Alimentary Pharmacology and Therapeutics
Review article: evidence for the role of gut microbiota in
irritable bowel syndrome and its potential influence on
therapeutic targets
H. L. DuPont
St Luke’s Medical Center, and Baylor
College of Medicine, The University of
Texas School of Public Health,
Houston, TX, USA.
Correspondence to:
Dr H. L. DuPont, UT School of Public
Health, 1200 Herman Pressler, E-733,
Houston, TX 77030, USA.
E-mail: hdupont@stlukeshealth.org
Publication data
Submitted 4 November 2013
First decision 18 November 2013
Resubmitted 5 March 2014
Accepted 6 March 2014
EV Pub Online 25 March 2014
This uncommissioned review article was
subject to full peer-review.
ª 2014 John Wiley & Sons Ltd
doi:10.1111/apt.12728
SUMMARY
Background
Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disease with a
substantial social and economic burden. Treatment options remain limited
and research on the aetiology and pathophysiology of this multifactorial
disease is ongoing.
Aim
To discuss the potential role of gut microbiota in the pathophysiology of
IBS and to identify possible interactions with pathophysiologic targets in
IBS.
Methods
Articles were identified via a PubMed database search [‘irritable bowel syn-
drome’ AND (anti-bacterial OR antibiotic OR flora OR microbiota OR mi-
croflora OR probiotic)]. English-language articles were screened for
relevance. Full review of publications for the relevant studies was con-
ducted, including additional publications that were identified from individ-
ual article reference lists.
Results
The role of gut microbiota in IBS is supported by varying lines of evidence
from animal and human studies. For example, post-infectious IBS in
humans is well documented. In addition, certain probiotics and nonsystem-
ic antibiotics appear to be efficacious in the treatment of IBS. Mechanisms
involved in improving IBS symptoms likely go beyond mere changes in the
composition of the gut microbiota, and accumulating animal data support
the interplay of microbiota with other IBS targets, such as the gut–brain
axis, visceral hypersensitivity, mucosal inflammation and motility.
Conclusion
The role of the gut microbiota is still being elucidated; however, it appears
to be one of several important factors that contributes to the aetiology and
pathophysiology of the irritable bowel syndrome.
Aliment Pharmacol Ther 2014; 39: 1033–1042
1033
H. L. DuPont
INTRODUCTION
Irritable bowel syndrome (IBS) is a chronic disease that
may affect up to 20% of the population and has a nega-
tive social and economic impact on patients.1–5 Globally,
the pooled prevalence of IBS is approximately 11% but
varies considerably, both by geographical location and by
diagnostic criteria applied.6 Compared with individuals
without IBS, patients with IBS symptoms report signifi-
cantly reduced health-related quality of life and reduced
work productivity.1–3 Despite the substantial burden of
IBS, treatment options remain limited and research on
the aetiology and pathophysiology of this multifactorial
disease is ongoing.5, 7–9
The gut microbiota has emerged as an important fac-
tor that may contribute to the pathophysiology of IBS.10
Proposed beneficial effects of the gut microbiota include
maintenance of intestinal homoeostasis, maintenance of
peristalsis, intestinal mucosal integrity, and protection
against pathogens through bacterial antagonism and
priming of host immune responses.11, 12 The putative
role of gut microbiota in IBS is supported by several
lines of evidence with varying degrees of literature sup-
port. These include the differences between microbiota
in IBS and non-IBS populations, the development of IBS
after intestinal infection (i.e. post-infectious IBS), the
interesting preliminary data on colonic faecal microbiota
transplantation (FMT) and the efficacy of certain probi-
otics, prebiotics, synbiotics and nonsystemic antibiotics
in the treatment of IBS.13–23
METHODS
This narrative review will discuss the role of the gut mic-
robiota in IBS, including possible interactions with other
pathophysiologic targets in IBS. Articles included in this
review were identified via the PubMed database through
December 2013 using the following search string: ‘irrita-
ble bowel syndrome’ AND (anti-bacterial OR antibiotic
