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Review

Pathophysiology of irritable bowel syndrome


Gerald J Holtmann*, Alexander C Ford*, Nicholas J Talley

Traditionally, irritable bowel syndrome has been considered to be a disorder with no known underlying structural or Lancet Gastroenterol Hepatol
biochemical explanation, but this concept is likely to be outdated. In this Review we challenge the widely accepted 2016; 1: 133–46

view that irritable bowel syndrome is an unexplained brain–gut disorder. There is epidemiological evidence that, in a *Joint first authors
major subset of patients, gastrointestinal symptoms arise first and only later do incident mood disorders occur. Department of
Additionally, possible mechanisms for gut–brain dysfunction have been identified, suggesting primary gut Gastroenterology and
Hepatology, Princess Alexandra
disturbances might be the underlying cause in a subgroup. Underlying mechanisms that could lead to irritable bowel Hospital Brisbane, and
syndrome include genetic factors (most notably an identified mutation of SCN5A); post-infectious changes, chronic Translational Research
infections and disturbances in the intestinal microbiota; low-grade mucosal inflammation, immune activation, and Institute, University of
Queensland, Brisbane, QLD,
altered intestinal permeability; disordered bile salt metabolism (in 10–20% of cases with diarrhoea); abnormalities in
Australia
serotonin metabolism; and alterations in brain function, which could be primary or secondary factors. Identical (Prof G J Holtmann MD); Leeds
irritable bowel syndrome symptoms are probably due to different disease processes; grouping patients with this Gastroenterology Institute,
disorder into either diarrhoea-predominant or constipation-predominant subtypes promotes heterogeneity. St James’s University Hospital,
Leeds, UK (Prof A C Ford MD);
An approach based on the underlying pathophysiology could help to develop therapies that target causes and
Leeds Institute of Biomedical
ultimately provide a cure for patients with irritable bowel syndrome. and Clinical Sciences,
University of Leeds, Leeds, UK
Introduction We would propose that these emerging disease concepts (Prof A C Ford); Faculty of
Health and Medicine,
Irritable bowel syndrome (IBS) is a functional bowel should form the basis of a future categorisation of IBS
University of Newcastle, NSW,
disorder characterised by chronic or recurrent abdominal subject to pathophysiological symptoms (table 1); to Australia (Prof N J Talley MD);
pain associated with either relief or exacerbation by support therapeutic decision making that targets specific and Division of
defecation, or a change in bowel habit.1 Most patients can disease mechanisms with appropriate treatments. Gastroenterology and
Hepatology, Mayo Clinic,
be classified, according to the predominant stool pattern The current therapeutic approach, aiming to improve
Rochester, MN, USA
they have, into IBS with diarrhoea, IBS with constipation, individual IBS symptoms, is not sufficiently effective (Prof N J Talley)
and those who have both diarrhoea and constipation, since similar symptoms could be due to several causes. Correspondence:
known as mixed-stool-pattern IBS. Prof Nicholas J Talley, University
IBS is one of the most widely recognised functional Defining IBS: one disorder, or many? of Newcastle, Australia, Hunter
Medical Research Institute,
bowel disorders, with more than 10% of the global adult Although IBS is traditionally considered to be a disorder
New Lambton Heights,
population reporting symptoms compatible with the with no known underlying pathological explanation for NSW 2305, Australia
condition in population-based surveys.2 In routine the symptoms that patients report, this concept is nicholas.talley@newcastle.
clinical practice, a diagnosis of IBS is made on the basis probably outdated. Conventionally, IBS is divided into edu.au
of typical symptoms.3 The use of investigations is often subgroups according to the predominant stool pattern
restricted to a selected panel of tests that help to exclude because this categorisation defines treatment options
known organic diseases that present with similar and so, by definition, it is a heterogeneous disorder. We
symptoms, such as inflammatory bowel disease or propose that there are, in fact, several different underlying
coeliac disease. disease mechanisms underlying these subtypes. This
In the past, IBS has been considered to have no concept is strongly supported by the observation that
underlying structural or biochemical basis, although in IBS symptoms can occur in the setting of established
this review we will challenge this accepted model. As a structural—but clinically inactive—gastrointestinal
result, unlike other organic gastrointestinal diseases, diseases, including inflammatory bowel disease,9 coeliac
treatment of IBS is often targeted towards the disease,10 idiopathic bile acid diarrhoea,11 and microscopic
predominant, or most troublesome, symptom the patient colitis.12 Similarly, patients with duodenal ulcers might
experiences, rather than being based on the underlying not have gastrointestinal symptoms until a complication
pathophysiology.4 As a consequence, treatments are not occurs, and other patients could continue to have
sufficiently effective and the natural history of the symptoms even after healing of the ulcer.13 Thus, factors
disorder in the long term is unchanged by most other than just the structural lesion are probably
therapeutic interventions.5 The prevalence and the poor responsible for the manifestation of symptoms.
response to established therapies for IBS has resulted in Initial research that aimed to explore the underlying
a substantial economic impact.6 Although there is no disease mechanisms of IBS centred on alterations of
excess mortality associated with IBS,7 this disorder has a gastrointestinal motility14 and visceral sensory function.15
considerable effect on quality of life, and IBS can However, despite the fact that alterations in both motor
induce serious disability.8 As a consequence, a better and sensory function are likely to be relevant for the
understanding of the potential underlying mechanisms manifestation of symptoms, the focus of subsequent
involved in the generation of symptoms is crucial for research has shifted towards possible explanations for
improving effectiveness of future treatments. these abnormalities. The role of several mechanisms has

