the major drawback.29
Design of Trials for Behavioral, Surgical,
and Complementary and Alternative
Medicine Interventions
In trials evaluating the efficacy of behavioral, surgical, or
many types of complementary and alternative medicine
interventions, it is not possible to mask the intervention
from the therapist (the individual implementing the inter-
vention) or from the patient. Expectation of benefit is the
most important variable to balance across intervention
arms. Some published trials of behavioral interventions
have compared symptom improvement in the active treat-
ment group to symptom changes in people who remain on a
waiting list to receive the intervention or who continue to
May 2016
receive “standard medical care.” However, both of them
create a negative expectancy of improvement and therefore
have potential to overestimate the efficacy of the investi-
gational treatment. A better approach is to identify an
alternative, active treatment that generates a similar
expectation of benefit and is assumed to be less effective.
Investigators have also tried to balance the amount of
contact time with the therapist and other characteristics
across treatment arms.30,31 The expectation of benefit
should be measured in both groups to confirm that the
treatment arms are balanced.14
A number of steps are recommended to minimize the
impact of investigator bias in behavioral trials: (1)
randomize patients to the treatment arms only after they
have been screened and found eligible; (2) have an expert
develop a detailed treatment manual for all treatment arms;
(3) use multiple well-trained interventionists and test
whether outcomes differ across interventionists; and (4) use
patient-completed outcome questionnaires or outcome as-
sessors who are blind to the treatment assignment of each
subject.
Duration of Treatment
Prior recommendations for treatment durations of trials
of 8 12 weeks were based on experience together with
considerations of cost and ability to retain patients. The
EMA guidelines differentiate between trials to establish
short-term efficacy, for which a treatment duration of 4
weeks or longer would be acceptable vs trials intended to
establish long-term efficacy, for which a minimum of 6
months is recommended.3 Extended patient follow-up
should be considered to determine the treatment dura-
bility and should also relate to the presumed treatment
mechanism and periodicity of symptoms. Recent long-term
studies of 6 months duration in parallel design32 or on de-
mand have now been undertaken in FGID patients.33
Adherence to Treatment and Study Protocol
During a clinical trial of FGID, adherence to medication is
critical in interpreting the results and efficacy of treatment.
Most trials accept 80% as a reasonable level of adherence
that allows valid assessment of the treatment intervention.
Measuring adherence can be achieved by measuring a
metabolite of a drug treatment, counting unused medica-
tion, use of electronic or paper diaries, prescription pur-
chase monitoring, patient interview, or physician
impression. Strategies that appear to enhance patient
adherence during clinical trials include short-term vs longer
trials, clear written instruction and education before and
during the trial, reminders to take medication, recording
symptoms or attending appointments, self-monitoring,
severity of condition or symptoms, efficacy of the treat-
ment, and patient education and understanding of the
importance of adherence.34
Considerations for Dietary Interventions
Major challenges in dietary trials include masking the
intervention and innovations in the choice of control diets.
Design of Treatment Trials for FGIDs 1473
Applying any standardized diet, such as the average national
diet, is likely to be an intervention, but it does control diet in
a standardized fashion. Recently, the methodological rigor of
dietary intervention trials has improved, with studies in
which all meals were provided in a masked fashion to the
patients for the duration of the trial.35,36
Considerations for Probiotic Trials
There is a rapidly increasing interest in using probiotics
and prebiotics for the treatment of FGIDs, but interpreting
the trials to date has been hampered by suboptimal trial
design, small sample sizes, and the wide variety of probiotic
strains and formulations that have been used.37 A minimum
requirement for probiotic trials is to demonstrate that the
test organisms are present in stools or in the lumen of the
gut in a representative subset of exposed subjects. Whether
for registration as drugs, or as food supplements or func-
tional foods, they require the same rigorous criteria, design,
and end points as classical pharmacological efficacy
studies.38
Considerations for Pediatric Trials
Compared with adults, there are far fewer published
clinical trials on FGID in the pediatric population. Primary
end points in children vary widely among studies. Devel-
opmental limitations make it difficult to obtain reliable
PROs in young children. In trials involving infants, toddlers,
and younger children, reports of symptoms are based on
parental observation, so-called “observer-reported out-
comes.” Unfortunately, minimally clinical important differ-
ences (MCIDs) and factors determining the magnitude of
placebo responses have not been established in pediatrics.
Pragmatic Clinical Trials
PCTs focus on the risks, benefits, and costs of competing
therapies within the context of usual practice settings.39
TREATMENT TRIALS
Whereas explanatory RCTs restrict variability in treatment
delivery between sites and between treatment arms, PCTs
aim to understand health outcomes between competing
management approaches for a common clinical dilemma,
may include a broad range of patients from diverse settings,
and may even allow for different patterns of care within a
study arm to emulate clinical reality. However, as PCTs do
not tightly control all aspects of study design, it can be
difficult to untangle mechanisms of action, or to isolate key
prognostic variables, and they are more susceptible to ef-
fects of investigator bias, patient expectancy, and ascer-
tainment bias related to self-selection for different
treatments.
Registering With ClinicalTrials.gov
All clinical trials should be registered before initiation on
a dedicated, publically accessible website. One example is
ClinicalTrials.gov, established by the National Institutes of
Health. US law now not only mandates reporting of clinical
trials, but also establishes penalties for noncompliance.
 1474 Irvine and Tack et al
Patient-Reported Outcomes Measurement
Definition and uses of patient-reported
outcomes. The patient report is of primary importance
in evaluating effectiveness of FGID therapies. PROs are
designed to capture the patients’ illness experience in a
structured format and may help bridge the gap between
patients and providers, while providing outcome targets for
clinical trials. The FDA, EMA, and other regulatory agencies
consider the patient report in drug approval, and have
developed guidance for development and use of PROs in
clinical trials.40,41 The National Institutes of Health has also
supported a major PRO initiative, called the Patient Re-
ported Outcome Measurement Information System
(PROMIS; www.nihpromis.org), designed to develop and
evaluate several PRO domains.42
Classification of Outcomes Measures
Individual symptoms can be measured across various
attributes, including frequency, severity, bothersomeness,
and predictability, among other factors.43 Individual symp-
toms and their attributes can be combined into symptom
clusters. FGID symptoms, in turn, may impact physical, so-
cial, and emotional function, measured in terms of HRQOL.
Finally, the broader illness experience of FGIDs, as
measured by HRQOL instruments, may have downstream
impacts on FGID-related resource utilization and work
productivity.44 Health utility measures, like the EQ-5D, are a
specialized form of PROs that inform cost utility
analyses—another key resource utilization outcome.45
Developing Patient-Reported Outcomes
for Clinical Trials: Guidance From
Regulatory Agencies
Regulatory agencies have developed detailed guidance
for how to validate and document developmental steps for a
PRO. Examples include the FDA guidance on Patient-
Reported Outcome Measures40 and guidance for IBS regis-
tration trials.2
TREATMENT TRIALS
PRO development should begin with a systematic review
of the literature to build a conceptual framework for
developing a new PRO. The framework should be expanded
based on direct input from representative patients of the
target population. Both the FDA and EMA emphasize
rigorous qualitative methods in conducting patient focus
groups or interviews. PRO developers next focus on creating
the individual items for the instrument, in easily understood
language. The FDA and EMA generally recommend no more
than 1-day recall periods for a PRO. Investigators must next
conduct quantitative empirical testing of the instrument in a
representative sample of patients, including both cross-
sectional and longitudinal psychometric testing. The provi-
sional PRO should undergo exploratory factor analysis to
evaluate the quantitative structure of the instrument, anal-
ysis of convergent validity by evaluating the relationship
with legacy instrument of relevance, and also measurement
of internal consistency and reliability of each PRO subscale.
Finally, the investigators must calculate the MCID for each
scale in the PRO.
Gastroenterology Vol. 150, No. 6
US Food and Drug Administration Interim
Guidance for Irritable Bowel Syndrome
Clinical Trial Outcomes
Recognizing that it would take time before an FDA-
qualified IBS PRO could be developed, the FDA agreed to
allow interim end points for registration trials until a final
PRO is developed. The interim guidance, published in May
2012, suggests the following co-primary end points:
abdominal pain and abnormal defecation. The standard 11-
point numeric rating scale should be used to measure
abdominal pain in IBS. For abnormal defecation, the FDA
recommends measuring stool frequency for IBS-C trials, and
stool form measured using the Bristol Stool Form Scale
(BSFS) for IBS-D trials. Using the tools of the numeric rating
scale and the BSFS, the FDA recommends specific IBS
responder definitions, which is largely followed by the
EMA.3
The FDA interim guidance for IBS trials has significant
limitations: Different inclusion criteria and different end
points are recommended for trials of IBS-C vs IBS-D, and
neither inclusion criteria nor end points are specified for
patients with IBS with constipation and diarrhea (IBS-M).
These limitations appear to restrict the target populations
that can be studied and the likely indications for drugs that
could be approved.
Binary Outcomes Measures
Many high-quality FGID RCTs have employed a binary
PRO end point, such as “adequate relief,” “satisfactory re-
lief,” or “considerable relief,”46 which provide a dichoto-
mous responder status (yes/no relief). Binary end points
are easy to administer and straightforward to interpret.46,47
Previous systematic reviews and the Rome III guidance
supported the use of binary end points as a standard for IBS
and FGID clinical trials.46–48 However, the FDA currently
discourages the use of these binary end points in clinical
registration trials, based on concerns about the possibility
that a clinical response with a binary end point may depend
on baseline severity, may not detect MCIDs, and may lack
capacity to track key illness domains or discriminate be-
tween clinical disease subgroups. Nevertheless, a working
party, which analyzed patient-level data from 12 existing
clinical trials in 10,000 patients, showed that the binary
response demonstrated excellent construct validity across a
wide range of variables and was able to detect MCIDs in key
bowel symptoms.49
Integrative Symptom Questionnaires
The IBS Severity Scoring System50 and the Functional
Bowel Disease Symptom Index51 are 2 well-validated
symptom questionnaires that integrate several compo-
nents of IBS symptoms into a single score. The IBS Severity
Scoring System instrument, a widely used PRO for IBS
clinical research studies, incorporates pain, abdominal
distention, bowel dysfunction, and HRQOL to estimate
overall patient illness severity. The Functional Bowel Dis-
ease Symptom Index51 also includes the resource utilization
variable—number of physician visits. However, neither
May 2016
meets current psychometric EMA or FDA standards for a
qualified PRO for clinical trials. Functional dyspepsia trials
have used several outcome measures, with varying degrees
of validation, but none meets all the FDA and EMA end point
criteria for registration trials.52
Pictograms
Verbal symptom descriptors are used in most PRO in-
struments to evaluate symptom patterns and severity in
FGIDs.2,36,52 Pictorial representations have been proven to
be effective in improving comprehension and recall of new
information.53 The use of pictograms to evaluate FGID is
being examined and in functional dyspepsia shows potential
to improve concordance between the clinician’s and pa-
tient’s evaluation of symptom pattern and severity
(Figure 1).54 The impact of cultural context on interpreta-
tion and acceptability of pictograms needs evaluation.
Measuring Abdominal Pain vs Discomfort
The Rome criteria have historically combined “pain” and
“discomfort” into the same symptom complexes. Abdominal
pain is a defining characteristic for many FGIDS and an
important driver of symptom severity, HRQOL decrements,
and health care resource utilization.55 FGID pain is typically
measured as severity, using the previously discussed numeric
rating scale, but less is known about the impact of other pain
attributes, including frequency, constancy, recency, duration,
predominance, predictability, speed of onset, and its relation
to bowel movements. Although past clinical trials have used
PROs that group pain and discomfort together,46,49 the sep-
aration between pain and discomfort is inconsistent across
patient groups, and discomfort often refers to a range of
symptoms, such as bloating, gas, fullness, flatulence, sensa-
tion of incomplete evacuation, and urgency. It is
Figure 1. Three pictograms depicting the patient experience of abdominal bloating and distension.
Design of Treatment Trials for FGIDs 1475
recommended that pain be measured separately from
discomfort, and that the type of nonpainful symptom be
specified.
Measuring Bloating
Bloating is reported by up to 31% of the general popu-
lation,56,57 and is also very common among patients with
FGIDs. The feeling of bloating should be distinguished from
visible abdominal distention, as they do not always over-
lap.43 The use of pictograms has been recommended to
express bloating more accurately.
Measuring Stool Frequency and Form
Stool form and frequency are now part of FDA and EMA
end points for IBS clinical trials. The BSFS is used as a vali-
dated measure of stool form that also correlates with intes-
tinal transit time.57 The BSFS has reasonable face validity for
patients and has improved the reliability of patient reports