OR flora OR microbiota OR microflora OR probiotic).
The search was limited to English-language articles with
the screening of >800 citation titles and abstracts to
determine potential relevance. Review of more than 200
publications was conducted and included additional pub-
lications that were identified from citations within indi-
vidual articles.
MICROBIOTA AS A TARGET IN IBS
Microbiota in IBS vs. the healthy human gut
Numerous studies have reported differences in the
mucosal and/or faecal microbiota of patients with IBS
1034
compared with healthy controls.13–16, 24–31 For example,
Kassinen et al. extracted bacterial genomic DNA from
faecal samples of patients with IBS (n = 24) and controls
(n = 23); not only was the microbiota significantly
altered in patients with IBS, but the composition varied
depending on the predominant form of IBS.15 These
findings were extended by a study examining the compo-
sition of faecal microbiota in patients with IBS (n = 62)
compared with healthy controls (n = 46), in which
researchers reported significant differences based on glo-
bal and deep molecular analysis with duplicate micro-
array and quantitative polymerase chain reaction.32 In
another investigation, bacterial DNA from faecal samples
of patients with diarrhoea-predominant IBS (IBS-D,
n = 23) were compared with healthy controls (n = 23),
and taxonomic, structural and diversity differences in gut
microbiota were reported. In particular, IBS-D was asso-
ciated with significantly higher levels of Enterobacteria-
ceae and significantly lower levels of Faecalibacterium
prausnitzii vs. healthy controls, which suggests an imbal-
ance of advantageous and potentially harmful intestinal
bacteria.14
Biopsy studies have shown reduced mucosal microbi-
ota diversity in patients with IBS compared with con-
trols,26, 28 and one study showed that the number of
mucosal-associated bacteria in patients with IBS nega-
tively correlated with number of stools passed.30 In a
related study, two patients with IBS-D followed up for
6–8 weeks experienced temporal instability in faecal bac-
teria content that correlated with changes in symptom-
atology.27 A comparison of microbial diversity in
luminal and mucosal niches of patients with IBS-D
(n = 16) and healthy controls (n = 21) identified signifi-
cantly lower faecal microbial biodiversity in patients with
IBS-D.13 Compared with mucosal samples, microbial
diversity was significantly higher in faecal samples in
both patient groups. Interestingly, the difference in bio-
diversity in faecal vs. mucosal samples was greater in the
healthy controls than in patients with IBS-D.13 Reduced
diversity in mucosal-associated bacteria in IBS was also
reported in a second study.26
In contrast, another investigation reported no signifi-
cant differences in mucosal and faecal microbial diversity
in patients with IBS (n = 47).16 This investigation did,
however, support the concept of significantly greater var-
iability in diversity in faecal samples from healthy con-
trols (n = 33) compared with those from patients with
IBS. Variations in study findings may be related to dif-
ferences in patient populations and methods of sample
collection.
Aliment Pharmacol Ther 2014; 39: 1033-1042
ª 2014 John Wiley & Sons Ltd
 Review: gut microbiota and therapy targets in irritable bowel syndrome
Small intestinal bacterial overgrowth (SIBO) has been
associated with some cases of IBS; however, issues such as
inconsistency of study findings, trial heterogeneity, meth-
odological problems, lack of validation of small bowel cul-
ture techniques, lack of validation of breath tests and
concerns regarding bias have led to the clinical relevance
of SIBO in IBS being questioned.18, 19, 33–35 A key issue is
the lack of a gold standard for the diagnosis of SIBO; in
particular, it has been demonstrated that the commonly
used lactulose breath test does not reliably distinguish
patients with IBS from healthy controls.36 Interestingly,
scintigraphy studies suggest that breath testing measures
variations in small bowel transit time occurring in patients
with IBS, rather than the presence of SIBO.37 Therefore,
SIBO may be a comorbid condition in a small subset of
patients with IBS instead of having a direct pathophysio-
logic link to the development of IBS.