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Review

Mechanism Causes Prevalence in patient Relevance in clinical setting


cohorts
Central processing of Alteration of the central processing of Minimal systemic inflammation, or effects of 10% to 20% Lowered sensory thresholds may be a key
afferent stimuli afferent stimuli (including visceral early childhood trauma, may alter the central driver for symptom manifestation
afferents) processing of afferent stimuli
Anxiety and depression Alteration of the central processing of Multifactorial, activation of immune systems Up to 75% Influences health care-seeking behaviour, can
afferents (including visceral) seems to aggravate underlying disturbances be targeted with antidepressants
Post-infectious IBS Post-inflammatory neuroplastic Exposure to pathogens causing alterations of 10% to 20% Prevention of infections, early intervention in
changes, visceral hyperalgesia gut permeability, inflammation affected patients (eg, antibiotics), potentially
primary prevention with probiotics
Post-inflammatory IBS As for post-infectious A chronic or transient immune process 10% to 30% of patient with Post-inflammatory IBS symptoms need to be
(ie, controlled by appropriate immune inflammatory bowel distinguished from symptoms that are due to
modulation) has triggered the same or similar disorders in remission occult activity of inflammatory bowel disease
events that cause symptoms in
post-infectious IBS
Bile acid Most likely genetically determined Type 2, or idiopathic, likely due to a genetic Up to 20% of patients with Targeted treatment (binding of bile acids)
malabsorption alteration of the function of the apical defect in the apical ileal bile acid transporter severe IBS-D symptoms available
ileal bile acid transporter
Visceral hyperalgesia Central and peripheral mechanisms Can occur after infections or inflammation 30% to 40% Can be assessed in specialised laboratories.
implicated (post-inflammatory visceral hyperalgesia), Treatment effects with psychotropic drugs
or CNS-mediated visceral hyperalgesia after may be explained by alterations of visceral
psychological trauma can occur sensory function
Mutations in SCN5A SCN5A encodes the α-subunit of the Genetically determined 2% of all IBS patients, but Relevant for constipation predominant IBS.
voltage-gated sodium channel NaV1.5 only 31% of patients with The anti-arrhythmic mexiletine has the
SCN5A mutations have IBS potential to “cure” symptoms in these patients
symptoms

Table 1: Factors relevant for the manifestation of IBS symptoms and frequency of these features in patients populations

been explored, including disorders of the gut–brain axis; suggest that by reversing this gastrointestinal dysfunction
diet; genetic factors; infections and disturbances in the (which is achievable since the gut is more accessible than
intestinal microbiota; low-grade mucosal inflammation, the brain) there is the potential to improve or even reverse
immune activation, and altered intestinal permeability; mood and gut dysfunction.
disordered bile salt metabolism; abnormalities in
serotonin metabolism; and alterations in brain function. The role of diet in IBS
Many patients with IBS report dietary triggers, although
Evidence that IBS is a gut–brain disorder often these are not reproduced when re-challenge
IBS symptoms that do not relate to the gastrointestinal occurs with the offending food in a double-blind
tract, most notably anxiety and depression, are highly manner.26 Nevertheless, some foods appear to be
prevalent in outpatient and community samples,16,17 and implicated in the generation of IBS symptoms, and a
these associations are not explained by health-care-seeking change in diet can rapidly alter the microbiome.27 High
behaviour alone. Such observations have led many to amounts of insoluble fibre were reported28 to exacerbate
conceptualise IBS as a primary disorder of brain–gut symptoms among patients with IBS more than 20 years
function,18 or even primary somatisation,19 with the brain ago, but in recent years there has been a resurgence of
driving the gut manifestations, fatigue, and other interest in the role of diet in IBS. Fermentable
complaints. However, there is now emerging epide- oligosaccharides, monosaccharides, and disaccharides
miological evidence from three prospective studies20–22 in and polyols (FODMAPs), which are present in stone
two different countries that in about half of patients, fruits, legumes, lactose-containing foods, and artificial
functional gastrointestinal symptoms arise first and that sweeteners, might exacerbate symptoms in a subgroup
mood disorders develop later, suggesting that primary gut of patients due to their fermentation and osmotic
disturbances might be the underlying driver of the mood effects.29 MRI studies30 show that when FODMAPs such
disorder in at least a subgroup of patients. In an as fructose are administered to healthy volunteers,
independent study23 of IBS and psychiatric disorders, the small bowel distension occurs because of increased
use of structured interviews showed that 40% of patients small bowel water content.
with a mood disorder and 23% of patients with anxiety A proportion of patients with IBS, who have no genetic,
developed these diagnoses after the onset of IBS. Other serological, or mucosal markers of coeliac disease, also
evidence implicates intestinal inflammation,24 the cytokine seem to have improvement in symptoms after the
response,24 and the gut microbiome25 in precipitating such withdrawal of gluten from their diet. These patients are
gut to brain alterations in IBS. If correct, the implications often labelled as having non-coeliac gluten sensitivity.
of these findings are potentially profound, because they In one multicentre double-blind trial,31 140 patients with

