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biochemical explanation, but this concept is likely to be outdated.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

www.thelancet.com/gastrohep Vol 1 October 2016 133

 Review

Mechanism Causes Prevalence in patient Relevance in clinical setting

Central processing of Alteration of the central processing of
afferent stimuli afferent stimuli (including visceral
afferents)
Anxiety and depression Alteration of the central processing of
afferents (including visceral)
Post-infectious IBS Post-inflammatory neuroplastic
changes, visceral hyperalgesia
Post-inflammatory IBS As for post-infectious
Bile acid Most likely genetically determined
malabsorption alteration of the function of the apical
ileal bile acid transporter
Visceral hyperalgesia Central and peripheral mechanisms
implicated
Mutations in SCN5A SCN5A encodes the α-subunit of the
voltage-gated sodium channel NaV1.5
cohorts
Minimal systemic inflammation, or effects of 10% to 20% Lowered sensory thresholds may be a key
early childhood trauma, may alter the central driver for symptom manifestation
processing of afferent stimuli
Multifactorial, activation of immune systems Up to 75% Influences health care-seeking behaviour, can
seems to aggravate underlying disturbances be targeted with antidepressants
Exposure to pathogens causing alterations of 10% to 20% Prevention of infections, early intervention in
gut permeability, inflammation affected patients (eg, antibiotics), potentially
primary prevention with probiotics
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
Type 2, or idiopathic, likely due to a genetic Up to 20% of patients with Targeted treatment (binding of bile acids)
defect in the apical ileal bile acid transporter severe IBS-D symptoms available
Can occur after infections or inflammation 30% to 40% Can be assessed in specialised laboratories.
(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
Genetically determined 2% of all IBS patients, but Relevant for constipation predominant IBS.
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;
diet; genetic factors; infections and disturbances in the
intestinal microbiota; low-grade mucosal inflammation,
immune activation, and altered intestinal permeability;
disordered bile salt metabolism; abnormalities in
serotonin metabolism; and alterations in brain function.
Evidence that IBS is a gut–brain disorder
IBS symptoms that do not relate to the gastrointestinal
tract, most notably anxiety and depression, are highly
prevalent in outpatient and community samples,16,17 and
these associations are not explained by health-care-seeking
behaviour alone. Such observations have led many to
conceptualise IBS as a primary disorder of brain–gut
function,18 or even primary somatisation,19 with the brain
driving the gut manifestations, fatigue, and other
complaints. However, there is now emerging epide-
miological evidence from three prospective studies20–22 in
two different countries that in about half of patients,
functional gastrointestinal symptoms arise first and that
mood disorders develop later, suggesting that primary gut
disturbances might be the underlying driver of the mood
disorder in at least a subgroup of patients. In an
independent study23 of IBS and psychiatric disorders, the
use of structured interviews showed that 40% of patients
with a mood disorder and 23% of patients with anxiety
developed these diagnoses after the onset of IBS. Other
evidence implicates intestinal inflammation,24 the cytokine
response,24 and the gut microbiome25 in precipitating such
gut to brain alterations in IBS. If correct, the implications
of these findings are potentially profound, because they
suggest that by reversing this gastrointestinal dysfunction
(which is achievable since the gut is more accessible than
the brain) there is the potential to improve or even reverse
mood and gut dysfunction.
The role of diet in IBS
Many patients with IBS report dietary triggers, although
often these are not reproduced when re-challenge
occurs with the offending food in a double-blind
manner.26 Nevertheless, some foods appear to be
implicated in the generation of IBS symptoms, and a
change in diet can rapidly alter the microbiome.27 High
amounts of insoluble fibre were reported28 to exacerbate
symptoms among patients with IBS more than 20 years
ago, but in recent years there has been a resurgence of
interest in the role of diet in IBS. Fermentable
oligosaccharides, monosaccharides, and disaccharides
and polyols (FODMAPs), which are present in stone
fruits, legumes, lactose-containing foods, and artificial
sweeteners, might exacerbate symptoms in a subgroup
of patients due to their fermentation and osmotic
effects.29 MRI studies30 show that when FODMAPs such
as fructose are administered to healthy volunteers,
small bowel distension occurs because of increased
small bowel water content.
A proportion of patients with IBS, who have no genetic,
serological, or mucosal markers of coeliac disease, also
seem to have improvement in symptoms after the
withdrawal of gluten from their diet. These patients are
often labelled as having non-coeliac gluten sensitivity.
In one multicentre double-blind trial,31 140 patients with

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


functional gastrointestinal symptoms were given a strict
3-week gluten-free diet. After those 3 weeks, those who
responded to this diet were asked to continue with the
trial, but were randomly assigned to either be re-
challenged with gluten or take placebo for another 7 days.
Among 77 patients who met criteria for IBS, 55 patients
(71%) responded to the gluten-free diet during the initial
3 weeks of the study. Of these 55 patients, 53 individuals
(96%) then entered the re-challenge phase of the study,
and 18 (34%) of the re-challenged patients reported a
symptomatic relapse after gluten ingestion, with a
corresponding reduction in quality of life. Thus gluten
could cause symptoms in a subgroup of patients without
evidence for a gluten sensitive enteropathy.
MRI studies32 have shown little difference in the effect of
gluten-free or gluten-containing bread on small-bowel
water content in healthy individuals, so gluten might
induce symptoms in people with IBS in other ways. In
another randomised trial33 in 45 patients with IBS with
diarrhoea symptoms who were given either a gluten-free
diet or a gluten-containing diet, small-bowel mucosal
permeability, measured by lactulose and mannitol
excretion, was higher in those randomly assigned to
receive a gluten-containing diet. Additionally, expression
levels of mRNA encoding tight junction proteins, such
as zona occludens 1, claudin-1, and occludin, were
significantly reduced in mucosal biopsies from individuals
receiving gluten, suggesting that gluten might impair
epithelial barrier function.
Evidence for IBS as a genetic disorder
Some investigators34 have reported that IBS aggregates in
families, and twin studies35 of IBS have shown higher
concordance in monozygotic twins than in dizygotic
twins, suggesting that genetic factors might play a role in
IBS. A mutation of the SCN5A-encoded voltage gated
sodium channel, type V (alpha subunit), which is
associated with congenital prolonged QT syndrome, has
previously been reported to be associated with abdominal
pain.36 This channel is also found in the interstitial cells
of Cajal and circular smooth muscle in the human
gastrointestinal tract. A pilot study37 assessing 49 patients
with IBS who reported at least moderately severe
abdominal pain showed a missense mutation in SCN5A,
leading to a loss of function of this channel in one patient,
which was not observed in the DNA of 1500 healthy
controls. A subsequent genome-wide association study38
was done in 584 patients with IBS and 1380 healthy
controls and then replicated in four independent cohorts.
It showed that this mutation was present in up to 2% of
individuals in the study with IBS. A greater proportion of
those with SCN5A mutation met criteria for IBS with
constipation than for IBS with diarrheoa. Administration
of the anti-arrhythmic drug mexiletine to one individual
with IBS with constipation led to normalisation of bowel
habit, suggesting a future option for targeted therapy in
this small subgroup of patients. This mutation is the first
www.thelancet.com/gastrohep Vol 1 October 2016
Review
to be linked to IBS and provides strong evidence that
genes, albeit uncommonly, can directly induce IBS
symptoms.
Swan and colleagues39 assessed the role of single
nucleotide polymorphisms (SNPs) in genes whose
expression is known to be altered by acute enteric
infection, by obtaining rectal biopsy samples from
individuals with IBS with diarrhoea or constipation
symptoms, patients with IBS after Campylobacter jejuni
infection in the previous 6 months, and healthy
volunteers. The authors reported that SNPs in tumour
necrosis factor superfamily member 15 (TNFSF15) and
genes coding for tumour necrosis factor alpha (TNFα),
which are also known to predispose to inflammatory
bowel disease, were associated with both IBS with
diarrhoea and post-infectious IBS. However, this finding
contrasts with those from a previous study,40 which
showed that SNPs in TNFSF15 were more strongly
associated with IBS with constipation.