on stool consistency. However, there are important limita-
tions of the BSFS, including occurrence of multiple BSFS
forms within the same bowel movement and the difficulty to
determine the “start” and “end” of a bowel movement.
In current constipation trials, and supported by FDA,
stool frequency is measured in a diary using terms of (1)
bowel movement, (2) spontaneous bowel movement
(without need for manual maneuvers or rescue laxatives),
and complete spontaneous bowel movement (adds a sen-
sory aspect in that the patient must experience a full evac-
uation without the residual feeling of retained stool).
Measuring Bowel Urgency
Bowel urgency is also a bothersome symptom that can
undermine HRQOL in patients with FGIDs like IBS55 and
fecal incontinence.56,58 The term urgency in IBS-D is
TREATMENT TRIALS
 1476 Irvine and Tack et al
multifaceted, and includes attributes like frequency, in-
tensity, interference, and fluctuation, which may need to be
taken into account when creating a PRO.
Health-Related Quality of Life Questionnaires
HRQOL is a type of PRO that captures biopsychosocial
health rather than individual symptoms. HRQOL is usually
measured with patient questionnaires or instruments that
collect data across several areas of health, including phys-
ical, psychological, and social functioning. HRQOL in-
struments are generally classified as either “generic,” which
measure HRQOL across many different conditions or pop-
ulations; or “disease-targeted,” when they measure HRQOL
in 1 or more specific conditions.59 Examples of the former
include the Short Form-36 Health Survey60 and the Sickness
Impact Profile.61 Disease-targeted HRQOL instruments
appear to be more responsive than generic HRQOL in-
struments to treatments for specific diseases. More than
110 disease-targeted HRQOL instruments were developed
in gastroenterology and cover a range of FGIDs.62 Of the
multiple disease-targeted instruments in IBS, the Irritable
Bowel Syndrome Quality of Life questionnaire63 has the
most extensive data supporting its validity.
Data Collection Strategies
Both the FDA and the EMA recommend the use of daily
diaries to assess the interim primary symptom outcomes in
IBS, while specific PROs are being developed. Most likely,
this recommendation can also be extended to other FGIDs
for which no guidelines have been produced to date. The use
of daily assessment serves to minimize recall bias and
avoids influence by the presence of the investigator.
Symptom ratings can be performed at a fixed time (eg,
bedtime), or at the time when symptoms actually occur. The
FDA suggests using an interactive voice response or per-
sonal digital assistant to assure accurate data collection
because concern has been raised that paper diaries may be
retrospectively completed just prior to a visit.64,65 A number
TREATMENT TRIALS
of secondary outcome variables, such as QOL question-
naires, use a longer retrospective recall period, and need to
be collected only intermittently during the course of a trial.
More recently, real-time capturing of symptom occurrence,
using electronic applications on hand-held devices, has the
potential to provide more accurate information on actual
onset of symptoms and their time course. However, patient
compliance is crucial and the gain over daily diaries
completed at a fixed time of day needs to be proven.
Adverse Events and Safety Monitoring
It is important to report all adverse events found in
treatment trials, as new or unexpected side effects may be
encountered when testing new therapies. An extension of
the Consolidated Standards of Reporting Trials (CONSORT)
statement66,67 encouraged the use of the term harms rather
than safety. If the collection of harms data is a key trial
objective, this fact should be reflected in the title and ab-
stract, as well as the body of the article. The methods section
should also clearly define how adverse events were
Gastroenterology Vol. 150, No. 6
measured. Details of individual adverse events, including
impact and severity, are needed to allow pooling across
trials to allow calculation not only of number needed to
treat, but also of number needed to harm.
Analysis and Data Reporting
Consolidated Standards of Reporting
Trials Guidelines
The original CONSORT statement, first published in
1996, was developed to improve the quality of reporting of
2-group, parallel RCTs.66,67 The latest iteration, the CON-
SORT 2010 Statement,68 re-emphasized the importance of
clearly and transparently reporting the reason the study
was undertaken, and how it was carried out and analyzed. It
includes a 22-item checklist, including key elements of sta-
tistical reporting to which investigators should adhere,67
and a flow diagram with 4 sections (ie, enrollment, alloca-
tion, follow-up, and analysis). Many journals now require
that manuscripts describing clinical trials conform to the
CONSORT guidelines.
Primary Efficacy Analysis
Defining minimally clinical important differences
and responder definitions. In general, a study should
have 1 and no more than 2 primary outcome measures.67
The FDA has published guidance on trial design, end
points, and responder definitions for the treatment of IBS.2
The most recent update of the EMA guidance follows the
same principles.3 The primary statistical analysis should
focus on the chosen primary outcome measure(s), and the
result of this planned analysis determines whether or not
the study has a positive result in support of a new
treatment.
Although the main outcome often is reported as a
comparison between the end of treatment and baseline
observations, it is also important that data are provided
describing how patients changed throughout the course of
the study. When 2 primary outcome variables are included
in the trial, the investigators should specify in advance
whether the trial is positive if only one of the outcome
measures is significant, or if they require that both be
significant. If significance of any primary outcome will
provide evidence for efficacy of the treatment, the analysis
should adjust for multiple comparisons.69 For all outcome
measures, the estimated effect of the intervention (differ-
ence between active and placebo treatment) and a 95%
two-sided confidence interval should be included.70 Sta-
tistically significant differences between study groups can
also be expressed using a P value (actual values). The
reciprocal of the therapeutic gain can also allow compu-
tation of the number of patients needed to treat to
encounter a patient who will experience a clinical
benefit.71
The statistical analysis should be based on an intention-
to-treat principle, which includes all patients randomized to
treatment.72 Dropouts can be considered treatment non-
responders, or the last observation of the primary outcome
May 2016
variable that was available can be carried forward. Both
approaches should be examined to test for differences in
results. Many studies also report a per-protocol (all patients
who followed the protocol) or an all-patients-treated (all
patients who received treatment after randomization)
analysis. These analyses may provide insight as to whether a
treatment works under optimal conditions but cannot
replace the intention-to-treat analysis.
In prespecified analyses, the effect of potential modi-
fiers such as sex, age, duration, or severity of disease, and
presence of psychological stress can be assessed using a
logistic regression analysis, where the binary dependent
variable represents the a priori specified definition of a
responder.73
Analysis of secondary outcome measures and
subgroups. It is recommended that changes in each of the
symptoms that comprise the entry criteria be analyzed by
intention to treat and reported. This may support (or refute)
the direction and magnitude of the interventional effect on
the primary outcome measure. Investigators sometimes
include a large number of secondary variables to identify
predictors of response or to explore other possible effects of
the intervention unrelated to the primary hypothesis. In
such cases, adjustment for repeated testing is needed, or the
intestiagors may use descriptive rather than inferential
statistics, or they may choose a conservative a level (eg, .01)
to protect against type I error without unduly inflating the
type II error rate.
Exploratory subgroup analyses are commonly per-
formed in trials addressing the effectiveness of therapies for
patients with FGIDs. This practice is controversial and some
researchers question its validity,67,74–76 particularly when
undertaken after initial evaluation of the dataset (post-hoc
subgroup analysis). The test of interaction is the most
appropriate type of subgroup analysis.76 Specific plans to
present and analyze harms data should be clearly described,
Figure 2. Elements of a
sample size calculation
including Type I and Type
II error.
Design of Treatment Trials for FGIDs 1477
and reported as actual incidence rates and 95% confidence
intervals.77
Sample size and power calculations. The protocol
should clearly specify the assumptions upon which the
sample size calculation was based.78 This includes the
minimum effect size that the trial is designed to detect, a
(type I) error level, the statistical power or b (type II) error
level, and when evaluating changes (differences) in contin-
uous outcomes, the standard deviation of the difference
(Figure 2). Trials have generally been powered to detect
differences between 10% and 15%, at a power of 80% and
an a level of 5%, using a 2-sided test. An allowance for
dropouts should also be made in determining the appro-
priate sample size, and the number and timing of the
dropouts should be reported.
For responder analyses, the protocol should clearly state
what constitutes a patient responder. The study must have
sufficient power to detect a clinically important difference in
the proportion of responders.79,80
Interim analysis and stopping rules. Plans for
interim analyses should be clearly prespecified in the study
protocol, but usually there is no compelling reason to
incorporate specific interim analyses for interventions in the
FGIDs. Unplanned preliminary analyses should be avoided
because premature presentation of results can affect the
further conduct of the trial and can lead to the reporting of
inaccurate observations.81,82 On the other hand, adaptive
clinical trial designs that explicitly allow for study design
modifications based on interim analyses have become
increasingly attractive due to their flexibility and efficiency
in pharmaceutical/clinical development.81–84 Limitations of
these designs include control of type I error rate, minimi-
zation of statistical and operational bias on the estimates of
treatment effects, and the interpretability of the results.84
The FDA provided draft guidance on adaptive design clin-
ical trials for drug and biologic development.85
TREATMENT TRIALS
 1478 Irvine and Tack et al
Interim analyses to assess the futility of continuing a
trial should be overseen by a Data and Safety Monitoring
Board that is independent from the investigators, should
test for equivalence rather than superiority of one treatment
relative to the other, and should use a priori defined liberal
equivalence margins for the effect size.
Noninferiority trials. The design and methods for the
statistical analysis of equivalence and noninferiority trials
can be complex and have not been developed to the extent
seen in superiority trials. The most important design and
analysis aspects are estimating the effect size of the active
comparator based on previous RCTs, selection of appro-
priate noninferiority margins, and determining the sample
size.86 The FDA has published Guidance for Industry Non-
Inferiority Clinical Trials.87
Ethical Issues
All investigational products should receive approval
from local regulatory agencies and all clinical trials should
be approved by local ethical committees before their start.
All patients should sign informed consent before any study-
related procedure, and all personnel involved in clinical
trials should adhere to Good Clinical Practice guidelines and
have recent (last 2 years) evidence of qualification. Most
hospitals and research institutions are also mandating
manuals documenting evidence of training in standard
operating procedures. Clinical trials should maintain a bal-
ance between scientific ambitions and the patients’ interest
in receiving effective therapy without being exposed to risk
or unnecessary evaluations. Adverse events must be moni-
tored and registered throughout the study, and serious
adverse events need to be rapidly reported and evaluated
for their relationship to the investigational treatment. For
the placebo-controlled study phases in which patients might
receive placebo or a treatment of uncertain therapeutic
value for longer periods, rescue medication should be
offered whenever possible. Patient benefit for participating
in trials may increase when an open-label follow-up treat-
TREATMENT TRIALS
ment can be offered after the controlled study phase.
Many studies offer financial compensation to partici-
pating patients for the time lost due to study visits. These
incentives, and other coverage of expenses (travel, food),
should be of reasonable magnitude to prevent patients from
enrolling in a study purely for financial reasons. Similarly,
financial compensation to physicians or institutions for
participating in clinical trials should also be reasonable and
concordant with standards of reimbursement based on
resource utilization or time commitment.
Recommendations for Future Research
Several issues that should be addressed with future
research include:
1. Examining and minimizing the magnitude of placebo
effects
2. Creating and validating measures of expectancy for
FGIDs (placebo, nocebo, and precebo)
Gastroenterology Vol. 150, No. 6
3. Assessing the natural history of FGID to determine
the appropriate duration of acute and long-term RCTs
4. Extending follow-up after RCTs to determine the
durability of interventions.
5. Further elucidating the characteristics of IBS-M
6. Developing PROs for IBS-M
7. Developing PROs, observer-reported outcomes and
pictograms for pediatric trials in FGID
8. Establishing normal bowel habit ranges in children
by age and sex
9. Assessing whether a 1-day recall period for out-
comes is appropriate
10. Assessing whether the current FDA and EMA guid-
ance for primary outcomes (co-primary outcomes)
for IBS are optimal or other outcomes (including
binary outcomes) are also valid
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accom-
panying this article are available online only with the elec-
tronic version of the article. Visit the online version of
Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.010.
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Reprint requests
Address requests for reprints to: Jan Tack, TARGID, University of Leuven,
Herestraat 49, 3000 Leuven, Belgium. e-mail: jan.tack@med.kuleuven.be.
Conflicts of interest
The authors disclose no conflicts.
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 Gastroenterology 2016;150:1481–1491