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Review

functional gastrointestinal symptoms were given a strict to be linked to IBS and provides strong evidence that
3-week gluten-free diet. After those 3 weeks, those who genes, albeit uncommonly, can directly induce IBS
responded to this diet were asked to continue with the symptoms.
trial, but were randomly assigned to either be re- Swan and colleagues39 assessed the role of single
challenged with gluten or take placebo for another 7 days. nucleotide polymorphisms (SNPs) in genes whose
Among 77 patients who met criteria for IBS, 55 patients expression is known to be altered by acute enteric
(71%) responded to the gluten-free diet during the initial infection, by obtaining rectal biopsy samples from
3 weeks of the study. Of these 55 patients, 53 individuals individuals with IBS with diarrhoea or constipation
(96%) then entered the re-challenge phase of the study, symptoms, patients with IBS after Campylobacter jejuni
and 18 (34%) of the re-challenged patients reported a infection in the previous 6 months, and healthy
symptomatic relapse after gluten ingestion, with a volunteers. The authors reported that SNPs in tumour
corresponding reduction in quality of life. Thus gluten necrosis factor superfamily member 15 (TNFSF15) and
could cause symptoms in a subgroup of patients without genes coding for tumour necrosis factor alpha (TNFα),
evidence for a gluten sensitive enteropathy. which are also known to predispose to inflammatory
MRI studies32 have shown little difference in the effect of bowel disease, were associated with both IBS with
gluten-free or gluten-containing bread on small-bowel diarrhoea and post-infectious IBS. However, this finding
water content in healthy individuals, so gluten might contrasts with those from a previous study,40 which
induce symptoms in people with IBS in other ways. In showed that SNPs in TNFSF15 were more strongly
another randomised trial33 in 45 patients with IBS with associated with IBS with constipation.
diarrhoea symptoms who were given either a gluten-free Chronic stress can modulate sensory and motor
diet or a gluten-containing diet, small-bowel mucosal function, via corticotropin-releasing hormone and
permeability, measured by lactulose and mannitol catecholaminergic signalling, and has therefore been
excretion, was higher in those randomly assigned to implicated in the pathophysiology of IBS. In a study41
receive a gluten-containing diet. Additionally, expression recruiting 111 individuals with IBS and 142 healthy
levels of mRNA encoding tight junction proteins, such controls, the role of SNPs in genes coding for
as zona occludens 1, claudin-1, and occludin, were corticotropin-releasing hormone-related genes was
significantly reduced in mucosal biopsies from individuals examined. The authors examined SNP genotypes
receiving gluten, suggesting that gluten might impair rs28364015 and rs6472258 in corticotropin-releasing
epithelial barrier function. hormone, and rs10474485 in corticotropin-releasing
hormone-binding protein, via direct sequencing and
Evidence for IBS as a genetic disorder real-time PCR, as well as assessing the emotional status
Some investigators34 have reported that IBS aggregates in of participants by use of validated questionnaires.
families, and twin studies35 of IBS have shown higher However, no genetic variation in these SNPs among
concordance in monozygotic twins than in dizygotic people with IBS and healthy controls was noted. The only
twins, suggesting that genetic factors might play a role in positive finding was that patients with IBS with diarrhoea
IBS. A mutation of the SCN5A-encoded voltage gated without the rs10474485A allele had significantly higher
sodium channel, type V (alpha subunit), which is levels of emotional arousal than did those with this allele,
associated with congenital prolonged QT syndrome, has suggesting that polymorphisms in corticotropin-releasing
previously been reported to be associated with abdominal hormone could be linked to the severity of emotional
pain.36 This channel is also found in the interstitial cells abnormalities in a subset of patients.
of Cajal and circular smooth muscle in the human Other investigators have examined the role of genes
gastrointestinal tract. A pilot study37 assessing 49 patients related to immune regulation and epithelial barrier
with IBS who reported at least moderately severe function,42 serotonin signalling,43,44 cannabinoid receptors,45
abdominal pain showed a missense mutation in SCN5A, and bile acid synthesis,46,47 with varying results. However,
leading to a loss of function of this channel in one patient, many of the described studies are hampered by a small
which was not observed in the DNA of 1500 healthy sample size and, to date, most genetic association studies
controls. A subsequent genome-wide association study38 of selected candidate genes in IBS have involved less than
was done in 584 patients with IBS and 1380 healthy 2000 patients. The largest genome-wide association study
controls and then replicated in four independent cohorts. to date in IBS contained only around 5500 individuals,48
It showed that this mutation was present in up to 2% of compared with 30 000–40 000 in some inflammatory
individuals in the study with IBS. A greater proportion of bowel disease cohorts.49,50 Perhaps as a result, a compre-
those with SCN5A mutation met criteria for IBS with hensive meta-analysis from 201551 could not confirm or
constipation than for IBS with diarrheoa. Administration refute a role for most of the SNPs implicated above, other
of the anti-arrhythmic drug mexiletine to one individual than a modest association with the SNP in TNFSF15.
with IBS with constipation led to normalisation of bowel Nevertheless, some of these data suggest that genetic
habit, suggesting a future option for targeted therapy in factors (aside from SCN5A) only play a modest role
this small subgroup of patients. This mutation is the first in IBS.