Chronic stress can modulate sensory and motor
function, via corticotropin-releasing hormone and
catecholaminergic signalling, and has therefore been
implicated in the pathophysiology of IBS. In a study41
recruiting 111 individuals with IBS and 142 healthy
controls, the role of SNPs in genes coding for
corticotropin-releasing hormone-related genes was
examined. The authors examined SNP genotypes
rs28364015 and rs6472258 in corticotropin-releasing
hormone, and rs10474485 in corticotropin-releasing
hormone-binding protein, via direct sequencing and
real-time PCR, as well as assessing the emotional status
of participants by use of validated questionnaires.
However, no genetic variation in these SNPs among
people with IBS and healthy controls was noted. The only
positive finding was that patients with IBS with diarrhoea
without the rs10474485A allele had significantly higher
levels of emotional arousal than did those with this allele,
suggesting that polymorphisms in corticotropin-releasing
hormone could be linked to the severity of emotional
abnormalities in a subset of patients.
Other investigators have examined the role of genes
related to immune regulation and epithelial barrier
function,42 serotonin signalling,43,44 cannabinoid receptors,45
and bile acid synthesis,46,47 with varying results. However,
many of the described studies are hampered by a small
sample size and, to date, most genetic association studies
of selected candidate genes in IBS have involved less than
2000 patients. The largest genome-wide association study
to date in IBS contained only around 5500 individuals,48
compared with 30 000–40 000 in some inflammatory
bowel disease cohorts.49,50 Perhaps as a result, a compre-
hensive meta-analysis from 201551 could not confirm or
refute a role for most of the SNPs implicated above, other
than a modest association with the SNP in TNFSF15.
Nevertheless, some of these data suggest that genetic
factors (aside from SCN5A) only play a modest role
in IBS.
135
 Review
A potential explanation for this negative finding is the
influence of the environment on gene function, leading
to activation or inactivation of specific genes that might
be relevant to underlying pathphysiology, also known as
epigenetics. In one study52 that explored genome-wide
DNA methylation from peripheral blood mononuclear
cells in 27 patients with IBS and 23 healthy controls
matched for age and sex, with gene expression assessed
by quantitative PCR, the link between epigenetic
changes in selected genes with clinical traits was tested.
The authors used validated questionnaires to assess
symptoms and mood. Genome-wide DNA methylation
profiling was different in patients with IBS compared
with healthy controls, with 133 differentially methylated
positions among genes that were linked to oxidative
stress and neuropeptide hormone activity. Some of the
epigenetic changes observed seemed to correlate with
mood scores among patients. These data suggest that not
only the genome but also genome-wide DNA methylation,
could play a role in the manifestation of IBS.
Evidence for a role of infection and disturbances
in the microbiota
Acute enteric infections frequently precede the onset of
IBS, particularly IBS with diarrhoea symptoms, or other
functional gastrointestinal disorders.53,54 A study done in
rats,55 in which mucosal inflammation was induced
chemically, suggests that the severity of inflammation
is linked to the severity of subsequent visceral
hypersensitivity, which might be one of the underlying
mechnisms for the development of symptoms.
Additionally, psychological stress appears to augment
visceral hypersensitivity in these animal models.56 In
support of this observation, when Wouters and
colleagues57 studied risk factors for post-infectious IBS in
a cohort of almost 19 000 people exposed to drinking
50μm
Figure 1: Histological presentation of colonic spirochaetosis
Colonic spirochaetosis indicated by blue fringe arrows on haematoxylin and
eosin staining and, inset, Warthin Starry staining.
136
water containing known gastrointestinal pathogens,
including norovirus, Giardia lamblia, and C jejuni, the
risk of developing ongoing symptoms consistent with
IBS was increased in those with pre-existing anxiety and
in younger individuals. There was an inverse correlation
between anxiety scores pre-exposure and CD4-positive
T lymphocytes expressing interleukin 2, and also an
association between a T-helper-2 cell cytokine phenotype
at the time of exposure and the subsequent development
of post-infectious IBS suggesting that susceptibility to
IBS after an acute enteric infection results from switching
on of a T-helper-2 immune-cell response. Similar results
have been reported from the Millenium cohort study,58
which acquired data from individuals in active military
service, and showed that a history of anxiety or depression
in the setting of acute gastroenteritis increased the risk of
subsequent post-infectious IBS. This finding provides
evidence that a biological link exists between psychological
factors and host susceptiblity to infection.
Further adding to the concept that gastrointestinal
infections are implicated in the pathophysiology of IBS
are data from Walker and colleagues.59 In this study59
gastrointestinal symptom questionnaires were adminis-
tered to a random population sample of 745 individuals,
who then underwent colonoscopy with terminal ileal
and colonic biopsy sampling. Individuals were classified
as having IBS according to the Rome III criteria,
and histopathological examination of colonic biopsy
specimens was undertaken. This study showed that
17 individuals had colonic spirochaetosis, of whom
six (35%) met criteria for IBS, with a significant odds
ratio for IBS among those with spirochaetosis (3·6,
95% CI 1·27–10·11), compared with those without.
Colonic biopsies from those with colonic spirochaetosis
showed a unique pathology, with increased eosinophils
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
controls, no differences were observed between patients
with diarrhoea symptoms of IBS and those with
post-infectious IBS, suggesting that they might share
common pathophysiologies.
www.thelancet.com/gastrohep Vol 1 October 2016

In one study63 including 13 patients with post-infectious
IBS, 19 patients with IBS unrelated to enteric infection,
and 16 healthy controls, the faecal microbiota of those
with post-infectious IBS differed significantly from that
of both patients with IBS and healthy controls, and there
was reduced diversity of both the mucosal and stool
microbiome in post-infectious IBS, compared with
healthy controls. Reduced diversity was significantly
correlated with both increased numbers of CD8 and
CD4RA-positive intraepithelial lymphocytes and lower
mood, as measured by the hospital anxiety and depression
score. Similar findings,64 in terms of a reduction
in bacterial diversity and a dysbiosis of microbial
communities, have also been reported in patients with
IBS with diarrhoea. However, it is uncertain what is cause
and what is consequence—has the infection changed the
microbiome or is an altered microbiome the reason why a
transient infection causes IBS?
The dysbiosis reported in some individuals with IBS
has been postulated to result in abnormal levels of
intestinal fermentation. In a case-control study65 of
14 patients with IBS with constipation and 12 sex-matched
healthy individuals, analysis of faecal microbiota revealed
significantly lower numbers of lactate-producing, lactate-
metabolising, and hydrogen-consuming bacteria in
patients with IBS. Assessment of starch fermentation in
vitro showed that the microbiota of patients with IBS
produced more sulphides and hydrogen, and less
butyrate, than those of healthy controls. A larger study66
assessed intestinal fermentation in 114 patients with
Rome III-defined IBS and 33 healthy controls, with
intraluminal pH measured via wireless motility capsule,
and amounts of short-chain fatty acids in stools. Colonic,
but not small bowel, pH was significantly lower in
patients with IBS than in controls, and this finding was
consistent across different stool patterns, suggesting
a higher proportion of colonic fermentation in IBS.
However, amounts of short-chain fatty acids were only
significantly reduced in those patients with IBS with
constipation. Others67 have reported that dysbiosis can
lead to excess methane production,which can slow colonic
transit and might contribute to constipation in IBS.
Colonisation of the small bowel by fermenting bacteria,
as occurs in small intestinal bacterial overgrowth, has
also been proposed as a pathophysiological mechanism
in IBS.68 A group of researchers in the USA69 using
lactulose hydrogen breath testing showed a prevalence of
presumed small intestinal bacterial overgrowth of almost
80% in individuals with symptoms suggestive of IBS.
However, other investigators70 have not replicated these
results, despite using similar methods. Additionally,
direct aspiration and culture of jejunal secretions,
although rarely used in the clinical setting, is considered
the gold standard for the diagnosis of small intestinal
bacterial overgrowth. A study71 that incorporated this
approach did not detect an increase in the prevalence of
small intestinal bacterial overgrowth among patients
www.thelancet.com/gastrohep Vol 1 October 2016
Review
with IBS compared with healthy controls, but there was a
significant increase in bacterial load in patients with IBS.