Development and Validation of the Rome IV Diagnostic

Questionnaire for Adults
Olafur S. Palsson,1 William E. Whitehead,1 Miranda A. L. van Tilburg,1 Lin Chang,2
William Chey,3 Michael D. Crowell,4 Laurie Keefer,5 Anthony J. Lembo,6 Henry P. Parkman,7
Satish S. C. Rao,8 Ami Sperber,9 Brennan Spiegel,10 Jan Tack,11 Stephen Vanner,12
Lynn S. Walker,13 Peter Whorwell,14 and Yunsheng Yang15
1
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 2Center for Neurobiology of Stress, David Geffen
School of Medicine, University of California, Los Angeles, California; 3Division of Gastroenterology, University of Michigan
Health System, Ann Arbor, Michigan; 4Mayo Clinic, Scottsdale, Arizona; 5Feinberg School of Medicine, Northwestern
University, Chicago, Illinois; 6Harvard Medical School, Boston, Massachusetts; 7Lewis Katz School of Medicine, Temple
University, Philadelphia, Pennsylvania; 8Digestive Health Center, Medical College of Georgia, Georgia Regents University,
Augusta, Georgia; 9Kibbutz Farod, D. N. Bikat Bet Hakerem, Israel; 10Mt. Sinai Medical Center, Los Angeles, California; 11KU
Leuven Center for GI Research, Leuven, Belgium; 12Division of Gastroenterology, Kingston General Hospital, Kingston, Ontario,
Canada; 13Department of Pediatrics, Adolescent Division, Vanderbilt University Medical Center, Nashville, Tennessee;
14
University Hospital of South Manchester, United Kingdom; and 15Chinese PLA General Hospital, Beijing, China