Post-infectious IBS
One of the most compelling arguments for microbiota
involvement in IBS pathophysiology is that in some
patients, an acute episode of gastroenteritis precedes the
onset of IBS. A meta-analysis of eight studies reported
an odds ratio (OR) of 7.3 [95% confidence interval (CI):
4.7–11.1] for developing IBS after a gastrointestinal
infection, supporting a link between the two.17 Addi-
tional studies have supported that intestinal infection
was strongly associated with a subsequent emergence of
IBS symptoms. When data from nine prospective studies
were pooled, the OR for developing post-infectious IBS
was 5.9 (95% CI: 3.6–9.5), and the risk remained
increased for up to 3 years post-infection.38 In the
meta-analysis, factors associated with a greater risk of
developing IBS post-infection were younger age; psycho-
logical disturbance (i.e. increased anxiety and/or depres-
sion as observed in four studies reporting Hospital
Anxiety and Depression Scale scores); and the nature of
the gastrointestinal illness (i.e. prolonged fever during
the acute episode, possibly indicative of more severe ill-
ness).38 In a 2013 study, the faecal microbiota of patients
with post-infectious IBS resembled that seen in idio-
pathic IBS-D.29
IBS therapeutic approaches targeting the gut
microbiota
Several treatments, including those with effects on the
gut microbiota, may be potentially useful in the manage-
ment of IBS, based on the current knowledge of IBS
pathophysiology (Figure 1). Although any therapy that
changes intestinal motility may have indirect effects on
Aliment Pharmacol Ther 2014; 39: 1033-1042
ª 2014 John Wiley & Sons Ltd
microbiota, the therapeutic approaches that are known
to directly target the microbiota include FMT, probiotics
and nonsystemic antibiotics.
Faecal microbiota transplantation. Preliminary data in
patients with IBS suggest a favourable response to colo-
nic FMT, which is consistent with the concept that the
gut microbiota has a role in the pathogenesis of IBS. In
one report, 10 patients (n = 5 with IBS) received antibi-
otics and bowel lavage followed by a colonic infusion of
faeces from a healthy donor.21 Examination of stool indi-
cated that FMT resulted in a novel microbiota mainly
composed of the bacterial species from the donor, and
the microbiota composition remained generally stable
over 24 weeks. Although of interest, the published evi-
dence for FMT in IBS is limited, and larger comparative
studies are needed to clarify the potential role for FMT
in the management of IBS.
Probiotics, prebiotics and synbiotics in IBS. The efficacy
of probiotics in IBS has been reviewed in several publica-
tions.39–43 Overall efficacy has been modest, with varia-
tion in strains of probiotics showing potential benefit.40–
42
One area of concern is that many of the marketed
probiotics have not been adequately evaluated in well-de-
signed clinical trials.44 While meta-analyses have been
positive, the pooled relative risks may be influenced by
the limitations of study methodologies and the possibility
of bias.22, 41 Also, given the heterogeneity of both probi-
otic composition and patient populations studied, the
ability to extrapolate findings is limited.22, 45 A 2013
meta-analysis of probiotics in IBS attempted to address
some of these limitations. The authors identified 10 stud-
ies meeting relatively robust criteria for inclusion (e.g.
randomised placebo-controlled design, IBS defined by
Rome criteria).22 As expected, efficacy varied by probiot-
ic species as well as by the IBS symptom evaluated. Also,
not all probiotic strains significantly improved pain, dis-
tention and flatulence, whereas improvements in other
symptoms such as stool frequency, urgency and straining
were not significant, and effects on quality of life were
inconsistent with probiotic therapy.22
The mechanism of action of probiotics in IBS may
extend beyond the modulation of the microbiota composi-
tion.46–48 For example, 4-week administration of a yogurt
containing probiotic, with known benefits in IBS, to
patients with IBS (n = 19) did not alter the composition
of their microbiota.46 However, the authors suggest that
probiotic effects on the functionality of the microbiota
may be of importance.46 In one study, probiotic adminis-
1035
H. L. DuPont