Investigators have subsequently gone on to treat
patients with IBS with the non-absorbable antibiotic
rifaximin and, in a small trial,72 both global symptoms
and bloating improved. In two subsequent phase 3
randomised trials73 including more than 1200 patients
with non-constipated IBS, significantly higher rates of
relief of global IBS symptoms and bloating was reported
in those randomly assigned to receive rifaximin than in
those given placebo. However, the benefit over placebo
was modest, with therapeutic gains of only 8–11%, and
none of the individuals in these trials underwent breath
testing to show the presence of small intestinal bacterial
overgrowth. Although these data suggest that the
gastrointestinal microbiota might play a role in symptom
generation, the small response rate in this study suggests
that various other factors are involved, or that rifaximin
fails to eradicate the key organisms in most patients.
Effects of targeted alterations of bacteria within the
gastrointestinal tract could provide further evidence that
supports the notion that specific bacteria play a role
within the pathophysiology of IBS. In a rat model74 of
visceral hypersensitivity, an effect of rifaximin on the ileal
microbiome was observed, with alterations in the
composition of bacterial communities, and an abundance
of Lactobacillus species. These changes appeared to
translate into a protective effect against ileal inflammation
and impairment in mucosal barrier function when
chronic psychological stress was applied to the rats, in
addition to reduced visceral hypersensitivity. These effects
were not seen with neomycin, another antibiotic. These
issues highlight that not only antibiotics but also some
probiotics appear to have modest beneficial effects on
symptoms in patients with IBS.75
Evidence for low-grade mucosal inflammation,
immune activation, and altered intestinal
permeability
Numerous studies, summarised in a previous systematic
review,76 have shown that low-grade mucosal inflammation
can be identified in some individuals with IBS, if strict
criteria are applied. This concept was first proposed almost
25 years ago,77 and although in most patients no cause can
be found, there is a possibility that either a previous, or
previously unrecognised, infection contributes to or is the
cause of this mucosal inflammation. This hypothesis is
supported by several studies54,78,79 that show a higher
prevalence of symptoms compatible with IBS in individuals
with a history of an acute enteric infection than in those
without such exposure, and a population-based study59 in
which colonic eosinophilia was shown in patients with IBS
with coexisting colonic spirochaetosis. Some studies80,81
have shown increased concentrations of pro-inflammatory
cytokines, and also higher numbers of mast cells, which
are in close proximity to enteric nerve fibres in the
gastrointestinal mucosa of individuals with IBS (figure 2).
137
 Review
As well as histological evidence of mucosal inflammation,
some investigators82 have shown that in patients with IBS,
there is an activation of the immune system, reflected by
increased concentrations of cytokines in the colonic
mucosa, and an increase in release of pro-inflammatory
cytokines from isolated peripheral blood mononuclear
cells, particularly in patients with IBS with diarrhoea.24
High concentrations of these cytokines were associated
with anxiety and depression (figure 3).24,83 Additionally,
other studies84 have shown increased activation of
B lymphocytes isolated from the blood of patients with
IBS. However, this activation of humoral immunity
has been suggested to be gastrointestinal-specific,85 with
microarray profiling identifying enhanced jejunal mucosal
humoral activity in patients with IBS with diarrhoea,
associated with proliferation and activation of B cells, and
immunoglobulin production. The biological markers of
humoral activation appeared to be positively associated
with bowel movements, stool form, and depression.85
50μm
Figure 2: Immunostaining of colonic mucosa in a patient with irritable
bowel syndrome
Increased mast cells in colonic mucosa in the lamina propria in a patient with IBS
(CD117 immunostaining).
600
500
400
TNFα (pg/mL)
300
200
100
r=0·384
p=0·030
0 observations96 in the duodenum of patients with IBS
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Anxiety score (HADS)
Figure 3: Association between anxiety scores and TNFα concentration
Association between the release of TNFα from peripheral blood mononuclear
cells and anxiety scores as measured with HADS. HADS=hospital anxiety and
depression score. Figure adapted from Liebregts and colleagues.24 Anxiety is
related to circulating TNFα, suggesting a possible mechanism by which subtle
intestinal inflammation in IBS might induce or worsen mood disturbance.
138
Whether these findings reflect genuine patho-
physiological mechanisms, or are random associations
remains unclear. Supernatants from cultured peripheral
blood mononuclear cells from patients with IBS diarrhoea
caused mechanical hypersensitivity when applied to
mouse colonic afferent nerve endings,86 and this effect
was blocked by the TNFα antagonist infliximab.
Supernatants from patients with IBS with constipation
had no such effect, although those from healthy
controls inhibited mechanosensitivity, via an opioidergic
mechanism. Analysis of IBS with diarrhoea supernatants
showed increased amounts of the cytokines interleukin 1β,
interleukin 10, TNFα, and interleukin 6 among others,
and the concentration of these cytokines appeared to
associate with the frequency and severity of pain. Work
from the same group of investigators87 has shown that
peripheral blood mononuclear cell supernatants from
healthy controls had greater inhibitory effects on
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
ago.88 More studies89,90 in patients with IBS without an
infective aetiology show a subset of these patients also
have abnormal levels of intestinal permeability, and in
one of these studies,90 this increase in permeability had a
significant association with anxiety and depression.
Increased density of epithelial gaps has been shown by
confocal laser endomicroscopy in the terminal ileum
of patients with IBS, compared with other patients
undergoing routine colonoscopy.91 Alterations in tight
junction proteins, such as zonula occludens-1, claudin-1,
and junctional adhesional molecules have been reported
in patients with IBS,92 and mast-cell degranulation has
also been reported to lead to decreased expression of
these tight junction proteins in both the upper and lower
gastrointestinal tract, probably via tryptase release.93–95
Of particular relevance to this finding are real-time
with suspected food intolerance with confocal laser
endomicroscopy; within 5 min of exposure to food
antigens intraepithelial lymphocytes increased, epithelial
gaps formed, and intervillous spaces widened, which
support the theory that intestinal impermeability can
occur in IBS. A disease model has been proposed
(figure 4).97
www.thelancet.com/gastrohep Vol 1 October 2016
 Review

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

www.thelancet.com/gastrohep Vol 1 October 2016 139

 Review
whether bile acid diarrhoea is a cause or a consequence of
IBS, with rapid transit associated with IBS perhaps
leading to bile acid depletion. Variants in the klotho β gene
have been shown in patients with IBS with diarrhoea,47
and these appear to associate with colonic transit,
modulated via SNPs in FGF-4, suggesting that colonic
transit and bile acid synthesis are intrinsically linked via
FGF-19, FGF-4, and klotho β.
Assessment of the association between faecal bile acids
and symptom subtypes among patients with IBS,
compared with healthy controls, has revealed that total
faecal bile acid levels were higher in those with IBS with
diarrhoea, and lower in those with IBS with constipation.104
Additionally, faecal bile acid concentrations had an
association with stool number and form. In a smaller
study46 of similar design, faecal bile acids were higher in
patients with IBS with diarrhoea, compared with patients
with constipation symptom of IBS and healthy controls,
and concentrations of 7alpha-hydroxy-4-cholesten-3-one
(C4), a marker of bile acid synthesis, were higher among
those patients with IBS with diarrhoea, and showed an
association with faecal bile acids. In another study105 of
patients with IBS with diarrhoea, markers of bile acid
synthesis including FGF-19, C4, and faecal bile acids were
measured, and the association between these markers
and colonic transit, colonic and intestinal permeability,
and colonic sensation and tone was studied. A third of
these patients had high concentrations of faecal bile
acids, and these individuals had significantly increased
intestinal permeability and borderline significant
increases in colonic transit. Almost 25% of patients had
increased amounts of C4, and in these individuals there
was an increase in faecal bile acids and a substantial
increase in colonic permeability.
Other investigators106 have replicated these findings,
reporting increased concentrations of bile acids in the
stool of patients with IBS with diarrhoea, but have also
studied the role of the intestinal microbiota, which
metabolise bile acids. In this study assessing 14 patients
with IBS with diarrhoea and 18 healthy controls, the
authors reported that the increase in faecal bile acids was
associated with a dysbiosis, with significant increases in
Escherichia coli and reductions in Leptum and Bifidobacteria
species. Building on this work, one study107 showed
differences in serum and faecal bile acid profiles and
different patterns of dysbiosis in patients with IBS with
diarrhoea and constipation symptoms compared with
healthy individuals, suggesting that modification of bile
acid profiles, perhaps via modulation of the intestinal
microbiota could have therapeutic potential in IBS.