The Rome IV Diagnostic Questionnaires were developed to
screen for functional gastrointestinal disorders, serve as
inclusion criteria in clinical trials, and support epidemio-
logic surveys. Separate questionnaires were developed for
adults, children and adolescents, and infants and toddlers.
For the adult questionnaire, we first surveyed 1162 adults
without gastrointestinal disorders, and recommended the
90th percentile symptom frequency as the threshold for
defining what is abnormal. Diagnostic questions were
formulated and verified with clinical experts using a
recursive process. The diagnostic sensitivity of the ques-
tionnaire was tested in 843 patients from 9 gastroenter-
ology clinics, with a focus on clinical diagnoses of irritable
bowel syndrome (IBS), functional constipation (FC), and
functional dyspepsia (FD). Sensitivity was 62.7% for IBS,
54.7% for FD, and 32.2% for FC. Specificity, assessed in a
population sample of 5931 adults, was 97.1% for IBS,
93.3% for FD, and 93.6% for FC. Excess overlap among IBS,
FC, and FD was a major contributor to reduced diagnostic
sensitivity, and when overlap of IBS with FC was permitted,
sensitivity for FC diagnosis increased to 73.2%. All ques-
tions were understandable to at least 90% of individuals,
and Rome IV diagnoses were reproducible in three-fourths
of patients after 1 month. Validation of the pediatric
questionnaires is ongoing.
Keywords: Sensitivity; Specificity; Functional Gastrointestinal
Disorder; Irritable Bowel Syndrome; Functional Constipation;
Functional Dyspepsia.
and to accomplish this they sometimes develop complex
diagnostic algorithms and combine requirements for lab-
oratory evaluations with symptom criteria. However,
there is also a need for a questionnaire that translates the
diagnostic criteria into questions that are understandable
to most patients, in order to enable standardized diag-
nostic assessment of individuals. Consequently, the Rome
Foundation appointed a Questionnaire Development
Committee (QDC) of individuals with expertise in test
development to develop a patient questionnaire that in-
corporates the Rome diagnostic criteria. These questions
can be used as inclusion criteria in clinical trials, as case
definitions in epidemiological surveys, or for clinic
screening.
The mandate of the QDC was to develop the Rome IV
Diagnostic Questionnaire for Adults based on the new Rome
IV criteria and to assess its performance with respect to
understandability by patients, test
retest reliability,
concordance with independent diagnoses by experienced
clinicians, and ability to discriminate patients with the 3
most common FGIDs, which are irritable bowel syndrome
(IBS), functional constipation (FC), and functional dyspepsia VALIDATION
(FD), from nonpatient controls recruited from the popula-
tion. Two pediatric questionnaires were also developed by a
QDC subcommittee, but testing of these is still underway
and will not be described here.
The process of developing and validating the Rome IV
Diagnostic Questionnaire for Adults consisted of 5 different
project steps, and these will be described in sequence.