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Review

A potential explanation for this negative finding is the water containing known gastrointestinal pathogens,
influence of the environment on gene function, leading including norovirus, Giardia lamblia, and C jejuni, the
to activation or inactivation of specific genes that might risk of developing ongoing symptoms consistent with
be relevant to underlying pathphysiology, also known as IBS was increased in those with pre-existing anxiety and
epigenetics. In one study52 that explored genome-wide in younger individuals. There was an inverse correlation
DNA methylation from peripheral blood mononuclear between anxiety scores pre-exposure and CD4-positive
cells in 27 patients with IBS and 23 healthy controls T lymphocytes expressing interleukin 2, and also an
matched for age and sex, with gene expression assessed association between a T-helper-2 cell cytokine phenotype
by quantitative PCR, the link between epigenetic at the time of exposure and the subsequent development
changes in selected genes with clinical traits was tested. of post-infectious IBS suggesting that susceptibility to
The authors used validated questionnaires to assess IBS after an acute enteric infection results from switching
symptoms and mood. Genome-wide DNA methylation on of a T-helper-2 immune-cell response. Similar results
profiling was different in patients with IBS compared have been reported from the Millenium cohort study,58
with healthy controls, with 133 differentially methylated which acquired data from individuals in active military
positions among genes that were linked to oxidative service, and showed that a history of anxiety or depression
stress and neuropeptide hormone activity. Some of the in the setting of acute gastroenteritis increased the risk of
epigenetic changes observed seemed to correlate with subsequent post-infectious IBS. This finding provides
mood scores among patients. These data suggest that not evidence that a biological link exists between psychological
only the genome but also genome-wide DNA methylation, factors and host susceptiblity to infection.
could play a role in the manifestation of IBS. Further adding to the concept that gastrointestinal
infections are implicated in the pathophysiology of IBS
Evidence for a role of infection and disturbances are data from Walker and colleagues.59 In this study59
in the microbiota gastrointestinal symptom questionnaires were adminis-
Acute enteric infections frequently precede the onset of tered to a random population sample of 745 individuals,
IBS, particularly IBS with diarrhoea symptoms, or other who then underwent colonoscopy with terminal ileal
functional gastrointestinal disorders.53,54 A study done in and colonic biopsy sampling. Individuals were classified
rats,55 in which mucosal inflammation was induced as having IBS according to the Rome III criteria,
chemically, suggests that the severity of inflammation and histopathological examination of colonic biopsy
is linked to the severity of subsequent visceral specimens was undertaken. This study showed that
hypersensitivity, which might be one of the underlying 17 individuals had colonic spirochaetosis, of whom
mechnisms for the development of symptoms. six (35%) met criteria for IBS, with a significant odds
Additionally, psychological stress appears to augment ratio for IBS among those with spirochaetosis (3·6,
visceral hypersensitivity in these animal models.56 In 95% CI 1·27–10·11), compared with those without.
support of this observation, when Wouters and Colonic biopsies from those with colonic spirochaetosis
colleagues57 studied risk factors for post-infectious IBS in showed a unique pathology, with increased eosinophils
a cohort of almost 19 000 people exposed to drinking and lymphoid follicles (figure 1).
In rodent models60,61 of post-infectious IBS probiotics
have been shown to modulate visceral hypersensitivity
and muscle hypercontractility, suggesting that the
gastrointestinal microbiota can influence the development
of post-infectious IBS. In a study by Jalanka-Touvinen
and colleagues,62 recruiting patients with IBS with
diarrhoea and post-infectious IBS, patients who, 6 months
after gastroenteritis, either did or did not report bowel
dysfunction, and healthy controls, differences in the
faecal microbiota were analysed with phylogenetic
microarray. The authors were able to separate patients
with IBS from healthy controls by using an index of
micobial dysbiosis and showed that Baceroidetes spp were
increased by 12 times in patients with IBS, although
healthy controls had significantly more uncultured
Clostridia spp. Although the faecal microbiota differed
between patients with post-infectious IBS and healthy
50μm controls, no differences were observed between patients
with diarrhoea symptoms of IBS and those with
Figure 1: Histological presentation of colonic spirochaetosis
Colonic spirochaetosis indicated by blue fringe arrows on haematoxylin and post-infectious IBS, suggesting that they might share
eosin staining and, inset, Warthin Starry staining. common pathophysiologies.

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In one study63 including 13 patients with post-infectious with IBS compared with healthy controls, but there was a
IBS, 19 patients with IBS unrelated to enteric infection, significant increase in bacterial load in patients with IBS.
and 16 healthy controls, the faecal microbiota of those Investigators have subsequently gone on to treat
with post-infectious IBS differed significantly from that patients with IBS with the non-absorbable antibiotic
of both patients with IBS and healthy controls, and there rifaximin and, in a small trial,72 both global symptoms
was reduced diversity of both the mucosal and stool and bloating improved. In two subsequent phase 3
microbiome in post-infectious IBS, compared with randomised trials73 including more than 1200 patients
healthy controls. Reduced diversity was significantly with non-constipated IBS, significantly higher rates of
correlated with both increased numbers of CD8 and relief of global IBS symptoms and bloating was reported
CD4RA-positive intraepithelial lymphocytes and lower in those randomly assigned to receive rifaximin than in
mood, as measured by the hospital anxiety and depression those given placebo. However, the benefit over placebo
score. Similar findings,64 in terms of a reduction was modest, with therapeutic gains of only 8–11%, and
in bacterial diversity and a dysbiosis of microbial none of the individuals in these trials underwent breath
communities, have also been reported in patients with testing to show the presence of small intestinal bacterial
IBS with diarrhoea. However, it is uncertain what is cause overgrowth. Although these data suggest that the
and what is consequence—has the infection changed the gastrointestinal microbiota might play a role in symptom
microbiome or is an altered microbiome the reason why a generation, the small response rate in this study suggests
transient infection causes IBS? that various other factors are involved, or that rifaximin
The dysbiosis reported in some individuals with IBS fails to eradicate the key organisms in most patients.
has been postulated to result in abnormal levels of Effects of targeted alterations of bacteria within the
intestinal fermentation. In a case-control study65 of gastrointestinal tract could provide further evidence that
14 patients with IBS with constipation and 12 sex-matched supports the notion that specific bacteria play a role
healthy individuals, analysis of faecal microbiota revealed within the pathophysiology of IBS. In a rat model74 of
significantly lower numbers of lactate-producing, lactate- visceral hypersensitivity, an effect of rifaximin on the ileal
metabolising, and hydrogen-consuming bacteria in microbiome was observed, with alterations in the
patients with IBS. Assessment of starch fermentation in composition of bacterial communities, and an abundance
vitro showed that the microbiota of patients with IBS of Lactobacillus species. These changes appeared to
produced more sulphides and hydrogen, and less translate into a protective effect against ileal inflammation
butyrate, than those of healthy controls. A larger study66 and impairment in mucosal barrier function when
assessed intestinal fermentation in 114 patients with chronic psychological stress was applied to the rats, in
Rome III-defined IBS and 33 healthy controls, with addition to reduced visceral hypersensitivity. These effects
intraluminal pH measured via wireless motility capsule, were not seen with neomycin, another antibiotic. These
and amounts of short-chain fatty acids in stools. Colonic, issues highlight that not only antibiotics but also some
but not small bowel, pH was significantly lower in probiotics appear to have modest beneficial effects on
patients with IBS than in controls, and this finding was symptoms in patients with IBS.75
consistent across different stool patterns, suggesting
a higher proportion of colonic fermentation in IBS. Evidence for low-grade mucosal inflammation,
However, amounts of short-chain fatty acids were only immune activation, and altered intestinal
significantly reduced in those patients with IBS with permeability
constipation. Others67 have reported that dysbiosis can Numerous studies, summarised in a previous systematic
lead to excess methane production,which can slow colonic review,76 have shown that low-grade mucosal inflammation
transit and might contribute to constipation in IBS. can be identified in some individuals with IBS, if strict
Colonisation of the small bowel by fermenting bacteria, criteria are applied. This concept was first proposed almost
as occurs in small intestinal bacterial overgrowth, has 25 years ago,77 and although in most patients no cause can
also been proposed as a pathophysiological mechanism be found, there is a possibility that either a previous, or
in IBS.68 A group of researchers in the USA69 using previously unrecognised, infection contributes to or is the
lactulose hydrogen breath testing showed a prevalence of cause of this mucosal inflammation. This hypothesis is
presumed small intestinal bacterial overgrowth of almost supported by several studies54,78,79 that show a higher
80% in individuals with symptoms suggestive of IBS. prevalence of symptoms compatible with IBS in individuals
However, other investigators70 have not replicated these with a history of an acute enteric infection than in those
results, despite using similar methods. Additionally, without such exposure, and a population-based study59 in
direct aspiration and culture of jejunal secretions, which colonic eosinophilia was shown in patients with IBS
although rarely used in the clinical setting, is considered with coexisting colonic spirochaetosis. Some studies80,81
the gold standard for the diagnosis of small intestinal have shown increased concentrations of pro-inflammatory
bacterial overgrowth. A study71 that incorporated this cytokines, and also higher numbers of mast cells, which
approach did not detect an increase in the prevalence of are in close proximity to enteric nerve fibres in the
small intestinal bacterial overgrowth among patients gastrointestinal mucosa of individuals with IBS (figure 2).