Evidence for a role of abnormalities in serotonin
metabolism
Serotonin, or 5-HT, is an important neurotransmitter in
the brain and the enteric nervous system. The intestinal
enterochromaffin cells, which function as sensory
transducers of intra-luminal stimuli such as pressure,
140
contain 90% of the body’s total stores of serotonin.108,109
Once released, serotonin can activate both intrinsic and
extrinsic primary afferent neurons, is integral to
gastrointestinal motility, and influences the transmission
of information to the CNS. The re-uptake of serotonin by
enterocytes is via the serotonin transporter (SERT),
where it is broken down to 5-hydroxy-indole acetic
acid (5HIAA), thereby limiting its action. Therapeutic
interventions targeting various 5-HT receptors have been
successfully tested in IBS, adding further support to the
notion that serotonin is relevant to the generation of
symptoms in IBS.110
Some of the earliest observations111 concerning the
putative role of serotonin metabolism in IBS came from
studies reporting chronic increases in enterochromaffin
cells in individuals who developed post-infectious IBS,
compared with individuals exposed to an acute enteric
infection but who recovered. Subsequently, a study112 that
measured serotonin concentrations in platelet-depleted
plasma showed reductions in the release of serotonin in
patients with IBS with constipation after a standard
meal, compared with post-infectious IBS and healthy
individuals, and a higher peak in postprandial serotonin
in post-infectious IBS than in either patients with
constipation IBS symptoms or healthy controls. Similar
results were obtained by another group of investigators113
in patients with IBS with either diarrhoea or constipation
symptoms and healthy controls under fed and fasting
conditions. This study also reported a 5-HIAA/5-HT
ratio within a normal range in patients with constipation
symptoms, but a reduced 5-HIAA/5-HT ratio in those
with IBS with diarrhoea, suggesting that patients with
diarrhoea might have reduced serotonin re-uptake, and
those with IBS with constipation might have impaired
release of serotonin. Furthermore, uptake of serotonin
by platelets was reduced in patients with IBS with
diarrhoea, and expression of serotonin transporter
mRNA in the duodenal mucosa was also reduced.114
The reduced expression of this transporter seemed to
be associated with duodenal immune activation, with
increased numbers of intraepithelial lymphocytes and
mast cells observed, and significant increases in
tryptase release. In one study,115 alterations in serotonin
metabolism in 154 patients with IBS did not have an
association with gastrointestinal symptoms, or mood.
However, the technical issues of avoiding contamination
from platelet release of serotonin in these studies remain
of concern.
Genetic factors influence serotonin metabolism.
Polymorphisms in 5-HT receptors, SERT, amd tryptophan
hydroxylase (TPH), the rate-limiting enzyme in serotonin
synthesis, have all been described in patients with IBS,
but are unconvincing. There have been numerous studies
examining the 5-HTTLPR polymorphism of SERT in
patients with IBS, summarised in a meta-analysis.116
Overall, when data were pooled from 3443 patients with
IBS and 3359 controls without IBS, there was no
www.thelancet.com/gastrohep Vol 1 October 2016

association between this polymorphism and IBS, but the
LL genotype appeared to be a risk factor for IBS with
constipation symptoms in east Asian populations.
There are few studies examining the association
between serotonin metabolism and immune activation,
mucosal inflammation, or intestinal barrier function.
Cremon and colleagues117 reported that colonic biopsies
from individuals with IBS show higher numbers of
serotonin-positive enterochromaffin cells than did
biopsies from healthy controls, but this proportion was
greater in IBS patients with diarrhoea symptoms
than in those with constipation symptoms. Mucosal
serotonin was also significantly greater among patients
with IBS in this study, and related to mast-cell counts,
and severity of abdominal pain. In a study by Barbaro
and colleagues,118 interferon gene expression in colonic
biopsy specimens from patients with IBS and
asymptomatic controls was measured by quantitative
PCR, and the amount of interferon γ was assessed by
ELISA. The effect of these on SERT expression in
Caco-2 cells in vitro was assessed, and the authors
showed that the interferon γ gene, its transcription
factor, and interferon γ protein expression were all
increased in the colonic mucosa of patients with IBS
and that, in vitro, SERT expression was downregulated
by interferon γ. Finally, a small study119 including
15 patients with IBS and 15 healthy controls reported
that oral administration of serotonin led to higher
concentrations of mucosal 5-HIAA in patients with
IBS, and also a decrease in expression of the tight
junction protein occludin. The clinical implications of
these findings remain to be established.
Evidence for a role of alterations in brain function
The observation from an epidemiological study120 that
individuals who have early adverse life events, such as
trauma or abuse, and the fact that psychological therapies
and antidepressants could be effective therapies for the
condition,121 support the concept of IBS being a disorder
of the gut that is driven by brain abnormalities. Studies
that make use of advanced imaging techniques and
analyse differences in brain activity between individuals
with IBS and healthy controls have allowed us to better
appreciate the key areas of the human brain that could be
involved in IBS. However, the absence of a control group
made up of patients with chronic non-gastrointestinal
pain, and shortage of studies identifying whether
symptoms began with gastrointestinal dysfunction first
or with psychological distress first, potentially limit
interpretation of the direction of this effect, and raises
the possibility that peripheral processes bring about the
changes in brain function observed.
Individuals with IBS show reduced inhibitory feedback
on the emotional arousal network,122 important for
controlling the autnomic modulation of gastro-
intestinal function, and increased activity after visceral
stimulation.123 Central processing of sensory information
www.thelancet.com/gastrohep Vol 1 October 2016
Review
has been shown to be aberrant in some individuals,124
with abnormalities seen on diffusion tensor imaging in
the white matter in regions of the brain that process this
information.125 The extent of these changes has been
linked to the duration and severity of symptoms,126,127
suggesting that the brain undergoes structural changes in
response to these stimuli. Rectal balloon distension in
patients with IBS showed increased engagement of
regions of the brain that are concerned with attentional
and behavioural responses to both the arrival of, and the
anticipation of, such stimuli.128–130 There could also be
heightened awareness of, or attention to, gastrointestinal
symptoms or stimuli, with reductions in the activity of
areas of the cortex involved in inhibiting or downregulating
the response to such stimuli.123
In another study131 in which anxiety and depression
levels were similar between patients with IBS and healthy
controls, the activity of the dorsolateral prefrontal cortex
was impaired during behavioural selection tasks in those
with IBS, suggesting that, even if patients with IBS are
not anxious or depressed, they have CNS dysfunction,
which can make individuals susceptible to stressors.
Early adverse life events, such as psychological trauma
before 18 years of age, can shape adult resting state
connectivity in both male and female patients in the
salience/executive (involving the thalamus, insula, and
anterior cingulate cortex) control network, a brain
network that has been implicated in the pathophysiology
of central pain amplification.132
IBS overlaps with ulcerative colitis and Crohn’s
disease,9 and in patients in stable remission from these
conditions, treatment with anti-TNFα has been shown to
improve visceral sensory function and positive attribution
biases.133 This finding is further evidence that an
inflammatory process that originates from the gut could
alter central processing of information, including visceral
afferents. Finally, learned behaviours might also induce
IBS symptoms. For example, a proportion of patients
with IBS show features of pelvic floor dyssenergia,134
suggesting that biofeedback might be an effective therapy
in these individuals.
Overall, there is no doubt that alterations of brain and
neural function play an essential role in the onset and
manifestation of symptoms in at least a subgroup of
patients. Therefore, the assumption that alterations of
brain–gut, as well as gut–brain, interactions are involved
in the pathogenesis is reasonable, although the disorder
might not always be initiated in the same organ.
Implications of pathophysiology for the
development of future therapies
Better understanding of the pathophysiological
mechanisms involved in IBS is crucial for the
development of future treatments. The clinical
categorisation of IBS is based on symptoms reported by
the patient. However, symptoms might be due to various
different underlying mechnisms and symptom-based
141
 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.