T he Rome working teams, which are composed of

clinical investigators and clinicians who are ex-
perts in the functional gastrointestinal disorders (FGIDs)
Abbreviations used in this paper: FC, functional constipation; FD, func-
tional dyspepsia; FGID, functional gastrointestinal disorders; IBS, irritable
bowel syndrome; OIC, opioid-induced constipation; QDC, Questionnaire
Development Committee; R4DQ, Rome IV Diagnostic Questionnaire.
that affect specific regions of the gut, devise diagnostic
Most current article
criteria for these disorders that are intended for use by
other clinicians and researchers (not patients). Their goal © 2016 by the AGA Institute
0016-5085/$36.00
is to make the criteria as sensitive and specific as possible, http://dx.doi.org/10.1053/j.gastro.2016.02.014
 1482 Palsson et al
Step 1. Survey The Normal Frequency of
Occurrence of Gastrointestinal
Symptoms in the General Population of
the United States to Guide the Rome IV
Working Teams in Defining an
Abnormal Symptom Frequency
The symptoms that the Rome working teams identified
as diagnostic of FGIDs are not pathognomonic for GI disease;
they are symptoms such as abdominal pain, nausea, vom-
iting, and heartburn that also occur occasionally in healthy
nonpatients. These symptoms are only considered clinically
significant and indicative of an FGID if they occur at an
abnormally high frequency. This observation has 2 impor-
tant consequences for the design of symptom-based diag-
nostic questionnaires: (1) the response scales used for
questions about the frequency of symptom occurrence must
have small enough steps to capture clinically significant
differences between individuals, and (2) the thresholds used
to define what is an abnormal frequency of occurrence will
vary for different symptoms because the normal frequency
of occurrence of these symptoms differs.
To address this, the QDC first developed and validated
new response scales for the Rome IV diagnostic question-
naire, with more response steps than the Rome III.1 The
committee then conducted a survey of a nationally repre-
sentative sample of US adults in order to provide the Rome
IV working teams with the data needed to set thresholds for
identifying meaningful, clinically significant deviations from
the normal frequency of occurrence of GI symptoms. A
sample of 1665 US adults stratified by sex (50% males), age,
race, and ethnicity was recruited by a market research firm,
CINT USA, Inc. (Los Angeles, CA) to complete an Internet
survey. After inconsistent responders (identified by 3
repeated survey questions) were eliminated, response sets
from 1277 individuals were retained for analysis.
For the purpose of setting frequency thresholds for
defining what should be considered abnormal, we identified
the 90th percentile for all questions (males and females
combined) and reported these to the committees as rec-
ommended thresholds. We reasoned that using these
thresholds for diagnoses would result in no more than 10%
of healthy subjects being misclassified as patients, and when
VALIDATION
these 90th percentile thresholds were combined for multiple
symptoms used to diagnose a disorder, the specificity could
be expected to be in excess of 90%. In the calculation of
these cutoffs, we excluded subjects who reported having a
prior medical diagnosis of upper GI diagnoses from analysis
of upper GI symptom thresholds, and conversely excluded
those reporting lower GI diagnoses from analysis of lower
GI symptoms.
Figure 1 illustrates how these data were analyzed: The
cardinal symptom defining IBS is the frequency of abdom-
inal pain, and the figure shows a histogram of the frequency
of all responses to the question on abdominal pain. If the
threshold for clinical significance is set at once a week as the
Rome IV Bowel Committee recommended, the proportion of
these population controls who might be misclassified as IBS
Gastroenterology Vol. 150, No. 6
is only 6.7%, indicating that the specificity of this symptom
criterion for IBS diagnosis is 93.3%. Figure 1 also shows
how the specificity of the diagnosis would be impacted if an
alternative threshold for clinical significance were selected,
and it shows that abdominal pain or discomfort is reported
significantly more frequently by females than by males.
Because males have a lower prevalence of abdominal pain
and discomfort than females, the 90th percentile for males
could be set at 2 to 3 days per month rather than once a
week, and the 90th percentile for females occurs once a
week, as is the case for the combined sample. For simplicity,
the QDC recommended that the frequency thresholds for
IBS diagnosis should be based on the 90th percentile for
women and men combined.
A summary report2 on the distribution of symptom
occurrence rates for all the Rome III symptoms was
distributed to the Rome IV working teams together with
recommendations for selecting frequency thresholds for
diagnosis. This report is available as a supplement to this
article. Most of the working teams adopted these
suggestions.
Step 2. Development of the Rome IV
Diagnostic Questionnaire for Adults
The 6 working teams that were tasked with updating the
Rome diagnostic criteria for the FGIDs in each region of the
GI tract were appointed in 2013 and were requested to
complete draft documents, including revised diagnostic
criteria by May 2014. These committees worked by e-mail
and conference calls, and met together for the first time at a
satellite meeting held in conjunction with Digestive Disease
Week 2014. Previous to this, the QDC completed its survey
of the base rates of symptom occurrence in the population
and also revised and validated new, more sensitive response
scales1 for patients to use when reporting their symptoms.
The QDC developed a draft of the Rome IV Diagnostic
Questionnaire (R4DQ) and distributed the questions
appropriate to each region of the GI tract to the chair and
co-chair of the working teams immediately before 3-day
meetings of all the committees in December 2014. The
chair and co-chair of the QDC met with each committee to
discuss how well the draft diagnostic questions embodied
the revised diagnostic criteria.
The QDC’s interactions with the working teams were
iterative: When the working teams revised their diagnostic
criteria based on feedback from the Rome Foundation’s
Editorial Committee, or the critiques submitted by outside
reviewers, the QDC revised the draft diagnostic questions.
After each revision to either the diagnostic criteria or the
diagnostic questions, the QDC asked the committees to again
review the diagnostic questions for consistency with the
diagnostic criteria.
Translatability Assessment
When the QDC was confident that the diagnostic ques-
tionnaire was in a near-final form, it was submitted to the
professional translation company, Transperfect Inc. (New
May 2016
Figure 1. This figure
shows a histogram of the
frequency of occurrence of
“discomfort or abdominal
pain” in the general popu-
lation after excluding
subjects with physician-
diagnosed lower gastroin-
testinal disorders. The
dotted vertical line shows
the recommended
threshold that is 90th
percentile for the com-
bined male and female
sample. MT, shows the
90th percentile for males;
FT, the 90th percentile for
females.
York, NY), for an assessment of the translatability into the
following major languages: Arabic, French, German, Hindi,
Italian, Japanese, Korean, Russian, and simplified Chinese.
This translatability assessment resulted in no changes to the
English version of the questionnaire, but did provide guid-
ance that will be useful to the translators when the Rome IV
questionnaire is translated into these and other languages.
Step 3: Understandability Assessment
In order to assess the understandability of the R4DQ, the
QDC recruited a new US general population sample of 589
adult subjects stratified by sex, age, race, ethnicity, and
years of education to complete an Internet survey. Each
subject was asked to evaluate one-third (approximately 28)
of the total questions. Subjects first answered each symptom
question and were then asked (1) whether the question was
difficult to understand (yes or no) and, if the question was
difficult, (2) what about the question made it difficult to
understand and (3) to give suggestions for alternative more
understandable wording. On average, 1.5 questions of 28
were rated as difficult to understand, and neither older age
nor fewer years of education were associated with the
number of questions rated difficult to understand. Seven
questions were rated difficult by 10% or more subjects, and
these were revised to enhance their simplicity and clarity
based on the suggestions of the subjects. The QDC
concluded that all questions in the final form of the R4DQ
are understandable to >90% of US adults, and that under-
standability is not influenced by age or education.
Final Reconciliation Between the Questionnaire
and Working Team Criteria
After completing the understandability and trans-
latability analyses and making minor changes to the
Rome IV Diagnostic Questionnaires 1483
questionnaire, the chair and co-chair of the QDC committee
again compared the questions with the Rome IV diagnostic
criteria and developed scoring criteria for assigning provi-
sional diagnoses based on questionnaire responses. This
review identified a need for the working teams to make
minor changes to the wording of the diagnostic criteria to
ensure agreement with the questionnaire, and these sug-
gestions were communicated to the working teams and
incorporated into the Rome IV diagnostic criteria.
Step 4. Clinical Validation of the English
Version of the Diagnostic Questionnaire
The preferred method for assessing the accuracy of a
new diagnostic test is to compare classifications based on
the new test to classifications based on an objectively
measured biological marker that is known to be related to
the pathophysiology of the disease. However, this is not
possible for the FGIDs because there is no consensus on
specific pathophysiological mechanisms for them, and no VALIDATION
biomarkers exist that can identify the FGIDs with acceptable
precision.3 Another barrier to validation of symptom criteria
for the FGIDs is that similar symptoms (eg, abdominal pain,
nausea, vomiting, constipation, and diarrhea) are present in
other diseases; examples are inflammatory bowel disease,
gastroesophageal reflux disease, celiac disease, and GI can-
cers. Many view the exclusion of other disease explanations
for symptoms as necessary for the diagnosis of the FGIDs.
In the absence of an objective reference standard for
diagnosis of FGIDs, 2 models of validation have been used4:
In the first model, the reference standard is a negative
endoscopy, alternative imaging study, or laboratory test to
exclude other diseases that could cause the symptoms, and
the measure of diagnostic accuracy is whether the symptom
criteria correctly identify patients who do not have an
 1484 Palsson et al
alternative basis for their symptoms.5,6 The second model
uses positive diagnoses made by experienced clinicians as
the reference standard, and the measure of diagnostic ac-
curacy is whether the symptom criteria are concordant with
the clinical diagnosis.7,8 A third model is a hybrid of the first
2; for example, Vanner et al9 first excluded from consider-
ation any patient with alarm signs or symptoms suggestive
of possible structural disease (eg, blood in stools or family
history of GI cancer) and then examined the agreement of
the Rome II symptom criteria with clinical diagnosis; he
found that the positive predictive value of the Rome II
criteria was 100%.
The QDC utilized a hybrid model for validation of the
criteria for IBS and FD: To be included as a reference case of
IBS, patients must have had a negative endoscopy within the
last 5 years as well as a positive clinical diagnosis; and to be
included as a reference case of FD, patients must have had a
negative upper endoscopy within the last 5 years plus a
positive clinical diagnosis. However, red flag signs or alarm
symptoms, such as blood in stools or a family history of
colon cancer, did not result in exclusion of the patient.
Aims of the Clinical Validation Study
The primary goal of the validation study was to test the
sensitivity of the R4DQ for identifying patients who were
diagnosed IBS, FC, or FD by clinicians. These reference
clinical diagnoses were made by experienced clinicians
before the patients completing the R4DQ, thus guaranteeing
that the reference diagnoses were independent. In addition,
a diagnosis of IBS required that the patient have a colo-
noscopy within the last 5 years, and a diagnosis of FD
required that the patient have an upper endoscopy within
the same time frame. Additional goals of this study were to
assess the test
retest reliability of the R4DQ by having
approximately 30 patients at each site complete the R4DQ a
second time after a 30-day interval, and to examine the
overlap between FGIDs diagnosed by the R4DQ.
Methods
The study was conducted at 9 clinical sites managed by
academic gastroenterologists who are familiar with the
FGIDs and with previous versions of the Rome criteria. Each
site was asked to recruit 100
150 patients, including 25%
VALIDATION
with a clinical diagnosis of IBS, 25% with a clinical diagnosis
of FC, 25% with a clinical diagnosis of FD, and 25% with
other FGID diagnoses. The purpose of concentrating
recruitment on IBS, FC, and FD was to insure that sufficient
numbers of patients could be recruited to have adequate
statistical power to test sensitivity. These are the most
common FGID diagnoses made in clinical practice.
Inclusion/Exclusion Criteria
To participate, subjects were required to have been
diagnosed with an FGID in a medical clinic, have personal
access to an Internet-connected computer or tablet and be
able to use it to answer questionnaires online; be able
read and write English fluently; be at least 18 years old;
have had GI symptoms for at least 6 months; and for the
Gastroenterology Vol. 150, No. 6
subsample of patients with IBS or FD clinical diagnosis,
have had an endoscopy (colonoscopy for IBS, upper GI
endoscopy for FD) with negative findings within the past 5
years. Individuals who had been diagnosed with the
following organic health problems likely to affect GI
symptoms were excluded from participation in the study:
inflammatory bowel disease (Crohn’s disease or ulcerative
colitis), cancer anywhere in the GI tract, current infection
of the GI tract, celiac disease, diabetes mellitus, and/or an
eating disorder. Individuals who had undergone bariatric
surgery or resection of any part of their bowels except
appendix or gallbladder operations were also excluded
from participation.
Enrollment and Questionnaire Completion
The research coordinator at each site reviewed the
medical records for the past 3
6 months to retrospectively
identify all patients assigned a clinical diagnosis of any FGID.
At sites where this retrospective medical record review did
not yield enough patients in all categories, prospective
enrollment of new patients was permitted. Enrollment and
data collection occurred between April 1 and September
15, 2015.
Research coordinators at the clinical sites sent e-mails or
letters to eligible patients explaining the purpose of the
study. Subjects were given the web address where they
could complete the questionnaire and, to ensure that the
database contained no information that could be used to
identify them, they were assigned a randomly selected ID
and a unique password to enter when they took the ques-
tionnaire. When potential study participants accessed the
study website, they first reviewed a study description and
recorded their consent before completing the online study
questionnaire.
The questionnaire included the Rome IV Diagnostic
Questionnaire (from 26 to 86 questions depending on skip
patterns); the Rome III Diagnostic Questionnaire modules
for IBS, FC, and FD (up to 27 questions); 6 demographic
questions; and 6 questions about the frequency and types of
medications used for GI symptoms. They were also asked
about excluded diagnoses to confirm eligibility. Completion
of the online questionnaires required 15 to 20 minutes, and
patients received $25 for participation.
The research coordinator at each site had access on the
study website to a password-protected study-management
interface to view a list of the IDs of all patients from their
site who had completed the questionnaire. The coordinators
were encouraged to contact all subjects who had not
completed the questionnaires within 2 weeks to remind
them to do so.
Research coordinators entered the primary FGID clinical
diagnosis (reference diagnosis) into the website interface
for all subjects who completed the questionnaire. The co-
ordinators also reviewed the medical records of question-
naire completers and abstracted data on all other GI
diagnoses and relevant medical tests, such as endoscopy,
transit study, gastric emptying study, esophageal pH study,
esophageal manometry, barium enema or magnetic
May 2016 Rome IV Diagnostic Questionnaires 1485