Predisposing host factors

Psychological factors, genetic makeup (serotonin transport genes,
inflammatory pathway genes [GN 3, IL-10, proinflammatory genes])

Small and large Microbiota dysbiosis: Disturbed brain

intestine and the bacterial diversity, altered and central and
intestinal nervous balance of Firmicutes peripheral nervous
and immune system (Veillonella, Lactobacillus, and system and
Faecalibacterium) and spinal excitability,
Chronic low-grade
Bacteroidetes (Prevotella), hypothalamus-
inflammation/immune
Bifidobacteriaceae, pituitary-adrenal
activation involving
Proteobacteria stress response
innate and adaptive
(Enterobacteriaceae)
immune activation
with changes in
toll-like receptor
expression and Abdominal pain,
changes in intestinal Transcription of antimicrobial changes in mood
epithelium proteins, cytokines, and or cognition, anxiety,
chemokines via NF- B pathway, and depression
serotonin release, mast cell
activation, regulatory T cells,
Mucosal neurotransmitters, and
permeability neuropeptides

Infection by enteric pathogen

in postinfectious IBS

Visceral hypersensitivity
and dysmotility

Afferent nerves of vagus nerve,

spinal cord, and autonomic
nervous system

Irritable bowel syndrome Intestinal stasis in

constipation form
Abdominal discomfort and
altered bowel habits

Figure 1 | Pathogenesis of IBS summarising multifactorial disordered pathways, the bidirectional gut–brain axis and
potential targets for therapy. IBS, irritable bowel syndrome; IL, interleukin.

tration has been reported to normalise cytokine levels [e.g.
interleukin-10 (IL-10) and IL-12] in patients with IBS.49 A
pilot neuroimaging study reported that healthy females
(n = 12) who ingested a fermented milk product with
probiotic for 4 weeks had significant reductions in the
activity of brain regions related to a sensory brain network
compared with females who ingested a nonfermented milk
control (n = 11) or had no intervention (n = 13).50
While probiotics have been more widely studied, the
potential benefits of prebiotics and synbiotics (formula-
tions combining probiotics with prebiotics) have also
been evaluated in the treatment of IBS.51, 52 For exam-
ple, the first investigation of a prebiotic (trans-galactooli-
gosaccharide mixture) in patients with IBS was an
18-week study in 44 patients randomly assigned to one
of three treatment groups: group 1 (n = 16), which
received placebo for 6 weeks followed by 3.5 g prebiotic
for 12 weeks; group 2 (n = 14), which received placebo
for 6 weeks followed by 7.0 g prebiotic for 12 weeks;
and group 3 (n = 14), which received placebo for