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


Search strategy and selection criteria
We searched and reviewed MEDLINE, Embase, and Embase
Classic using the terms “irritable bowel syndrome” and
“pathophysiology”, to identify relevant publications between
Jan 1, 2006, and March 31, 2016, and to provide an update
the major pathophysiological mechanisms that have now
been described in IBS. We included only publications in
English. We selected publications suitable for this Review on
the basis of novelty and effect that these new data appear to
have for contemporary and emerging concepts of
pathophysiology. 1126 publications were identified initially,
from which we selected publications whose findings were, in
our view, of the greatest importance.
cases, a completely different set of mechanisms could
lead to IBS and diarrhoea, such as abnormal bile acid
metabolism, or IBS and constipation, such as the
establishment of a methanogenic flora after infection,
with methane gas slowing intestinal transit, or a learned
behavioural response, leading to pelvic floor dysfunction
and constipation. A variety of gastrointestinal and
extraintestinal factors are likely to influence the
manifestation of IBS (figure 5).
Another factor to be taken into consideration is that
the manifestations of IBS might not be an all-or-none
event. Multiple hits could be necessary, and hence
various factors potentially contribute to the manifestation
of symptoms. On analysing the reported prevalence of
the various mechanisms, there is a possibility that a
considerable proportion of patients are affected by more
than one underlying pathway. Thus a single factor is
unlikely to be sufficient to cause IBS, but a combination
of various factors in a single patient might result in IBS.
On the basis of this finding, patients with severe
symptoms are more likely to have symptoms caused by a
combination of factors, which is a testable hypothesis,
and a possible avenue for further study.
Contributors
NJT prepared the initial outline of the report. ACF did the literature
search. GJH and ACF prepared the initial draft of the review.
All authors contributed to the subsequent revisions and final approval
of the report.
Declaration of interests
GJH has received research funding from Bayer Healthcare. ACF has
received research funding from Almirall and GE Healthcare, speakers
fees from GE Healthcare, and served on advisory boards for Almirall.
NJT has received research funding from Abbott, GI therapies, Janssen,
Prometheus, Rome Foundation and Salix, and served as an adviser for
Allergan, Adelphi Values, Commonwealth laboratories, GI therapies,
Prometheus, and Yuhan, and speaker fees for Rome Foundation.
GJH and NJT have received NHMRC funding for research into
functional gut disorders.
Acknowledgments
We thank Marjorie M Walker for providing figures 1 and 2.
References
1 Pimentel M, Talley NJ, Quigley EM, Hani A, Sharara A,
Mahachai V. Report from the multinational irritable bowel
syndrome initiative 2012. Gastroenterology 2013; 144: e1–5.
www.thelancet.com/gastrohep Vol 1 October 2016
Review
2 Lovell RM, Ford AC. Global prevalence of and risk factors for
irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol
2012; 10: 712–21.
3 Ford AC, Moayyedi P, Lacy BE, et al. American College of
Gastroenterology monograph on the management of irritable bowel
syndrome and chronic idiopathic constipation. Am J Gastroenterol
2014; 109 (suppl 1): S2–26.
4 Talley NJ, Holtmann G, Walker MM. Therapeutic strategies for
functional dyspepsia and irritable bowel syndrome based on
pathophysiology. J Gastroenterol 2015; 50: 601–13.
5 Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P.
Irritable bowel syndrome: a 10-year natural history of symptoms,
and factors that influence consultation behavior. Am J Gastroenterol
2008; 103: 1229–39.
6 Peery AF, Crockett SD, Barritt AS, et al. Burden of gastrointestinal,
liver, and pancreatic diseases in the United States. Gastroenterology
2015; 149: 1731–41.
7 Chang JY, Locke GR, McNally, MA, et al. Impact of functional
gastrointestinal disorders on survival in the community.
Am J Gastroenterol 2010; 105: 822–32.
8 Mikocka-Walus A, Turnbull D, Moulding N, Wilson I, Andrews JM,
Holtmann G. Psychological comorbidity and complexity of
gastrointestinal symptoms in clinically diagnosed irritable bowel
syndrome patients. J Gastroenterol Hepatol 2008; 23: 1137–43.
9 Halpin SJ, Ford AC. Prevalence of symptoms meeting criteria for
irritable bowel syndrome in inflammatory bowel disease:
systematic review and meta-analysis. Am J Gastroenterol 2012;
107: 1474–82.
10 Sainsbury A, Sanders DS, Ford AC. Prevalence of irritable bowel
syndrome-type symptoms in patients with celiac disease:
a meta-analysis. Clin Gastroenterol Hepatol 2013; 11: 359–65.
11 Slattery SA, Niaz O, Aziz Q, Ford AC, Farmer AD. Systematic review
with meta-analysis: the prevalence of bile acid malabsorption in the
irritable bowel syndrome with diarrhoea. Aliment Pharmacol Ther
2015; 42: 3–11.
12 Kamp EJ, Kane JS, Ford AC. Irritable bowel syndrome and
microscopic colitis: a systematic review and meta-analysis.
Clin Gastroenterol Hepatol 2016; 14: 659–68.
13 Gururatsakul M, Holloway RH, Bellon M, Bartholomeusz D,
Talley NJ, Holtmann GJ. Complicated and uncomplicated peptic
ulcer disease: altered symptom response to a nutrient challenge
linked to gastric motor dysfunction. Digestion 2014; 89: 239–46.
14 Sullivan MA, Cohen S, Snape WJ Jr. Colonic myoelectrical activity
in irritable-bowel syndrome: effect of eating and anticholinergics.
N Engl J Med 1978; 298: 878–83.
15 Ritchie J. Pain from distension of the pelvic colon by inflating a
balloon in the irritable colon syndrome. Gut 1973; 14: 125–32.
16 Henningsen P, Zimmermann T, Sattel H. Medically unexplained
physical symptoms, anxiety and depression: a meta-analytic review.
Psychosom Med 2003; 65: 528–33.
17 Patel P, Bercik P, Morgan DG, et al. Irritable bowel syndrome is
significantly associated with somatisation in 840 patients, which
may drive bloating. Aliment Pharmacol Ther 2015; 41: 449–58.
18 Tanaka Y, Kanazawa M, Fukudo S, Drossman DA. Biopsychosocial
model of irritable bowel syndrome. J Neurogastroenterol Motil 2011;
17: 131–39.
19 Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes:
one or many? Lancet 1999; 354: 936–39.
20 Koloski NA, Jones M, Kalantar J, Weltman M, Zaguirre J, Talley NJ.
The brain-gut pathway in functional gastrointestinal disorders is
bidirectional: a 12-year prospective population-based study. Gut
2012; 61: 1284–90.
21 Jones MP, Van Oudenhove L, Talley NJ. Functional gastrointestinal
disorders (FGIDs) and psychological disorders: strong evidence that
the link is bidirectional, but psychological distress is more likely to
precede a new diagnosis of an FGID. Gastroenterology 2012;
142 (suppl 1): S570 (abstr).
22 Koloski NA, Jones MP, Talley NJ. Evidence that independent
gut-to-brain and brain-to-gut pathways operate in the irritable bowel
syndrome and functional dyspepsia: a 1-year population-based
prospective study. Aliment Pharmacol Ther 2016; 44: 592–600.
23 Sykes MA, Blanchard EB, Lackner J, Keefer L, Krasner S.
Psychopathology in irritable bowel syndrome: support for a
psychophysiological model. J Behav Med 2003; 26: 361–72.
143
 Review
24 Liebregts T, Adam B, Bredack C, et al. Immune activation in
patients with irritable bowel syndrome. Gastroenterology 2007;
132: 913–20.
25 Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions
and functional bowel disorders. Gastroenterology 2014; 146: 1500–12.
26 Young E, Stoneham MD, Petruckevitch A, Barton J, Rona R.
A population study of food intolerance. Lancet 1994; 343: 1127–30.
27 David LA, Maurice CF, Carmody RN, et al. Diet rapidly and
reproducibly alters the human gut microbiome. Nature 2014;
505: 559–63.
28 Francis CY, Whorwell PJ. Bran and irritable bowel syndrome:
time for reappraisal. Lancet 1994; 344: 39–40.