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As well as histological evidence of mucosal inflammation, Whether these findings reflect genuine patho-
some investigators82 have shown that in patients with IBS, physiological mechanisms, or are random associations
there is an activation of the immune system, reflected by remains unclear. Supernatants from cultured peripheral
increased concentrations of cytokines in the colonic blood mononuclear cells from patients with IBS diarrhoea
mucosa, and an increase in release of pro-inflammatory caused mechanical hypersensitivity when applied to
cytokines from isolated peripheral blood mononuclear mouse colonic afferent nerve endings,86 and this effect
cells, particularly in patients with IBS with diarrhoea.24 was blocked by the TNFα antagonist infliximab.
High concentrations of these cytokines were associated Supernatants from patients with IBS with constipation
with anxiety and depression (figure 3).24,83 Additionally, had no such effect, although those from healthy
other studies84 have shown increased activation of controls inhibited mechanosensitivity, via an opioidergic
B lymphocytes isolated from the blood of patients with mechanism. Analysis of IBS with diarrhoea supernatants
IBS. However, this activation of humoral immunity showed increased amounts of the cytokines interleukin 1β,
has been suggested to be gastrointestinal-specific,85 with interleukin 10, TNFα, and interleukin 6 among others,
microarray profiling identifying enhanced jejunal mucosal and the concentration of these cytokines appeared to
humoral activity in patients with IBS with diarrhoea, associate with the frequency and severity of pain. Work
associated with proliferation and activation of B cells, and from the same group of investigators87 has shown that
immunoglobulin production. The biological markers of peripheral blood mononuclear cell supernatants from
humoral activation appeared to be positively associated healthy controls had greater inhibitory effects on
with bowel movements, stool form, and depression.85 colorectal sensory afferent nerve endings in a mouse
model of visceral hypersensitivity than did those from
patients with IBS. Concentrations of β-endorphin derived
from these peripheral blood mononuclear cells were
lower in patients with IBS, hence their reduced inhibitory
effects compared with healthy controls, suggesting that
an alteration in immune function could cause the visceral
hypersensitivity seen in IBS.
The cause of this altered immune function remains
unclear, but one possible explanation is a defect in the
integrity of the gastrointestinal mucosal epithelial
barrier. Patients with post-infectious IBS were shown to
have increased intestinal permeability, as measured by
use of urinary excretion of lactulose and mannitol,
compared with controls without IBS more than 10 years
50μm ago.88 More studies89,90 in patients with IBS without an
infective aetiology show a subset of these patients also
Figure 2: Immunostaining of colonic mucosa in a patient with irritable have abnormal levels of intestinal permeability, and in
bowel syndrome one of these studies,90 this increase in permeability had a
Increased mast cells in colonic mucosa in the lamina propria in a patient with IBS
(CD117 immunostaining). significant association with anxiety and depression.
Increased density of epithelial gaps has been shown by
confocal laser endomicroscopy in the terminal ileum
600
of patients with IBS, compared with other patients
500 undergoing routine colonoscopy.91 Alterations in tight
junction proteins, such as zonula occludens-1, claudin-1,
400
and junctional adhesional molecules have been reported
TNFα (pg/mL)

300 in patients with IBS,92 and mast-cell degranulation has


also been reported to lead to decreased expression of
200 these tight junction proteins in both the upper and lower
100
r=0·384 gastrointestinal tract, probably via tryptase release.93–95
p=0·030
Of particular relevance to this finding are real-time
0 observations96 in the duodenum of patients with IBS
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
with suspected food intolerance with confocal laser
Anxiety score (HADS)
endomicroscopy; within 5 min of exposure to food
Figure 3: Association between anxiety scores and TNFα concentration antigens intraepithelial lymphocytes increased, epithelial
Association between the release of TNFα from peripheral blood mononuclear gaps formed, and intervillous spaces widened, which
cells and anxiety scores as measured with HADS. HADS=hospital anxiety and
depression score. Figure adapted from Liebregts and colleagues.24 Anxiety is
support the theory that intestinal impermeability can
related to circulating TNFα, suggesting a possible mechanism by which subtle occur in IBS. A disease model has been proposed
intestinal inflammation in IBS might induce or worsen mood disturbance. (figure 4).97