1036 Aliment Pharmacol Ther 2014; 39: 1033-1042

ª 2014 John Wiley & Sons Ltd
 Review: gut microbiota and therapy targets in irritable bowel syndrome
18 weeks.51 The prebiotic treatment groups had qualita-
tive changes in faecal flora compared with the placebo
group (i.e. relative proportions of Bifidobacterium spp.)
and significant improvements compared with the placebo
group in terms of stool consistency, flatulence composite
scores and patient subjective global assessments.
A synbiotic preparation (n = 132) containing a probi-
otic [viable lyophilised Lactobacillus paracasei B21060
(5 9 109 colony-forming units)] and prebiotic [xylooli-
gosaccharides (700 mg) and glutamine (500 mg)] or a
control formulation (n = 135) was administered for
12 weeks in patients with IBS based on Rome II crite-
ria.52 The synbiotic preparation alleviated IBS symptoms
but failed to demonstrate a significant benefit vs. the
administration of a control formulation, except in a sub-
group of patients with diarrhoea predominance (n = 47;
27 received synbiotic, 20 received control). These results
contrast with those of a previous uncontrolled open-label
study of Bifidobacterium longum W11 and an oligosac-
charide-based synbiotic preparation, which improved
intestinal function in patients with constipation-variant
IBS based on Rome II criteria.53
Nonsystemic antibiotics in IBS. Most randomised, pla-
cebo-controlled studies have evaluated nonsystemic
agents (e.g. neomycin, rifaximin) for the treatment of
IBS (Table 1).54–58 A randomised, double-blind study in
patients with IBS meeting Rome I criteria compared neo-
mycin [n = 55; 25 patients with IBS-D, 18 with constipa-
tion-predominant IBS (IBS-C), 10 with other/unknown
forms of IBS] with placebo (n = 56; 21 patients with
IBS-D, 20 with IBS-C and 15 with other/undetermined
forms of IBS).54 A significantly greater reduction from
baseline in IBS symptoms (primary endpoint: composite
score based on abdominal pain, diarrhoea, constipation)
was observed with neomycin compared with placebo
(35.0  5.0% vs. 11.4  9.3%; P < 0.05). A subanalysis
of patients with IBS-C (neomycin, n = 19; placebo,
n = 20) indicated that neomycin treatment resulted in a
significantly greater global percentage improvement in
IBS compared with placebo (36.7  7.9% vs.
5.0  3.2%; P < 0.001).55
Two randomised, double-blind, placebo-controlled tri-
als (n = 1260) evaluated rifaximin 550 mg three times a
day in patients with IBS-D meeting Rome II criteria.56
After 14 days of treatment, adequate relief of global IBS
symptoms for ≥2 of the first 4 weeks post-treatment (i.e.
primary endpoint) was achieved in significantly more
patients in the rifaximin group compared with those in
the placebo group in each study and in a pooled analysis
Aliment Pharmacol Ther 2014; 39: 1033-1042
ª 2014 John Wiley & Sons Ltd
(40.7% vs. 31.7%, pooled data; P < 0.001), and relief was
sustained for at least 10 weeks post-treatment.56
Improvement post-treatment was consistent with another
smaller randomised, double-blind, placebo-controlled
study of a lower dose of rifaximin (400 mg three times a
day; n = 43) vs. placebo (n = 44) for 10 days in patients
with IBS meeting Rome I criteria.58 Patients treated with
rifaximin experienced a greater mean percentage global
improvement in IBS at 10 weeks post-treatment com-
pared with those receiving placebo (36.4  31.5% vs.
21.0  22.1%; P = 0.02).58
Another randomised, double-blind, placebo-controlled
study (n = 124 patients, with 20%, 38.3% and 41.7%
receiving IBS-D, IBS-C and alternating IBS diagnoses
respectively) evaluating rifaximin for chronic bloating
and flatulence indicated that, in a subgroup of patients
with IBS meeting Rome II criteria (n = 70), a signifi-
cantly larger response was observed with rifaximin
800 mg/day after 10 days compared with placebo (40.5%
vs. 18.2% respectively; P = 0.04).57 A meta-analysis of
randomised, placebo-controlled studies evaluating rifaxi-
min for IBS reported that global symptoms of IBS
improved significantly with rifaximin vs. placebo (OR:
1.57; P < 0.001), with a number needed to treat of 10.59
In a 2012 observational study, patients with IBS (total
n = 106; 88 IBS-D, 7 IBS-C, 11 alternating IBS) were
treated with rifaximin; patients responded (i.e. experi-
enced reduction in bloating, flatulence, diarrhoea and
pain) after 2 weeks, and results were maintained for at
least 3 months.60 In addition, several retrospective chart
reviews of rifaximin treatment for IBS suggest a low
potential for loss of efficacy with repeated courses of rif-
aximin. In two retrospective chart reviews (both in
patients with nonconstipated forms of IBS), clinical
improvement was documented in ~75% of patients with-
out loss of response during retreatments.61, 62 Similarly,
another retrospective chart review of rifaximin-treated
patients meeting Rome I criteria for IBS showed that
69% of patients had a clinical response. This was greater
than the response reported with other antibiotics (i.e.
38% of 24 patients treated with neomycin experienced a
response).63 Retreatment with rifaximin (n = 16) was
associated with clinical improvement in all cases,
whereas retreatment with other antibiotics (e.g. doxycy-
cline, amoxicillin and clavulanate acid, neomycin) was
effective in only two of eight cases (25%).
As suggested with probiotics, the action of nonsystem-
ic antibiotics in IBS may extend beyond direct effects on
the composition of the gut microbiota. For example,
additional mechanisms of action for rifaximin have been
1037
H. L. DuPont