29 Shepherd SJ, Parker FC, Muir JG, Gibson PR. Dietary triggers of
abdominal symptoms in patients with irritable bowel syndrome:
randomized placebo-controlled evidence. Clin Gastroenterol Hepatol
2008; 6: 765–71.
30 Murray K, Wilkinson-Smith V, Hoad C, et al. Differential effects of
FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols)
on small and large intestinal contents in healthy subjects shown by
MRI. Am J Gastroenterol 2014; 109: 110–19.
31 Elli L, Tomba C, Branchi F, et al. Evidence for the presence of
non-celiac gluten sensitivity in patients with functional gastrointestinal
symptoms: results from a multicenter randomized double-blind
placebo-controlled gluten challenge. Nutrients 2016; 8: 84.
32 Coletta M, Gates FK, Marciani L, et al. Effect of bread gluten
content on gastrointestinal function: a crossover MRI study on
healthy humans. Br J Nutr 2016; 115: 55–61.
33 Vazquez-Roque MI, Camilleri M, Smyrk T, et al. A controlled trial of
gluten-free diet in patients with irritable bowel syndrome-diarrhea:
effects on bowel frequency and intestinal function. Gastroenterology
2013; 144: 903–11.
34 Saito YA, Petersen GM, Larson JJ, et al. Familial aggregation of
irritable bowel syndrome: a family case-control study.
Am J Gastroenterol 2010; 105: 833–41.
35 Lembo A, Zaman M, Jones M, Talley NJ. Influence of genetics on
irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia:
a twin study. Aliment Pharmacol Ther 2007; 25: 1343–50.
36 Locke GR 3rd, Ackerman MJ, Zinsmeister AR, Thapa P, Farrugia G.
Gastrointestinal symptoms in families of patients with an
SCN5A-encoded cardiac channelopathy: evidence of an intestinal
channelopathy. Am J Gastroenterol 2006; 101: 1299–304.
37 Saito YA, Strege PR, Tester DJ, et al. Sodium channel mutation in
irritable bowel syndrome: evidence for an ion channelopathy.
Am J Physiol Gastrointest Liver Physiol 2009; 296: G211–18.
38 Beyder A, Mazzone A, Strege PR, et al. Loss-of-function of the
voltage-gated sodium channel NaV1.5 (channelopathies) in patients
with irritable bowel syndrome. Gastroenterology 2014; 146: 1659–68.
39 Swan C, Duroudier NP, Campbell E, et al. Identifying and testing
candidate genetic polymorphisms in the irritable bowel syndrome
(IBS): association with TNFSF15 and TNFα. Gut 2013; 62: 985–94.
40 Zucchelli M, Camilleri M, Andreasson AN, et al. Association of
TNFSF15 polymorphism with irritable bowel syndrome. Gut 2011;
60: 1671–77.
41 Sasaki A, Sato N, Suzuki N, et al. Associations between
single-nucleotide polymorphisms in corticotropin-releasing
hormone-related genes and irritable bowel syndrome. PLoS One
2016; 11: e0149322.
42 Wouters MM, Lambrechts D, Knapp M, et al. Genetic variants in
CDC42 and NXPH1 as susceptibility factors for constipation and
diarrhoea predominant irritable bowel syndrome. Gut 2014;
63: 1003–11.
43 Grasberger H, Chang L, Shih W, et al. Identification of a functional
TPH1 polymorphism associated with irritable bowel syndrome
bowel habit subtypes. Am J Gastroenterol 2013; 108: 1766–74.
44 Jun S, Kohen R, Cain KC, Jarrett ME, Heitkemper MM.
Associations of tryptophan hydroxylase gene polymorphisms with
irritable bowel syndrome. Neurogastroenterol Motil 2011; 23: 233–39.
45 Camilleri M, Kolar GJ, Vazquez-Roque MI, Carlson P, Burton DD,
Zinsmeister AR. Cannabinoid receptor 1 gene and irritable bowel
syndrome: phenotype and quantitative traits.
Am J Physiol Gastrointest Liver Physiol 2013; 304: G553–60.
46 Wong BS, Camilleri M, Carlson P, et al. Increased bile acid
biosynthesis is associated with irritable bowel syndrome with
diarrhea. Clin Gastroenterol Hepatol 2012; 10: 1009–15.
144
47 Wong BS, Camilleri M, Carlson PJ, et al. A klothoβ variant mediates
protein stability and associates with colon transit in irritable bowel
syndrome with diarrhea. Gastroenterology 2011; 140: 1934–42.
48 Ek WE, Reznichenko A, Ripke S, et al. Exploring the genetics of
irritable bowel syndrome: a GWA study in the general population
and replication in multinational case-control cohorts. Gut 2014;
64: 1774–82.
49 Beaudoin M, Goyette P, Boucher G, et al. Deep resequencing of
GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that
are associated with ulcerative colitis. PLoS Genet 2013; 9: e1003723.
50 Franke A, McGovern DP, Barrett JC, et al. Genome-wide
meta-analysis increases to 71 the number of confirmed Crohn’s
disease susceptibility loci. Nat Genet 2010; 42: 1118–25.
51 Czogalla B, Schmitteckert S, Houghton LA, et al. A meta-analysis of
immunogenetic case-control association studies in irritable bowel
syndrome. Neurogastroenterol Motil 2015; 27: 717–27.
52 Mahurkar S, Polytarchou C, Iliopoulos D, Pothoulakis C, Mayer EA,
Chang L. Genome-wide DNA methylation profiling of peripheral
blood mononuclear cells in irritable bowel syndrome.
Neurogastroenterol Motil 2016; 28: 410–22.
53 Ford AC, Thabane M, Collins SM, et al. Prevalence of uninvestigated
dyspepsia 8 years after a large waterborne outbreak of bacterial
dysentery: a cohort study. Gastroenterology 2010; 138: 1727–36.
54 Marshall JK, Thabane M, Garg AX, et al. Eight year prognosis of
postinfectious irritable bowel syndrome following waterborne
bacterial dysentery. Gut 2010; 59: 605–11.
55 Adam B, Liebregts T, Gschossmann JM, et al. Severity of mucosal
inflammation as a predictor for alterations of visceral sensory
function in a rat model. Pain 2006; 123: 179–86.
56 Liebregts T, Adam B, Bertel A, et al. Psychological stress and the
severity of post-inflammatory visceral hyperalgesia. Eur J Pain 2007;
11: 216–22.
57 Wouters MM, Van Wanrooy S, Nguyen A, et al. Psychological
comorbidity increases the risk for postinfectious IBS partly by
enhanced susceptibility to develop infectious gastroenteritis.
Gut 2016; 65: 1279–88.
58 Riddle MS, Welsh M, Porter CK, et al. The epidemiology of irritable
bowel syndrome in the US military: findings from the millennium
cohort study. Am J Gastroenterol 2016; 111: 93–104.
59 Walker MM, Talley NJ, Ingañas L, et al. Colonic spirochetosis is
associated with colonic eosinophilia and irritable bowel syndrome
in a general population in Sweden. Hum Pathol 2015; 46: 277–83.
60 Liebregts T, Adam B, Bertel A, et al. Effect of E Coli Nissle 1917 on
post-inflammatory visceral sensory function in a rat model.
Neurogastroenterol Motil 2005; 17: 410–14.
61 Verdú EF, Bercík P, Bergonzelli GE, et al. Lactobacillus paracasei
normalizes muscle hypercontractility in a murine model of
postinfective gut dysfunction. Gastroenterology 2004; 127: 826–37.
62 Jalanka-Tuovinen J, Salojärvi J, Salonen A, et al. Faecal microbiota
composition and host-microbe cross-talk following gastroenteritis and
in postinfectious irritable bowel syndrome. Gut 2014; 63: 1737–45.
63 Sundin J, Rangel I, Fuentes S, et al. Altered faecal and mucosal
microbial composition in post-infectious irritable bowel
syndrome patients correlates with mucosal lymphocyte
phenotypes and psychological distress. Aliment Pharmacol Ther
2015; 41: 342–51.
64 Carroll IM, Ringel-Kulka T, Siddle JP, Ringel Y. Alterations in
composition and diversity of the intestinal microbiota in patients
with diarrhea-predominant irritable bowel syndrome.