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Evidence for a role of disordered bile acid reticulum-resident protein klotho β, reducing the
metabolism production of new bile acids.98,99 Although abnormalities
Bile acids are produced in the liver, released into the of bile acid metabolism have been recognised for many
duodenum, and undergo enterohepatic recirculation years in patients with terminal ileal Crohn’s disease, after
after reabsorption in the terminal ileum, via the apical terminal ileal resection, and idiopathic bile acid
ileal bile acid transporter. Typically, more than 95% of diarrhoea,100,101 these issues have only been studied in any
bile acids are reabsorbed here, with the rest passing into detail in patients with IBS in the past 10 years.
the colon, and returning to hepatocytes via the portal Cross-sectional surveys102,103 show that up to 20% of
vein, where they are recycled. This recycling leads to patients who meet criteria for IBS with diarrhoea might
stimulation of the nuclear farnesoid X receptor in the have evidence of idiopathic bile acid diarrhoea, shown by
intestinal enterocyte, which induces transcription of 23-seleno 25-homotaurocholic acid retention scanning.
fibroblast growth factor (FGF)-19. The upregulation of In one of these studies,102 treatment of patients with the
FGF-19 feeds back negatively on the hepatocyte via bile acid sequestrant colestipol led to an improvement in
the FGF-4 receptor, mediated via the endoplasmic IBS symptoms. However, there is uncertainty as to

IBS Phyla B Non-IBS Phyla B


Increased permeability Normal function
Inflammation
Cytokine release Phyla C
Phyla C

Phyla A Phyla A

Gas from fermentation by bacteria

Gut epithelium

Bacterial antigen Lamina propria


TNFα Treg
IL5
TH2
IL10
IL13 IL4
IL13

TLR

Degranulation
Serotonin
Mast cell Histamine
Proteases

Nerves Nerves

Muscle fibre Muscle fibre

Symptoms No symptoms

Figure 4: A proposed gut–brain disease model in irritable bowel syndrome


Adapted from Talley and Fodor with permission.97 Different people have distinct gut microbiota; the hypothesis is that the differences set in motion an inflammatory
cascade in those who are genetically predisposed and subject to a specific environmental hit. A new insult (eg, acute infectious gastroenteritis or a food antigen)
could damage intestinal permeability, leading to a cascade of microbes upregulating mast cells through the T-helper-2-cell pathway. Toll-like receptors (TLR) on mast
cells may interact directly with relevant microbes. Mast cells accumulate in the lamina propria and release histamine (which interacts with histamine 1–4 receptors),
proteases (PAR1 receptor), and probably serotonin (5-HT3 and 5-HT4 receptors). Chemical signalling, via receptors, results in neural excitation and smooth muscle
contraction, leading to abdominal pain, abnormal intestino-abdominal reflex responses (that, combined with fermentation by gas-producing bacteria in the lumen,
triggers bloating), and disturbed intestinal transit (manifest as diarrhoea or constipation, or both, depending on the balance of upregulatory and downregulatory
responses). Cytokines and chemokines are released into the circulation inducing extra-intestinal symptoms

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Review

whether bile acid diarrhoea is a cause or a consequence of contain 90% of the body’s total stores of serotonin.108,109
IBS, with rapid transit associated with IBS perhaps Once released, serotonin can activate both intrinsic and
leading to bile acid depletion. Variants in the klotho β gene extrinsic primary afferent neurons, is integral to
have been shown in patients with IBS with diarrhoea,47 gastrointestinal motility, and influences the transmission
and these appear to associate with colonic transit, of information to the CNS. The re-uptake of serotonin by
modulated via SNPs in FGF-4, suggesting that colonic enterocytes is via the serotonin transporter (SERT),
transit and bile acid synthesis are intrinsically linked via where it is broken down to 5-hydroxy-indole acetic
FGF-19, FGF-4, and klotho β. acid (5HIAA), thereby limiting its action. Therapeutic
Assessment of the association between faecal bile acids interventions targeting various 5-HT receptors have been
and symptom subtypes among patients with IBS, successfully tested in IBS, adding further support to the
compared with healthy controls, has revealed that total notion that serotonin is relevant to the generation of
faecal bile acid levels were higher in those with IBS with symptoms in IBS.110
diarrhoea, and lower in those with IBS with constipation.104 Some of the earliest observations111 concerning the
Additionally, faecal bile acid concentrations had an putative role of serotonin metabolism in IBS came from
association with stool number and form. In a smaller studies reporting chronic increases in enterochromaffin
study46 of similar design, faecal bile acids were higher in cells in individuals who developed post-infectious IBS,
patients with IBS with diarrhoea, compared with patients compared with individuals exposed to an acute enteric
with constipation symptom of IBS and healthy controls, infection but who recovered. Subsequently, a study112 that
and concentrations of 7alpha-hydroxy-4-cholesten-3-one measured serotonin concentrations in platelet-depleted
(C4), a marker of bile acid synthesis, were higher among plasma showed reductions in the release of serotonin in
those patients with IBS with diarrhoea, and showed an patients with IBS with constipation after a standard
association with faecal bile acids. In another study105 of meal, compared with post-infectious IBS and healthy
patients with IBS with diarrhoea, markers of bile acid individuals, and a higher peak in postprandial serotonin
synthesis including FGF-19, C4, and faecal bile acids were in post-infectious IBS than in either patients with
measured, and the association between these markers constipation IBS symptoms or healthy controls. Similar
and colonic transit, colonic and intestinal permeability, results were obtained by another group of investigators113
and colonic sensation and tone was studied. A third of in patients with IBS with either diarrhoea or constipation
these patients had high concentrations of faecal bile symptoms and healthy controls under fed and fasting
acids, and these individuals had significantly increased conditions. This study also reported a 5-HIAA/5-HT
intestinal permeability and borderline significant ratio within a normal range in patients with constipation
increases in colonic transit. Almost 25% of patients had symptoms, but a reduced 5-HIAA/5-HT ratio in those
increased amounts of C4, and in these individuals there with IBS with diarrhoea, suggesting that patients with
was an increase in faecal bile acids and a substantial diarrhoea might have reduced serotonin re-uptake, and
increase in colonic permeability. those with IBS with constipation might have impaired
Other investigators106 have replicated these findings, release of serotonin. Furthermore, uptake of serotonin
reporting increased concentrations of bile acids in the by platelets was reduced in patients with IBS with
stool of patients with IBS with diarrhoea, but have also diarrhoea, and expression of serotonin transporter
studied the role of the intestinal microbiota, which mRNA in the duodenal mucosa was also reduced.114
metabolise bile acids. In this study assessing 14 patients The reduced expression of this transporter seemed to
with IBS with diarrhoea and 18 healthy controls, the be associated with duodenal immune activation, with
authors reported that the increase in faecal bile acids was increased numbers of intraepithelial lymphocytes and
associated with a dysbiosis, with significant increases in mast cells observed, and significant increases in
Escherichia coli and reductions in Leptum and Bifidobacteria tryptase release. In one study,115 alterations in serotonin
species. Building on this work, one study107 showed metabolism in 154 patients with IBS did not have an
differences in serum and faecal bile acid profiles and association with gastrointestinal symptoms, or mood.
different patterns of dysbiosis in patients with IBS with However, the technical issues of avoiding contamination
diarrhoea and constipation symptoms compared with from platelet release of serotonin in these studies remain
healthy individuals, suggesting that modification of bile of concern.
acid profiles, perhaps via modulation of the intestinal Genetic factors influence serotonin metabolism.
microbiota could have therapeutic potential in IBS. Polymorphisms in 5-HT receptors, SERT, amd tryptophan
hydroxylase (TPH), the rate-limiting enzyme in serotonin
Evidence for a role of abnormalities in serotonin synthesis, have all been described in patients with IBS,
metabolism but are unconvincing. There have been numerous studies
Serotonin, or 5-HT, is an important neurotransmitter in examining the 5-HTTLPR polymorphism of SERT in
the brain and the enteric nervous system. The intestinal patients with IBS, summarised in a meta-analysis.116
enterochromaffin cells, which function as sensory Overall, when data were pooled from 3443 patients with
transducers of intra-luminal stimuli such as pressure, IBS and 3359 controls without IBS, there was no