Table 1 | Published randomised, placebo-controlled, clinical data for antibiotics in the management of IBS

Antibiotic study Dosage Patient population Primary outcome (antibiotic vs. placebo)* P-value
Neomycin
Pimentel et al.54 500 mg b.d. for 10 days IBS (Rome I); n = 111 Per cent reduction in composite <0.05
IBS score†: 35.0% vs. 11.4%
Pimentel et al.55 500 mg b.d. for 10 days IBS (Rome I); n = 39‡ Global improvement in IBS <0.001
symptoms: 36.7% vs. 5.0%
Rifaximin
Pimentel et al.56 550 mg t.d.s. for 14 days Nonconstipated IBS Adequate relief of global IBS symptoms 0.01
(Rome II); n = 623 during ≥2 of first 4 weeks post-treatment:
40.8% vs. 31.2%
Pimentel et al.56 550 mg t.d.s. for 14 days Nonconstipated IBS Adequate relief of global IBS symptoms 0.03
(Rome II); n = 637 during ≥2 of first 4 weeks post-treatment:
40.6% vs. 32.2%
Sharara et al.57 400 mg b.d. for 10 days IBS (Rome II); n = 70§ Global symptom improvement: 0.04
40.5% vs. 18.2%
Pimentel et al.58 400 mg t.d.s. for 10 days IBS (Rome I); n = 87 Global IBS symptom improvement: 0.02
36.4% vs. 21.0%

b.d., two times a day; t.d.s., three times a day.

* Per cent of patients, unless otherwise indicated.
† Composite score of three main IBS symptoms: abdominal pain, diarrhoea, constipation.
‡ Subgroup of patients with constipation-predominant IBS.
§ Subgroup of patients in the study who had IBS.

proposed, such as a reduction in bacterial pathogen viru- Microbiota–gut–brain axis

lence,64 the stabilisation of gut mucosa (i.e. protection
against bacterial infection),65 anti-inflammatory proper-
ties,65 and the preservation of normal colonic flora.66
Other potential pathogenic processes in IBS that may be
modulated by rifaximin include visceral hypersensitivity
and mucosal-immune reactivity (based on animal model
data).67
INTERPLAY OF MICROBIOTA AND OTHER
TREATMENT TARGETS IN IBS
Gut microbiota is one of many factors contributing to
the pathophysiology of IBS, and each represents a poten-
tial target for therapy (Figure 1). Given the complexity
of the interactions between these factors/targets, it is pos-
sible that therapies directly targeting the microbiota may
also impact other pathways either directly or indirectly
through their effects on the gut microbiota. The majority
of the evidence supporting the potential interplay of the
gut microbiota with other targets is derived from animal
studies (where there is no suitable IBS model), meaning
that in the absence of human studies, clinical relevance
cannot be established. Nonetheless, these pre-clinical
studies have led to the development of hypotheses on
gut microbiota interaction and are laying the ground-
work for future investigation.
The important role of the brain–gut/gut–brain axis in
IBS and in other functional gastrointestinal diseases has
been previously reported on,68–72 while the concept of a
microbiota–gut–brain axis in health and disease is
emerging.73–75 Of related interest, in patients with cir-
rhosis (n = 25), differences in gut microbiota were
observed vs. healthy controls (n = 10), and there was a
direct correlation between several bacterial taxa and cog-
nitive function, particularly in 17 patients with hepatic
encephalopathy.76 As noted above, animal data interpre-
tation has limitations, especially given the lack of suitable
IBS animal models; however, pre-clinical data can pro-
vide insight into the potential relationship between the
microbiota and the gut–brain axis. For example, mice
administered a mixture of nonsystemic antibiotics had
an altered microbiota, increased exploratory behaviour
and less apprehensive behaviour compared with con-
trols.77 After a 2-week antibiotic washout period, these
behavioural changes were reversed as the microbiota
normalised. The authors noted that, consistent with the
behavioural changes, mice receiving the antibiotic mix-
ture also had higher levels of central brain-derived neu-
rotropic factor in the hippocampus and lower levels in
the amygdala compared with controls.77 Collins et al.