Neurogastroenterol Motil 2012; 24: 521–30.
65 Chassard C, Dapoigny M, Scott KP, et al. Functional dysbiosis
within the gut microbiota of patients with constipated-irritable
bowel syndrome. Aliment Pharmacol Ther 2012; 35: 828–38.
66 Ringel-Kulka T, Choi CH, Temas D, et al. Altered colonic bacterial
fermentation as a potential pathophysiological factor in irritable
bowel syndrome. Am J Gastroenterol 2015; 110: 1339–46.
67 Kim G, Deepinder F, Morales W, et al. Methanobrevibacter smithii is the
predominant methanogen in patients with constipation-predominant
IBS and methane on breath. Dig Dis Sci 2012; 57: 3213–18.
68 Lin HC. Small intestinal bacterial overgrowth: a framework for
understanding irritable bowel syndrome. JAMA 2004; 292: 852–58.
69 Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal
bacterial overgrowth reduces symptoms of irritable bowel
syndrome. Am J Gastroenterol 2000; 95: 3503–06.
www.thelancet.com/gastrohep Vol 1 October 2016

70 Bratten JR, Spanier J, Jones MP. Lactulose breath testing does not
discriminate patients with irritable bowel syndrome from healthy
controls. Am J Gastroenterol 2008; 103: 958–63.
71 Posserud I, Stotzer PO, Björnsson ES, Abrahamsson H, Simrén M.
Small intestinal bacterial overgrowth in patients with irritable bowel
syndrome. Gut 2007; 56: 802–08.
72 Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a
nonabsorbed oral antibiotic (rifaximin) on the symptoms of the
irritable bowel syndrome: a randomized trial. Ann Int Med 2006;
145: 557–63.
73 Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for
patients with irritable bowel syndrome without constipation.
N Engl J Med 2011; 364: 22–32.
74 Xu D, Gao J, Gillilland M 3rd, et al. Rifaximin alters intestinal
bacteria and prevents stress-induced gut inflammation and visceral
hyperalgesia in rats. Gastroenterology 2014; 146: 484–96.
75 Ford AC, Quigley EM, Lacy BE, et al. Efficacy of prebiotics,
probiotics, and synbiotics in irritable bowel syndrome and chronic
idiopathic constipation: systematic review and meta-analysis.
Am J Gastroenterol 2014; 109: 1547–61.
76 Ford AC, Talley NJ. Mucosal inflammation as a potential etiological
factor in irritable bowel syndrome: a systematic review.
J Gastroenterol 2011; 46: 421–31.
77 Collins SM. Is the irritable gut an inflamed gut?
Scand J Gastroenterol Suppl 1992; 192: 102–05.
78 Wensaas KA, Langeland N, Hanevik K, Mørch K, Eide GE,
Rortveit G. Irritable bowel syndrome and chronic fatigue 3 years
after acute giardiasis: historic cohort study. Gut 2012; 61: 214–19.
79 Cremon C, Stanghellini V, Pallotti F, et al. Salmonella
gastroenteritis during childhood is a risk factor for irritable bowel
syndrome in adulthood. Gastroenterology 2014; 147: 69–77.
80 Mearin F, Perelló A, Balboa A, et al. Pathogenic mechanisms of
postinfectious functional gastrointestinal disorders: results 3 years
after gastroenteritis. Scand J Gastroenterol 2009; 44: 1173–85.
81 Gwee KA, Collins SM, Read NW, et al. Increased rectal mucosal
expression of interleukin 1β in recently acquired post-infectious
irritable bowel syndrome. Gut 2003; 52: 523–26.
82 Coëffier M, Gloro R, Boukhettala N, et al. Increased
proteasome-mediated degradation of occludin in irritable bowel
syndrome. Am J Gastroenterol 2010; 105: 1181–88.
83 Zhen Y, Chu C, Zhou S, Qi M, Shu R. Imbalance of tumor necrosis
factor-α, interleukin-8 and interleukin-10 production evokes barrier
dysfunction, severe abdominal symptoms and psychological
disorders in patients with irritable bowel syndrome-associated
diarrhea. Mol Med Rep 2015; 12: 5239–45.
84 Ohman L, Lindmark AC, Isaksson S, et al. B-cell activation in
patients with irritable bowel syndrome (IBS).
Neurogastroenterol Motil 2009; 21: 644–50.
85 Vicario M, González-Castro AM, Martínez C, et al. Increased humoral
immunity in the jejunum of diarrhoea-predominant irritable bowel
syndrome associated with clinical manifestations. Gut 2015;
64: 1379–88.
86 Hughes PA, Harrington AM, Castro J, et al. Sensory neuro-immune
interactions differ between irritable bowel syndrome subtypes.
Gut 2013; 62: 1456–65.
87 Hughes PA, Moretta M, Lim A, et al. Immune derived opioidergic
inhibition of viscerosensory afferents is decreased in irritable bowel
syndrome patients. Brain Behav Immun 2014; 42: 191–203.
88 Marshall JK, Thabane M, Garg AX, et al. Intestinal permeability in
patients with irritable bowel syndrome after a waterborne outbreak
of acute gastroenteritis in Walkerton, Ontario.
Aliment Pharmacol Ther 2004; 20: 1317–22.
89 Vazquez-Roque MI, Camilleri M, Smyrk T, et al. Association of
HLA-DQ gene with bowel transit, barrier function, and
inflammation in irritable bowel syndrome with diarrhea.
Am J Physiol Gastrointest Liver Physiol 2012; 303: G1262–69.
90 Shulman RJ, Jarrett ME, Cain KC, Broussard EK, Heitkemper MM.
Associations among gut permeability, inflammatory markers, and
symptoms in patients with irritable bowel syndrome. J Gastroenterol
2014; 49: 1467–76.
91 Turcotte JF, Kao D, Mah SJ, et al. Breaks in the wall: increased gaps
in the intestinal epithelium of irritable bowel syndrome patients
identified by confocal laser endomicroscopy (with videos).
Gastrointest Endosc 2013; 77: 624–30.
www.thelancet.com/gastrohep Vol 1 October 2016
Review
92 Bertiaux-Vandaële N, Youmba SB, Belmonte L, et al. The expression
and the cellular distribution of the tight junction proteins are altered
in irritable bowel syndrome patients with differences according to
the disease subtype. Am J Gastroenterol 2011; 106: 2165–73.
93 Wilcz-Villega EM, McClean S, O’Sullivan MA. Mast cell tryptase
reduces junctional adhesion molecule-A (JAM-A) expression in
intestinal epithelial cells: implications for the mechanisms of
barrier dysfunction in irritable bowel syndrome. Am J Gastroenterol
2013; 108: 1140–51.
94 Martínez C, Lobo B, Pigrau M, et al. Diarrhoea-predominant
irritable bowel syndrome: an organic disorder with structural
abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160–68.
95 Vivinus-Nébot M, Dainese R, Anty R, et al. Combination of allergic
factors can worsen diarrheic irritable bowel syndrome: role of
barrier defects and mast cells. Am J Gastroenterol 2012; 107: 75–81.
96 Fritscher-Ravens A, Schuppan D, Ellrichmann M, et al.
Confocal endomicroscopy shows food-associated changes in the
intestinal mucosa of patients with irritable bowel syndrome.
Gastroenterology 2014; 147: 1012–20.
97 Talley NJ, Fodor AA. Bugs, stool, and the irritable bowel syndrome:
too much is as bad as too little? Gastroenterology 2011; 141: 1555–59.
98 Lundåsen T, Gälman C, Angelin B, Rudling M. Circulating intestinal
fibroblast growth factor 19 has a pronounced diurnal variation and
modulates hepatic bile acid synthesis in man. J Intern Med 2006;
260: 530–36.
99 Triantis V, Saeland E, Bijl N, Oude-Elferink RP, Jansen PL.
Glycosylation of fibroblast growth factor receptor 4 is a key regulator
of fibroblast growth factor 19-mediated down-regulation of
cytochrome P450 7A1. Hepatology 2010; 52: 656–66.
100 Hofmann AF. The syndrome of ileal disease and the broken
enterohepatic circulation: cholerhetic enteropathy. Gastroenterology
1967; 52: 752–57.