140 www.thelancet.com/gastrohep Vol 1 October 2016


Review

association between this polymorphism and IBS, but the has been shown to be aberrant in some individuals,124
LL genotype appeared to be a risk factor for IBS with with abnormalities seen on diffusion tensor imaging in
constipation symptoms in east Asian populations. the white matter in regions of the brain that process this
There are few studies examining the association information.125 The extent of these changes has been
between serotonin metabolism and immune activation, linked to the duration and severity of symptoms,126,127
mucosal inflammation, or intestinal barrier function. suggesting that the brain undergoes structural changes in
Cremon and colleagues117 reported that colonic biopsies response to these stimuli. Rectal balloon distension in
from individuals with IBS show higher numbers of patients with IBS showed increased engagement of
serotonin-positive enterochromaffin cells than did regions of the brain that are concerned with attentional
biopsies from healthy controls, but this proportion was and behavioural responses to both the arrival of, and the
greater in IBS patients with diarrhoea symptoms anticipation of, such stimuli.128–130 There could also be
than in those with constipation symptoms. Mucosal heightened awareness of, or attention to, gastrointestinal
serotonin was also significantly greater among patients symptoms or stimuli, with reductions in the activity of
with IBS in this study, and related to mast-cell counts, areas of the cortex involved in inhibiting or downregulating
and severity of abdominal pain. In a study by Barbaro the response to such stimuli.123
and colleagues,118 interferon gene expression in colonic In another study131 in which anxiety and depression
biopsy specimens from patients with IBS and levels were similar between patients with IBS and healthy
asymptomatic controls was measured by quantitative controls, the activity of the dorsolateral prefrontal cortex
PCR, and the amount of interferon γ was assessed by was impaired during behavioural selection tasks in those
ELISA. The effect of these on SERT expression in with IBS, suggesting that, even if patients with IBS are
Caco-2 cells in vitro was assessed, and the authors not anxious or depressed, they have CNS dysfunction,
showed that the interferon γ gene, its transcription which can make individuals susceptible to stressors.
factor, and interferon γ protein expression were all Early adverse life events, such as psychological trauma
increased in the colonic mucosa of patients with IBS before 18 years of age, can shape adult resting state
and that, in vitro, SERT expression was downregulated connectivity in both male and female patients in the
by interferon γ. Finally, a small study119 including salience/executive (involving the thalamus, insula, and
15 patients with IBS and 15 healthy controls reported anterior cingulate cortex) control network, a brain
that oral administration of serotonin led to higher network that has been implicated in the pathophysiology
concentrations of mucosal 5-HIAA in patients with of central pain amplification.132
IBS, and also a decrease in expression of the tight IBS overlaps with ulcerative colitis and Crohn’s
junction protein occludin. The clinical implications of disease,9 and in patients in stable remission from these
these findings remain to be established. conditions, treatment with anti-TNFα has been shown to
improve visceral sensory function and positive attribution
Evidence for a role of alterations in brain function biases.133 This finding is further evidence that an
The observation from an epidemiological study120 that inflammatory process that originates from the gut could
individuals who have early adverse life events, such as alter central processing of information, including visceral
trauma or abuse, and the fact that psychological therapies afferents. Finally, learned behaviours might also induce
and antidepressants could be effective therapies for the IBS symptoms. For example, a proportion of patients
condition,121 support the concept of IBS being a disorder with IBS show features of pelvic floor dyssenergia,134
of the gut that is driven by brain abnormalities. Studies suggesting that biofeedback might be an effective therapy
that make use of advanced imaging techniques and in these individuals.
analyse differences in brain activity between individuals Overall, there is no doubt that alterations of brain and
with IBS and healthy controls have allowed us to better neural function play an essential role in the onset and
appreciate the key areas of the human brain that could be manifestation of symptoms in at least a subgroup of
involved in IBS. However, the absence of a control group patients. Therefore, the assumption that alterations of
made up of patients with chronic non-gastrointestinal brain–gut, as well as gut–brain, interactions are involved
pain, and shortage of studies identifying whether in the pathogenesis is reasonable, although the disorder
symptoms began with gastrointestinal dysfunction first might not always be initiated in the same organ.
or with psychological distress first, potentially limit
interpretation of the direction of this effect, and raises Implications of pathophysiology for the
the possibility that peripheral processes bring about the development of future therapies
changes in brain function observed. Better understanding of the pathophysiological
Individuals with IBS show reduced inhibitory feedback mechanisms involved in IBS is crucial for the
on the emotional arousal network,122 important for development of future treatments. The clinical
controlling the autnomic modulation of gastro- categorisation of IBS is based on symptoms reported by
intestinal function, and increased activity after visceral the patient. However, symptoms might be due to various
stimulation.123 Central processing of sensory information different underlying mechnisms and symptom-based