resonance imaging of the colon, and fecal stool test for ova/ Results
parasites. A total of 881 patients enrolled and completed the study
The research coordinators randomly selected a subset questionnaire across the 9 sites, but 38 were disqualified
of questionnaire completers with clinical diagnoses of IBS, because they were found not to meet study criteria after
FD, and functional constipation and invited them to com- enrollment, leaving 843 for analysis. Females comprised
plete the questionnaire a second time 30 days after the 76.3% of the 843 evaluable patients, and age ranged from
first completion, for an additional payment of $25. Re- 18 to 81 years (mean 43.6 years). Race/ethnicity distribu-
minders to complete the repeat test were sent by e-mail as tion was 85.3% white, 4.3% black, 4.5% Asian, and 6.0%
needed. other or not disclosed. Among US patients, 8.2% reported
Hispanic ethnicity. Table 1 shows the frequency of all FGID
clinical diagnoses (not Rome IV diagnoses based on the
Data Analysis questionnaire) found in the medical records of the 843
For the primary analysis of diagnostic test sensitivity, patients in the analysis sample.
the data from all clinical sites were pooled. Sensitivity and
95% confidence intervals for sensitivity were computed for
each diagnosis (IBS, FC, and FD) separately. Sensitivity was Sensitivity of the Rome IV Criteria
defined as the proportion of all patients with a primary Columns 1
3 in Table 2 show the sensitivity statistics
clinical diagnosis of the index disorder who fulfilled Rome for the 3 most prevalent FGIDS: IBS, FC, and FD. (The data
IV criteria for the same diagnosis based on questionnaire on specificity in columns 4
5 come from the Three Country
responses. Patients receiving a secondary clinical diagnosis Population Survey and will be discussed later.)
of the index disorder were excluded from the analysis due Irritable bowel syndrome: sensitivity ana-
to a concern that clinicians may vary in the amount of time lysis. The sensitivity of the Rome IV criteria for IBS is
and effort devoted to secondary diagnoses in a busy clinic comparable with levels previously reported for Rome III,4
and may make secondary diagnoses of IBS or FD without but is suboptimal. The QDC examined the impact on diag-
endoscopy, thus causing secondary diagnoses to be less nostic sensitivity of each of the 3 changes made to the Rome
reliable. III criteria:
Specificity, which is defined as the proportion of all 1. The threshold frequency of abdominal pain was made
patients without the index clinical diagnosis who also do more stringent, changing from 2
3 days per month in
not fulfill Rome IV questionnaire criteria for the index Rome III to at least once a week in Rome IV. If the
diagnosis, was not a goal of the analysis of data collected frequency of abdominal pain was relaxed to 2
3 days
from the clinical sites for the following reasons: (1) The
ability to discriminate patients with the index FGID from
patients with other FGIDs is less relevant to the perfor- Table 1.Frequency of All Clinical Functional Gastrointestinal
mance of the diagnostic questionnaire than is the ability to Disorder Diagnoses in the Sample of 843
discriminate true cases from general population controls Gastrointestinal Patients, Including Multiple
because it is known that there is a high degree of overlap Diagnoses for the Same Patient
between FGIDs in specialty medical clinics. (2) The design % of Total
of the study was not appropriate for estimating the ability FGID diagnosis No. of cases sample
to discriminate the index disorder from other FGIDs even in
the medical clinic because the patient sample was not Irritable bowel syndrome 442 52.4
representative of the clinic population; instead, patients Functional constipation 235 27.9
were selectively recruited based on having established Functional dyspepsia 153 18.1
Functional bloating 96 11.4
clinical diagnoses of specific FGIDs. Consequently, we esti-
Functional diarrhea 79 9.4
mated specificity of the Rome IV criteria from a large, Functional abdominal pain 71 8.4 VALIDATION
representative population sample (see Three Country Functional fecal incontinence 55 6.5
Population Survey), which was recruited specifically for Chronic idiopathic nausea 34 4
this purpose. Dysphagia 13 1.5
Secondary sensitivity analyses were performed to assess Globus 11 1.3
Functional heartburn 11 1.3
the influence of symptom frequency thresholds and other
Functional vomiting 9 1.1
specifics of the diagnostic criteria on test accuracy. Addi- Unspecified belching 7 0.8
tionally, the degree of overlap between FGID diagnoses Cyclic vomiting 7 0.8
based on Rome IV criteria was calculated. In this analysis, all Functional chest pain 5 0.6
FGID diagnoses (primary and secondary) recorded in the Proctalgia fugax 3 0.4
medical record were included. Test
retest reliability was Rumination syndrome 2 0.2
assessed for each of the 3 key FGID diagnoses in the study Sphincter of Oddi dysfunction 2 0.2
Chronic proctalgia 2 0.2
by computing percent agreement and k statistics between 2
Aerophagia 1 0.1
administrations of the questionnaire to the same subjects Levator ani 1 0.1
approximately 1 month apart, for each of the 3 primary
diagnoses separately.
 1486 Palsson et al
Table 2.Sensitivity and Specificity of the 3 Most Common Functional Gastrointestinal Disorders
Clinical validation sample
Diagnosis Sensitivity, %
IBS 62.7
FD 54.7
FC excluding OIC and IBS 33.9
FC including OIC and IBS 70.5
CI, confidence interval.
per month and all other Rome IV criteria remained
the same, this would increase the sensitivity of Rome
IV to 69.9%.
2. “Discomfort” was dropped from the key qualifying
symptom, “abdominal discomfort or pain”; Rome IV
requires “abdominal pain.” However, this more
restrictive phrasing did not reduce diagnostic sensi-
tivity: The proportion of patients with a primary
clinical diagnosis of IBS who reported “abdominal
discomfort or pain” at least weekly on the Rome III
pain question was similar to the proportion who re-
ported “abdominal pain” at least weekly on the
equivalent Rome IV question (74.9% vs 78.4%
respectively).
3. Rome III required that pain or discomfort improve
after defecation and that changes in stool frequency
and/or consistency occur “when the pain started.” By
contrast, Rome IV requires only that pain and defe-
cation are “associated” in time or that changes in stool
consistency and frequency are “associated” with
abdominal pain. However, this change did not have a
significant impact on the sensitivity of the Rome
criteria.
To understand the causes of misclassifications in IBS, we
examined which Rome IV diagnoses were assigned by the
questionnaire to the 140 patients who received a clinical
diagnosis of IBS but did not meet Rome IV criteria for IBS.
The most common Rome IV diagnoses were FC (35 of 140),
FD (34 of 140), functional diarrhea (22 of 140), and levator
VALIDATION
ani syndrome (20 of 140). We also tabulated the clinical
diagnoses assigned to 192 patients who met the Rome IV
criteria for IBS but did not receive a clinical diagnosis of IBS
by their physician. The most common clinical diagnoses
(either primary or secondary diagnosis) were FC (95 of
192), FD (58 of 192), functional bloating (27 of 192),
functional abdominal pain (25 of 192), and functional
diarrhea (17 of 192). These data show that the core symp-
toms that combine to diagnose IBS are the ones accounting
for most misclassifications, and they suggest that clinicians
likely base their clinical diagnoses on the predominant or
most bothersome symptom when patients present with the
constellation of constipation, diarrhea, abdominal pain, and
bloating. A significant number of misclassifications also
result from the overlap of FD with IBS.
Gastroenterology Vol. 150, No. 6
Population control sample
95% CI Specificity, % 95% CI
57.8
67.6 97.1 96.6
97.6
46.3
63.1 93.3 92.5
94.0
27.0
40.8 94.5 93.9
95.2
63.8
77.2 93.1 92.5
93.9
Functional dyspepsia: sensitivity analysis. The
Rome IV criteria for unspecified FD had a sensitivity of
54.7% (Table 2). Sensitivity was defined as the proportion
of patients with a physician primary diagnosis of FD who
fulfilled Rome IV criteria for unspecified FD, a Rome IV
diagnosis that requires that the patient meet symptom
criteria for either postprandial distress syndrome or
epigastric pain syndrome. Only patients who had an upper
endoscopy were included in this analysis. It was not
possible to examine the sensitivity of the questionnaire for
diagnosing postprandial distress syndrome and epigastric
pain syndrome because clinicians usually did not distin-
guish between these subtypes of FD.
To understand the causes of misclassifications in FD, we
examined the other Rome IV diagnoses assigned to 63 clinic
patients who received a clinical diagnosis of FD, but did not
meet Rome IV criteria for FD. The most common Rome IV
diagnoses were unspecified functional bowel disorder (20 of
63) and IBS (19 of 63). To further explore the causes of
misclassification, we examined the medical diagnoses
assigned to 308 patients who met the Rome IV criteria for
FD, but did not receive a clinical diagnosis of FD by their
physician. The most common clinical diagnoses (either pri-
mary or secondary diagnosis) were IBS (172 of 308), FC
(102 of 308), functional bloating (37 of 308), and functional
abdominal pain (32 of 308). These analyses suggest that
patients in whom FD symptoms overlap the symptoms of
IBS or constipation are the ones more likely to be
misclassified.
Functional constipation: sensitivity analysis. The
Rome IV criteria for FC require that patients meeting
symptom criteria for opioid-induced constipation (OIC) and
IBS be excluded from the diagnosis of FC. When this is done,
the sensitivity of the Rome IV criteria for identifying clini-
cally diagnosed FC is only 33.9%, which indicates that cli-
nicians are classifying many more patients as FC than are
being classified FC by the Rome IV criteria. However, when
the Rome IV criteria were relaxed to permit patients with
OIC and IBS to be classified as FC if they met the other FC
criteria (ie, when comorbid diagnoses were permitted), the
sensitivity increased to 70.5% (Table 2).
To understand the causes of misclassifications in FC, we
examined which Rome IV diagnoses were assigned by the
questionnaire to the 121 patients who received a clinical
diagnosis of FC but did not meet Rome IV criteria for FC. The
most common Rome IV diagnoses were IBS (84 of 121), FD
May 2016 Rome IV Diagnostic Questionnaires 1487