101 Thaysen EH, Pedersen L. Idiopathic bile acid catharsis. Gut 1976;
17: 965–70.
102 Bajor A, Tornblom H, Rudling M, Ung KA, Simrén M.
Increased colonic bile acid exposure: a relevant factor for symptoms
and treatment in IBS. Gut 2015; 64: 84–92.
103 Aziz I, Mumtaz S, Bholah H, Chowdhury FU, Sanders DS,
Ford AC. High prevalence of idiopathic bile acid diarrhea among
patients with diarrhea-predominant irritable bowel syndrome
based on Rome III criteria. Clin Gastroenterol Hepatol 2015;
13: 1650–55.
104 Shin A, Camilleri M, Vijayvargiya P, et al. Bowel functions, fecal
unconjugated primary and secondary bile acids, and colonic transit
in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol
2013; 11: 1270–75.
105 Camilleri M, Busciglio I, Acosta A, et al. Effect of increased bile acid
synthesis or fecal excretion in irritable bowel syndrome-diarrhea.
Am J Gastroenterol 2014; 109: 1621–30.
106 Duboc H, Rainteau D, Rajca S, et al. Increase in fecal primary bile
acids and dysbiosis in patients with diarrhea-predominant irritable
bowel syndrome. Neurogastroenterol Motil 2012; 24: 513–20.
107 Dior M, Delagrèverie H, Duboc H, et al. Interplay between bile acid
metabolism and microbiota in irritable bowel syndrome.
Neurogastroenterol Motil 2016; published online April 5.
http://dx.doi.org/10.1111/nmo.12829.
108 Berger M, Gray JA, Roth BL. The expanded biology of serotonin.
Annu Rev Med 2009; 60: 355–66.
109 Gershon MD, Wade PR, Kirchgessner AL, Tamir H. 5-HT receptor
subtypes outside the central nervous system: roles in the physiology
of the gut. Neuropsychopharmacology 1990; 3: 385–95.
110 Gershon MD, Tack J. The serotonin signaling system: from basic
understanding to drug development for functional GI disorders.
Gastroenterology 2007; 132: 397–414.
111 Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of
enterochromaffin cell hyperplasia, anxiety, and depression in
postinfectious IBS. Gastroenterology 2003; 125: 1651–59.
112 Dunlop SP, Coleman NS, Blackshaw E, et al. Abnormalities of
5-hydroxytryptamine metabolism in irritable bowel syndrome.
Clin Gastroenterol Hepatol 2005; 3: 349–57.
113 Atkinson W, Lockhart S, Whorwell PJ, Keevil B, Houghton LA.
Altered 5-hydroxytryptamine signaling in patients with
constipation- and diarrhea-predominant irritable bowel syndrome.
Gastroenterology 2006; 130: 34–43.
145
 Review
114 Foley S, Garsed K, Singh G, et al. Impaired uptake of serotonin by
platelets from patients with irritable bowel syndrome correlates with
duodenal immune activation. Gastroenterology 2011; 140: 1434–43.
115 Thijssen AY, Mujagic Z, Jonkers DM, et al. Alterations in serotonin
metabolism in the irritable bowel syndrome. Aliment Pharmacol Ther
2016; 43: 272–82.
116 Zhang ZF, Duan ZJ, Wang LX, Yang D, Zhao G, Zhang L.
The serotonin transporter gene polymorphism (5-HTTLPR) and
irritable bowel syndrome: a meta-analysis of 25 studies.
BMC Gastroenterol 2014; 14: 23.
117 Cremon C, Carini G, Wang B, et al. Intestinal serotonin release,
sensory neuron activation, and abdominal pain in irritable bowel
syndrome. Am J Gastroenterol 2011; 106: 1290–98.
118 Barbaro MR, Di Sabatino A, Cremon C, et al. Interferon-gamma is
increased in the gut of patients with irritable bowel syndrome and
modulates serotonin metabolism. Am J Physiol Gastrointest Liver Physiol
2016; 310: G439–47.
119 Keszthelyi D, Troost FJ, Jonkers DM, et al. Visceral hypersensitivity
in irritable bowel syndrome: evidence for involvement of serotonin
metabolism—a preliminary study. Neurogastroenterol Motil 2015;
27: 1127–37.
120 Park SH, Videlock EJ, Shih W, Presson AP, Mayer EA, Chang L.
Adverse childhood experiences are associated with irritable bowel
syndrome and gastrointestinal symptom severity.
Neurogastroenterol Motil 2016; 28: 1252–60.
121 Ford AC, Quigley EM, Lacy BE, et al. Effect of antidepressants and
psychological therapies, including hypnotherapy, in irritable bowel
syndrome: systematic review and meta-analysis. Am J Gastroenterol
2014; 109: 1350–65.
122 Hall GB, Kamath MV, Collins S, et al. Heightened central affective
response to visceral sensations of pain and discomfort in IBS.
Neurogastroenterol Motil 2010; 22: 276–80.
123 Tillisch K, Mayer EA, Labus JS. Quantitative meta-analysis identifies
brain regions activated during rectal distension in irritable bowel
syndrome. Gastroenterology 2011; 140: 91–100.
124 Hong JY, Kilpatrick LA, Labus J, et al. Patients with chronic visceral
pain show sex-related alterations in intrinsic oscillations of the
resting brain. J Neurosci 2013; 33: 11994–2002.
125 Ellingson BM, Mayer E, Harris RJ, et al. Diffusion tensor imaging
detects microstructural reorganization in the brain associated with
chronic irritable bowel syndrome. Pain 2013; 154: 1528–41.
146
126 Jiang Z, Dinov ID, Labus J, et al. Sex-related differences of cortical
thickness in patients with chronic abdominal pain. PLoS One 2013;
8: e73932.
127 Piche M, Chen JI, Roy M, Poitras P, Bouin M, Rainville P.
Thicker posterior insula is associated with disease duration in
women with irritable bowel syndrome (IBS) whereas thicker
orbitofrontal cortex predicts reduced pain inhibition in both IBS
patients and controls. J Pain 2013; 14: 1217–26.
128 Elsenbruch S, Rosenberger C, Bingel U, Forsting M,
Schedlowski M, Gizewski ER. Patients with irritable bowel
syndrome have altered emotional modulation of neural responses
to visceral stimuli. Gastroenterology 2010; 139: 1310–19.
129 Elsenbruch S, Rosenberger C, Enck P, Forsting M, Schedlowski M,
Gizewski ER. Affective disturbances modulate the neural
processing of visceral pain stimuli in irritable bowel syndrome:
an fMRI study. Gut 2010; 59: 489–95.
130 Larsson MB, Tillisch K, Craig AD, et al. Brain responses to visceral
stimuli reflect visceral sensitivity thresholds in patients with
irritable bowel syndrome. Gastroenterology 2012; 142: 463–72.
131 Aizawa E, Sato Y, Kochiyama T, et al. Altered cognitive function of
prefrontal cortex during error feedback in patients with irritable
bowel syndrome, based on fMRI and dynamic causal modeling.
Gastroenterology 2012; 143: 1188–98.
132 Gupta A, Kilpatrick L, Labus J, et al. Early adverse life events and
resting state neural networks in patients with chronic abdominal
pain: evidence for sex differences. Psychosom Med 2014;
76: 404–12.
133 Gray M, Chao C-Y, Talley NJ, Koloski NA, Holtmann G. In patients
with Crohn’s disease functional MRI reveals an alteration of
amygdala function induced by anti-TNFα that is associated with
positive self-attribution biases and reduced symptom response to a
standardised nutrient challenge. Gastroenterology 2016;
150 (suppl 1): S526–27 (abstr).
134 Suttor VP, Prott GM, Hansen RD, Kellow JE, Malcolm A.
Evidence for pelvic floor dyssynergia in patients with irritable bowel
syndrome. Dis Colon Rectum 2010; 53: 156–60.
135 Keely S, Walker MM, Marks E, Talley NJ. Immune dysregulation in
the functional gastrointestinal disorders. Eur J Clin Invest 2015;
45: 1350–59.
www.thelancet.com/gastrohep Vol 1 October 2016