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Review

categorisation, when made use of in clinical trials, will translated into clinical practice but, in the future, could
result in pathophysiologically complex and diverse allow more targeted therapies to be developed, ultimately
patient cohorts. This variation is likely to account for the bringing a “cure” to patients with IBS.
obvious heterogeneity and modest therapeutic gains
obtained to date for all pharmacological therapies in Conclusion
IBS. Instead, the underlying pathophysiologies need to There is unlikely to be a single overarching disease model
be specifically addressed to achieve relief of symptoms that accounts for all IBS; rather there are potentially
(table 2). This emerging knowledge remains to be multiple causes (and multiple diseases) that lead to pain
and diarrhoea, or pain and constipation, although many
might share similar pathways that in turn explains the
Proposed treatment phenotypic similarities and variability in symptoms,
Dietary intolerance or High-fibre diet vs fibre withdrawal
including switching between predominant bowel patterns.
deficiency Low-FODMAP diet One attractive model for a major subset postulates that
Gluten-free diet disease begins in the gut. In those genetically predisposed
SCN5A mutation Voltage-gated sodium channel blockers— who have a suspectible microbiome, infections or other
eg, mexiletine
environmental antigens (eg, foods) alter the microbiome
Dysbiosis Probiotics and promote increased intestinal permeability.97,135 The
Dietary alterations
Antibiotics—eg, rifaximin for selected patients presentation of antigens in the mucosa leads to a
Low-grade mucosal Anti-histamine drugs—eg, ebastine T-helper-2 cell response, in turn promoting a subtle
inflammation inflammatory infiltrate and loss of immune homoeostasis,
Increased gut Drugs acting on tight junctions—eg, larazotide or which in some cases leads to recruitment of mast cells
permeability lubiprostone that degranulate. These changes induce, via peripheral
Increased faecal bile Bile acid sequestrants—eg, colestipol or mechansims, gut visceral hypersensitivity and secondary
acids colestyramine
motor abnormalities, and cytokine and intestinal homing-
Reduced faecal bile Drugs acting on the ileal bile acid transporter—
T-cell responses, which could drive increased anxiety and
acids eg, elobixibat
other non-gastrointestinal symptoms, such as fatigue and
Abnormalities of Drugs acting on 5-HT receptors—eg, ramosetron,
5-HT metabolism ondansetron, or prucalopride generalised pains. Yet another subset might develop IBS
through primary abnormalities of the stress pathway,
Table 2: Proposed future pathophysiology based categorisation and
which in turn alters gut permeability and sets off an
treatment of irritable bowel syndrome
immune activation cascade that results in IBS. In other

Central processing of information,


personality traits, anxiety, depression
Acute or chronic stressor Regulation of gut function (motility, sensory secretion)

Genes
Life experiences Visceral afferent function

Antibiotics Gastrointestinal immune system


Control of gut function and nutrient
intake
Environment

Gastrointestinal infections Gastrointestinal microbiome

Diet

Methanogenic flora affecting transit,


bile acid metabolisms

Figure 5: Potential factors that determine the manifestation of irritable bowel syndrome symptoms
Multiple interacting pathways can affect the manifestation of IBS. Environmental factors dominate, but genetic makeup is also likely to be crucial for the onset and
manifestation of symptoms.

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Declaration of interests one or many? Lancet 1999; 354: 936–39.
GJH has received research funding from Bayer Healthcare. ACF has 20 Koloski NA, Jones M, Kalantar J, Weltman M, Zaguirre J, Talley NJ.
received research funding from Almirall and GE Healthcare, speakers The brain-gut pathway in functional gastrointestinal disorders is
fees from GE Healthcare, and served on advisory boards for Almirall. bidirectional: a 12-year prospective population-based study. Gut
NJT has received research funding from Abbott, GI therapies, Janssen, 2012; 61: 1284–90.
Prometheus, Rome Foundation and Salix, and served as an adviser for 21 Jones MP, Van Oudenhove L, Talley NJ. Functional gastrointestinal
Allergan, Adelphi Values, Commonwealth laboratories, GI therapies, disorders (FGIDs) and psychological disorders: strong evidence that
Prometheus, and Yuhan, and speaker fees for Rome Foundation. the link is bidirectional, but psychological distress is more likely to
GJH and NJT have received NHMRC funding for research into precede a new diagnosis of an FGID. Gastroenterology 2012;
functional gut disorders. 142 (suppl 1): S570 (abstr).
22 Koloski NA, Jones MP, Talley NJ. Evidence that independent
Acknowledgments gut-to-brain and brain-to-gut pathways operate in the irritable bowel
We thank Marjorie M Walker for providing figures 1 and 2. syndrome and functional dyspepsia: a 1-year population-based
prospective study. Aliment Pharmacol Ther 2016; 44: 592–600.
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