(67 of 121), proctalgia fugax (28 of 121), and levator ani
syndrome (21 of 121). We also tabulated the clinical di-
agnoses assigned to 55 patients who met the Rome IV
criteria for FC but did not receive a clinical diagnosis of FC
by their physician. The most common clinical diagnoses
(either primary or secondary diagnosis) were IBS (39 of 55),
FD (12 of 55), and functional bloating (10 of 55). These data
show that two-thirds of the misclassifications are due to the
overlap of IBS with symptoms of FC, and the requirement
that a patient meeting criteria for IBS cannot be assigned a
diagnosis of FC.
We infer from this that the clinicians in our study were,
for the most part, not behaving as if a diagnosis of IBS or OIC
rules out a clinical diagnosis of FC. Such behavior is
consistent with statements in the Rome IV Bowel Disorders
chapter that FC and constipation-predominant IBS
frequently overlap and should be seen as parts of a spec-
trum rather than as distinct disorders. This view is also
supported by recent studies showing that the symptoms of
FC and constipation-predominant IBS frequently over-
lap10,11 and, over time, many patients transition back and
forth between these 2 diagnostic categories.11 Therefore, a
major cause of low sensitivity for the FC criteria is that the
Rome IV criteria do not permit FC to overlap with IBS-C and
OIC.
Overlap of Rome IV Diagnoses of Irritable Bowel
Syndrome, Functional Dyspepsia, and
Functional Constipation
Table 3 shows the overlap between Rome IV diagnoses
in the clinical validation study. This is a complex table
because it shows the prevalence of each diagnosis in pa-
tients with each of the other 2 diagnoses and enables the
reader to compare this overlap with the prevalence of the
separate diagnoses. For example, the cell in the second row
of the third column shows that 66.9% (257 of 384) patients
with FD have IBS, which is greater than the prevalence of
IBS in the whole sample (50.7% [427 of 843 patients]).
Conversely, the cell in the third row of the second column
shows that 60.2% (257 of 427) of patients with IBS also
have FD, which is greater than the prevalence of FD in the
total sample (45.6% [384 of 843 patients]). The degree of
overlap among the other combinations of diagnoses shows a
similar excess overlap. This excess overlap in the symptoms
of IBS, FD, and FC is consistent with the sensitivity analyses
shown previously that identified the overlap among the
symptoms of these disorders as a factor that consistently
contributes to lower sensitivity for the diagnostic criteria.
Test
Retest Reliability of the Rome IV Diagnostic
Questionnaire for Adults
A subsample of the clinic patients completed retests with
the diagnostic questionnaire approximately 1 month after
the first administration. Percentage agreement between the
2 administrations was assessed with regard to the 3 key
diagnoses. Only data from the 140 patients who completed
the questionnaire the second time within a range of 20
40
days after the first one were included in the analysis. Mean
time interval between administrations was 31.1 days. The
agreement between the first and second questionnaire
administration for the diagnoses was 75.7% for IBS (k ¼
0.51), 76.4% (k ¼ 0.53) for FD, and 79.2% (k ¼ 0.44) for FC
(k values in the range from 0.41 to 0.60 are considered
indicative of moderate agreement).12
Step 5. Assessment of Specificity,
Prevalence, and Overlap of Functional
Gastrointestinal Disorder Diagnoses in
the Three Country Population Survey
Study Aims
The primary aims of this survey were to estimate the
specificity of the Rome IV criteria for distinguishing patients
with the 3 most common FGID diagnoses (IBS, FC, and FD)
from healthy population controls, to estimate the prevalence
in the population of the FGIDs based on Rome IV criteria,

Table 3.Overlap Between Rome IV Diagnoses of Irritable Bowel Syndrome, Functional Dyspepsia, and Functional
Constipation in the Clinic Validation Study (Irritable Bowel Syndrome and Opioid-Induced Constipation Were Not
Excluded From Functional Constipation in This Table) VALIDATION

IBS FD FC Total sample

(n ¼ 427) (n ¼ 384) (n ¼ 287) (N ¼ 843)

IBS — 66.9a (257/384) 56.0a (161/287) 50.7a (427/843)

FD 60.2b (257/427) — 52.3a (150/287) 45.6a (384/843)
FC 37.7b (161/427) 39.0b (150/384) — 34.0a (287/843)
Total sample 50.7b (427/843) 45.6b (384/843) 34.0b (287/843) 843

Note: Data are presented as % (n/N).

a
Percent of patients with the diagnosis in the column heading who also have the diagnosis in the row heading, for example, in
the second row, third column, 66.9% (257/384) patients with FD also had IBS. This compares with an overall prevalence of IBS
in the total clinical validation sample (column 5) of 50.7%.
b
Percent of patients with the diagnosis in the row heading who also have the diagnosis in the column heading, for example, in
the third row, second column, 60.2% (257/427) patients with IBS also had FD, compared with a prevalence of FD in the whole
sample of 45.6% (row 5).
 1488 Palsson et al Gastroenterology Vol. 150, No. 6

and to assess the overlap of Rome IV diagnoses of IBS, FC, Table 4.Demographic characteristics of the analysis sample
and FD. from the Rome IV Three Country Population Survey

United United
Characteristic States Canada Kingdom Overall
Methods
Qualtrics Inc. (Provo, UT), a global survey research Sample size 1949 1988 1994 5931
company, was commissioned to identify nationally repre- (valid responders)
sentative general population samples of adults based on Sex, %
specific demographic quotas in the United States, English- Female 49.4 49.3 48.9 49.2
speaking Canada, and the United Kingdom. Recruitment Male 50.6 50.7 51.1 50.8
Age groups, %
was stratified based on sex, age, years of education, race, 18
39 y 38.7 39.2 38.9 38.9
and, for the US sample, Hispanic ethnicity. Qualtrics directed 40
64 y 40.5 40.1 40.4 40.4
interested subjects to the study website at the University of 65þ y 20.9 20.6 20.7 20.7
North Carolina at Chapel Hill for survey completion. Years of education, %
The survey included up to 86 R4DQ questions <13 34.6 33.8 37.1 35.2
(depending on skip pattern); up to 27 questions from the 13
16 49.2 44.6 42.0 45.2
>16 16.2 21.6 20.9 19.6
IBS, FC, and FD modules of the Rome III Diagnostic Ques-
Race/ethnicity, %
tionnaire; 15 questions from the Physical Health Question- Asian 1.9 9.1 3.1 4.7
naire13; 8 questions from the SF-8 Health Survey14; 15 Black 20.2 1.8 1.2 6.6
demographic questions; 8 questions on medical history; 4 White 56.7 75.3 83.8 72.0
questions on access to health care; 1 question on diet; and 3 Hispanic 19.1
questions on psychological distress related to GI symptoms. (United States only)
The median completion time for the survey was 19 minutes. Other/mixed 2.1 4.0 1.8 2.6
Missing race informationa 0.0 9.9a 10.2a 6.7a
A total of 6300 respondents completed the survey in the
3 countries, 2100 in each country. Subjects who self-
reported on the questionnaire that they had been diag- a
Race/ethnicity data were collected in the Canadian and UK
nosed with inflammatory bowel disease, celiac disease, or GI samples only after the initial pilot sampling that amounted to
cancer, or who had undergone GI resection except gall- 10% of the total final sample.
bladder or appendix, were excluded from analysis. An
additional 369 (5.9%) who failed data-quality checks were
Results
also excluded, leaving 5931 valid response sets for statis-
Estimates for the population prevalence of the FGIDs and
tical analysis. The demographic characteristics of this anal-
the estimated specificity of a Rome IV diagnosis of each
ysis sample are presented in Table 4.
FGID are given in Table 5.

Data Analysis Overlap Between Irritable Bowel Syndrome,

A primary aim for the Three Country Population Survey
was to estimate the specificity of the Rome IV criteria for
distinguishing patients with the 3 primary FGID diagnoses
(IBS, FC, and FD) from healthy population controls. Those
results are presented in Table 2. For each index diagnosis of
an upper GI disorder, we first eliminated subjects who re-
ported a relevant upper GI medical diagnosis, and then
calculated the proportion of these nonpatient population
VALIDATION
Functional Constipation, and
Functional Dyspepsia
Table 6 shows the overlap among the 3 most common
FGIDs. The overlap among all pairs of FGID diagnoses is 3
6
times the prevalence of these diagnoses in the population.
Development and Validation

controls who did not fulfill the Rome IV diagnostic criteria

for the index disorder. Similarly, for each index diagnosis of
a lower GI disorder, we eliminated subjects who reported a
relevant lower GI medical diagnosis and then calculated the
proportion of these nonpatient population controls who did
not fulfill the Rome IV diagnostic criteria for the index lower
GI FGID. The prevalence estimates (as distinct from speci-
ficity estimates) were performed on all available subjects,
including those with self-reported medical GI diagnoses.
These estimates of specificity and prevalence were per-
formed on the pooled samples from all three countries. A
third aim of the Three Country Population Survey was to
estimate the overlap between the 3 most common FGIDs
(IBS, FD, and FC) in the general population. For these ana-
lyses, subjects with IBS could also be diagnosed with FC.
of the Pediatric Rome IV
Diagnostic Questionnaires
In contrast to the adult questionnaire, where one version
is used to assess all patients, several different assessments
are available for the pediatric population. The Questionnaire
on Pediatric Gastrointestinal Symptoms was first developed
to measure Rome II criteria in children and adolescents
(aged 4
18 years), and updates were made for Rome III.
Questionnaires for both parents and children (aged 10 years
and older) were developed, and evidence exists for their
reliability and validity.15
18 In addition, an infant/toddler
version was developed and tested recently, based on
parental report of infant/toddler symptoms.19 The mandate
of the pediatric subcommittee of the QDC was to update
May 2016 Rome IV Diagnostic Questionnaires 1489