1038 Aliment Pharmacol Ther 2014; 39: 1033-1042

ª 2014 John Wiley & Sons Ltd
 Review: gut microbiota and therapy targets in irritable bowel syndrome
has provided a comprehensive review of data on the
bidirectional interactions between the gut microbiota and
the brain (animal-based studies), noting that while ani-
mal data support the influence of gut microbiota on
brain development and function, information elucidating
the possible underlying mechanisms is lacking.75 Current
knowledge on how intestinal microbiota dysbiosis, the
gut–brain axis and pathophysiologic changes help to
explain the disease pathophysiology in IBS is summar-
ised in Figure 1.
Inflammation and visceral hypersensitivity
The gut microbiota may contribute to the low-grade
inflammation and intestinal immune activation described
in IBS through effects on cytokine levels and toll-like
receptor activity.24, 78, 79 In a study of patients with IBS
(n = 77) undergoing colonoscopy to rule out inflamma-
tory bowel disease, patients were categorised based on
biopsy as non-inflamed IBS, nonspecific microscopic
colitis or lymphocytic colitis.80 Increases in lymphocytic
populations were observed in all patient subgroups, even
those with no overt signs of inflammation, suggesting a
pathophysiologic role of immune activation in IBS. The
authors speculated that bacterial antigens could be one
of the factors triggering immune activation.80
Visceral hypersensitivity has also been implicated in
IBS, and the influence of gut microbiota on both visceral
hypersensitivity and inflammation has been suggested in
a variety of animal models, several of which are sum-
marised in this section. In one study, the transfer of fae-
cal microbiota of patients with IBS to germ-free rats was
accompanied by a transfer of visceral hypersensitivity
(assessed by colorectal distention) when these IBS
human microbiota-associated (HMA) rats were com-
pared with healthy HMA rats.81 An investigation of
whether changes in gut flora and gut inflammatory cell
activity impacted visceral hypersensitivity in mice dem-
onstrated that, in the absence of sterile precautions (i.e.
allowing for the fluctuation of gut bacterial content), the
mice had a substantial increase in visceral sensitivity over
time that was associated with a slightly increased activity
of inflammatory cells.82 When an anti-inflammatory
agent (i.e. dexamethasone) was administered, both
inflammatory activity and visceral hypersensitivity were
reduced, lending further support to the interplay between
inflammation and visceral sensitivity. Overall, these
results support the hypothesis that perturbations of the
gut microbiota are associated with small changes
in inflammatory activity in the gut that can change vis-
ceral perception; this is a possible rationale for the
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administration of certain probiotics for IBS. To assess
for a protective effect from antibiotic-induced increases
in visceral sensitivity, a probiotic (L. paracasei) was co-
administered with an antibiotic in mice. Visceral hyper-
sensitivity and histology improved; however, total
Lactobacilli populations were undetectable,82 suggesting
that the beneficial effects observed may not simply be
related to recolonisation of the microbiota.
In rats with induced post-inflammatory chronic
hypersensitivity to colorectal distention, the administra-
tion of a probiotic resulted in the normalisation of vis-
ceral sensitivity.83
The protective effect of three different probiotic
strains was assessed in rat models of psychological stress
(i.e. chronic maternal deprivation-induced visceral hyper-
sensitivity associated with altered colonic paracellular
permeability or acute partial restraint-induced visceral
hypersensitivity).84 Only one of the three probiotic
strains, L. paracasei NCC2461 (Lpa), demonstrated
reversal of visceral hypersensitivity to colorectal disten-
tion and complete restoration of gut paracellular perme-
ability. Thus, effects of probiotics on visceral
hypersensitivity appear to be strain specific. In the partial
restraint-induced animal model, anti-nociceptive effects
on visceral hypersensitivity were observed only when
Lpa and the spent culture medium were both present.
The authors suggested a potential synergistic interplay
between the probiotic and intraluminal bacterial prod-
ucts.84
The effect of oral rifaximin on gut microbiota, intesti-
nal inflammation and visceral hyperalgesia was evaluated
in a model of visceral hyperalgesia (chronic water avoid-
ance and restraint stress in adult Wistar rats).67 Rifaxi-
min administration significantly reduced the ileal
bacterial load and altered the bacterial composition in
the distal ileum (i.e. dominance of Lactobacilli post-treat-
ment). In addition, rifaximin inhibited mucosal inflam-
mation, barrier impairment and visceral hyperalgesia.
Although these animal data are interesting, the associa-
tions between gut microbiota and inflammation and vis-
ceral hypersensitivity remain speculative and require
support from clinical investigations in patients with IBS.
Motility
In addition, bacterial factors in the gut may cause
changes in motor function that may underlie IBS symp-
toms.85 Colonisation with different bacterial species in
rats showed that changes in the composition of gut mic-
robiota were associated with altered (either impeded or
increased) gastrointestinal motility.86 It has also been
1039
H. L. DuPont