Table 5.Population Prevalence of the Rome IV Functional Gastrointestinal Disorders in the Three Country General
Population Survey

Specificity, %
Diagnosis Subjects, n Prevalence, % (95% CI)

Functional dysphagia 266 4.5 97.1 (96.7
97.6)

Functional heartburn 107 1.8 99.0 (98.7
99.3)
Reflux hypersensitivity 85 1.4 99.3 (99.1
99.6)
Globus sensation 61 1.0 99.1 (98.8
99.3)
Functional chest pain 59 1.0 99.2 (99.0
99.5)
Excessive belching 50 0.8 99.6 (99.4
99.8)
FD 551 9.3 93.3 (92.5
94.0)
Postprandial distress syndrome 454 7.7 94.2 (93.5
94.9)
Epigastric pain syndrome 212 3.6 98.0 (97.6
98.4)
Rumination 202 3.4 97.6 (97.2
98.1)
Chronic nausea and vomiting 80 1.3 99.0 (98.8
99.3)
Cyclic vomiting 71 1.2 99.2 (98.9
99.4)
Cannabinoid hyperemesis syndrome 10 0.2 99.9 (99.8
100.0)
Functional biliary pain 12 0.2 99.9 (99.8
100.0)
Central abdominal pain syndrome 1 0 —
Functional bowel disorder unspecified 752 12.7 88.4 (87.9
89.3)
FC excluding IBS and OIC 374 6.3 94.5 (93.9
95.2)
FC with IBS and OIC 525 8.9 93.2 (92.5
93.9)
IBS 341 5.7 97.1 (96.6
97.6)
OIC 88 1.5 99.2 (98.9
99.5)
FD 323 5.4 95.3 (94.7
95.9)
Functional bloating/distention 51 0.9 99.3 (99.1
99.6)
Proctalgia fugax 318 5.4 96.3 (95.8
96.9)
Levator ani syndrome 101 1.7 99.0 (98.7
99.3)
Fecal incontinence 196 3.3 98.0 (97.6
98.4)

CI, confidence interval.

these questionnaires based on the Rome IV criteria. Reli-
ability and validity testing is currently ongoing, therefore,
the current article will only describe the development of the
questionnaire itself.
The committee followed procedures similar to those
described here for the Rome IV Diagnostic Questionnaire for
Adults, but with important exceptions: First, the new
response scales developed for the adult questionnaire were
not used in the pediatric questionnaires because they are
not appropriate for the cognitive developmental level of
children. For example, percentages can be difficult to un-
derstand and apply by children as young as age 10 years
old. Although the new response scales would be appropriate
for parental report, the committee desired to keep response

Table 6.Overlap Between Irritable Bowel Syndrome, Functional Dyspepsia, and Functional Constipation in the General
Population (Irritable Bowel Syndrome and Opioid-Induced Constipation Not Excluded From Functional Constipation
in This Table)
VALIDATION
Total
IBS FD FC sample
(n ¼ 341) (n ¼ 551) (n ¼ 525) (N ¼ 5931)

IBS — 31.6a (174/551) 20.0a (105/525) 5.7a (341/5931)

FD 51.0b (174/341) — 23.0a (121/525) 9.3a (551/5931)
FC 30.8b (105/341) 22.0b (121/525) — 8.9a (525/5931)
Total sample 5.7b (341/5931) 9.3b (551/5931) 8.9b (525/5931) 5931

Note: Data are presented as % (n/N).

a
Percent of patients with the diagnosis in the column heading who also have the diagnosis in the row heading, for example, in
the second row, third column, 31.6% (174/551) patients with FD also had IBS. This compares with an overall prevalence of IBS
in the total sample (column 5) of 5.7%.
b
Percent of patients with the diagnosis in the row heading who also have the diagnosis in the column heading, for example, in
the third row, second column, 51.0% (174/341) patients with IBS also have FD, compared to a prevalence of FD in the whole
sample of 9.3% (row 5).
 1490 Palsson et al
scales similar for parents and children so that they can be
compared in research and clinical practice. Secondly,
because fewer resources were available for the validation of
the 2 pediatric questionnaires, current validation efforts
focus on comparison of questionnaire diagnoses with clin-
ical diagnoses, and the prevalence of Rome IV symptoms in
a normal sample of US adults. These will be presented in
another publication as data become available.
Discussion
The studies presented here show that the Rome IV
Diagnostic Questionnaire for Adults has adequate sensitivity
and excellent specificity for IBS and FD diagnoses: for IBS,
sensitivity was 62.7% and specificity was 94.5%; and for FD,
sensitivity was 54.7% and specificity was 93.3%. For FC, on
the other hand, the sensitivity of the diagnostic question-
naire was inadequate: sensitivity was 33.9% and specificity
was 93.6%. The poor performance of the diagnostic ques-
tionnaire for FC was related to the Rome IV requirement
that patients meeting criteria for IBS or OIC be excluded
from the diagnosis of FC. When these exclusions were
removed, 70.5% of the patients given a clinical diagnosis of
FC were identified by the questionnaire.
We also showed that the questions on this diagnostic
questionnaire are understandable to at least 90% of US
adults and that comprehension of the questions is not
significantly affected by older age or by limited education.
Diagnoses of IBS, FC, and FD based on the questionnaire
were reliable for three-fourths of clinic patients during a 30-
day interval.
A unique strength of this series of studies was the in-
clusion of secondary analyses to identify the sources of
misclassifications by the diagnostic questionnaire: A major
contributor to reduced sensitivity was revealed to be the
overlap of symptoms related to IBS, FC, and FD. In partic-
ular, these sensitivity analyses suggest that FC and
constipation-predominant IBS are on a continuum. This is
consistent with recent research10,11 and with the opinions
expressed by the Rome IV Bowel Committee, although it
is not reflected in the Rome IV diagnostic criteria for IBS
and FC.
The sensitivity of the Rome IV Diagnostic Questionnaire
for Adults for identifying patients with IBS was also influ-
VALIDATION
enced by the threshold frequency of abdominal pain
required to make the diagnosis. The Rome IV criteria for IBS
appear less sensitive than the Rome III criteria because
Rome IV requires abdominal pain at least once a week, and
Rome III required abdominal discomfort or pain only 2
3
days per month.
This series of studies has several limitations:
1. The symptoms of the FGIDs fluctuate over time,20 and
there was a lapse of unknown duration between the
clinical diagnosis and the time the questionnaire was
completed. Treatment occurred during this interval,
and might have reduced the patient’s symptoms.
Test
retest agreement over 1 month was about 75%,
which could be regarded as the upper limit of
Gastroenterology Vol. 150, No. 6
concordance between the clinical diagnosis and the
diagnostic questionnaire.
2. Another reason perfect agreement between clinical
diagnosis and a questionnaire-based diagnosis would
not be expected is that clinicians are able to consider
additional sources of information, such as physiolog-
ical tests, medical history, and family history, while
the questionnaire-based diagnosis relies exclusively
on the patient’s self-reported symptoms.
3. No effort was made to define the minimum diagnostic
workup at the participating clinical sites except for
the requirement that upper endoscopy was required
to diagnose FD and colonoscopy was required to di-
agnose IBS. Variations in practices between centers
might have resulted in heterogeneity of the reference
diagnostic groups.
4. Some Rome IV diagnoses now require physiological
tests (eg, disordered defecation), exclusion of
structural disease (eg, functional esophageal disor-
ders), physical examination findings (eg, tenderness
in levator ani syndrome), or physician judgment
(eg, whether abdominal pain has a central or a
peripheral cause in central abdominal pain syn-
drome) in addition to symptoms; these disorders
cannot be diagnosed by self-reported symptoms on
a questionnaire. Thus, not all of the Rome IV clas-
sification system can be validated by the study
design used here.
Despite these limitations, the studies described here
show that the R4DQ for adults has adequate sensitivity and
excellent specificity for the diagnosis of IBS, FD, and many of
the other FGIDs. The R4DQ is understandable to 90% of
patients, and diagnoses based on the questionnaire show
good test
retest reliability. The Diagnostic Questionnaire is
also translatable to other languages, and this should make it
possible to carry out cross-cultural and global epidemiologic
studies. Future studies should allow, rather than arbitrarily
excluding, the overlap of symptoms of IBS, FC, and FD and
should explore the implications of this overlap for diag-
nostic classification and treatment.
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Reprint requests
Address requests for reprints to: Olafur S. Palsson, PsyD, UNC Center for
Functional GI & Motility Disorders, 4111 Bioinformatics Building, 130 Mason
Farm Road, Campus Box 7080, Chapel Hill, North Carolina 27599-7080.
e-mail: opalsson@med.unc.edu.
Conflicts of interest
The authors disclose no conflicts.
VALIDATION