reported that bacterial components (e.g., lipopolysaccha-
rides) may interact with specific toll-like receptors and
directly affect the contractile function of human colonic
smooth muscle cells.87 Anti-motility agents are often
used in IBS-D,88 and their effect may be related in part
to changes in gut flora.
CONCLUSIONS
Animal and human data support an interplay between
the gut microbiota and pathophysiologic factors targeted
by agents evaluated for the management of IBS. Further
research on bacterial populations identified in stool and
associated with intestinal mucosa of healthy individuals
may provide new insight and opportunities to normalise
gut homoeostasis in patients with IBS. Currently, several
probiotics and nonsystemic antibiotics are efficacious for
the treatment of patients with IBS. However, given the
complexity of the IBS disease process, it is likely that the
mechanisms of these agents are not limited to their
direct effects on microbiota composition.9, 48, 89–92 Gut
microbiota appears to be one of several important factors
that may contribute to the aetiology and pathophysiology
of IBS. Future research on metabolic and/or immunolog-
ical pathways and microbial genes in the gastrointestinal
tract (metagenomics) and their effects on protein expres-
sion will help elucidate the role of gut microbiota in this
burdensome condition.19, 75
While much is known about the pathophysiology of
IBS and the role of the microbiota, a great deal more is
unknown. Studies are needed to further refine the role of
the intestinal microbiota in the gut–brain axis and in the
chronic inflammation associated with the disorder, and
how these factors influence the important intestinal
events in the syndrome. As we define these factors, IBS
will move from a functional syndrome to a disease with
a defined biochemical and immunological origin.
AUTHORSHIP
Guarantor of the article: H. L. DuPont.
Author contributions: H. L. DuPont provided concept
and scientific content for the development of the
manuscript, critically reviewed and edited all drafts of
the manuscript, and approved the final version of the
manuscript.
ACKNOWLEDGEMENTS
Declaration of personal interests: In 2011, Dr DuPont
served as a consultant to Salix Pharmaceuticals, Inc. on
the topic of antibiotic resistance with chronic use of
rifaximin and has received research grants from Santau-
rus, Inc., a company that has been acquired by Salix
Pharmaceuticals, Inc.
Declaration of funding interests: Writing and editorial
support were provided under the direction of the author
by Mary Beth Moncrief, PhD, and Kulvinder Singh,
PharmD, Synchrony Medical Communications, LLC,
West Chester, PA, and funded by Salix Pharmaceuticals,
Inc.

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