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PRIMER

Irritable bowel syndrome
Paul Enck1, Qasim Aziz2, Giovanni Barbara3, Adam D. Farmer2, Shin Fukudo4,
Emeran A. Mayer5, Beate Niesler6, Eamonn M. M. Quigley7, Mirjana Rajilic´-Stojanovic´8,
Michael Schemann9, Juliane Schwille-Kiuntke1, Magnus Simren10, Stephan Zipfel1
and Robin C. Spiller11
Abstract | Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with a high population
prevalence. The disorder can be debilitating in some patients, whereas others may have mild or
moderate symptoms. The most important single risk factors are female sex, younger age and
preceding gastrointestinal infections. Clinical symptoms of IBS include abdominal pain or discomfort,
stool irregularities and bloating, as well as other somatic, visceral and psychiatric comorbidities.
Currently, the diagnosis of IBS is based on symptoms and the exclusion of other organic diseases,
and therapy includes drug treatment of the predominant symptoms, nutrition and psychotherapy.
Although the underlying pathogenesis is far from understood, aetiological factors include increased
epithelial hyperpermeability, dysbiosis, inflammation, visceral hypersensitivity, epigenetics and
genetics, and altered brain–gut interactions. IBS considerably affects quality of life and imposes a
profound burden on patients, physicians and the health-care system. The past decade has seen
remarkable progress in our understanding of functional bowel disorders such as IBS that will be
summarized in this Primer.

Irritable bowel syndrome (IBS) is a functional bowel IBS is a multifactorial disease. Hence, the under­
disorder (that is, not associated with structural or bio­ lying pathogenesis is considered complex and the pre­
chemical abnormalities that are detectable with the cur­ cise molecular pathophysiology is far from understood.
rent routine diagnostic tools) characterized by abdominal Several functional alterations have been described, such
pain or discomfort, stool irregularities and bloating as altered visceral sensitivity, functional brain alterations,
(BOX 1). Symptoms can be debilitating in many individ­ bowel motility and secretory dysfunctions, and somatic
uals, but may be mild or moderate in other patients. and psychiatric comorbidities. Furthermore, gastroin­
In addition, IBS is often associated with other somatic testinal abnormalities — such as immune activation,
comorbidities (for example, pain syndromes, overactive gut dysbiosis (microbial imbalance), impaired mucosal
bladder and migraine), psychiatric conditions (includ­ functions, nerve sensitization, post-infectious plasticity,
ing depression and anxiety) and visceral sensitivity. The altered expression and release of mucosal and immune
population prevalence of IBS is high (~11%) and the mediators, and altered gene expression profiles — have
condition has considerable consequences for quality of been associated with IBS. However, a coherent link
life (QOL) that are comparable to other chronic diseases, between particular pathologies and IBS symptoms is
such as diabetes mellitus and hepatitis. IBS is diagnosed yet to be established.
based on symptoms, and a distinction is made between Moreover, results from studies assessing the contrib­
the following subtypes of IBS: IBS with pain or discom­ ution of most of the proposed pathological factors are
Correspondence to P.E.
fort and predominant constipation (IBS‑C), IBS with inconsistent and the particular aetiology is often not
Department of Internal
Medicine VI (Psychosomatic
diarrhoea (IBS‑D), mixed IBS (IBS‑M) and unsubtyped related to particular gut symptoms. For example, some
Medicine and IBS (IBS‑U) (FIG. 1). Moreover, other ­diseases (including studies have found evidence for gut micro-­inflammation
Psychotherapy), other functional gastrointestinal diseases, such as func­ in IBS, whereas others could not confirm this finding,
University Hospital Tübingen, tional dyspepsia and gastroesophageal reflux disease) that despite similar gastrointestinal symptoms. Such dis­
Osianderstraße 5,
may cause the typical IBS symptoms should be excluded. crepancies, which also apply to the other biomarker
72076 Tübingen, Germany.
paul.enck@uni-tuebingen.de Although a substantial proportion of patients will experi­ candidates (not only to inflammation), strongly sug­
ence spontaneous remission over time, there is currently gest the existence of IBS subpopulations, which, despite
Article number: 16014
doi:10.1038/nrdp.2016.14 no treatment that cures IBS; relief of s­ ymptoms is the the similar­ity in gut symptoms, can be defined and
Published online 24 March 2016 most that can be achieved. distinguished by their pathophysiology and in-depth

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PRIMER

Author addresses most European countries, the United States and China1.
Population statistics for IBS in most African and many
1
Department of Internal Medicine VI (Psychosomatic Medicine and Psychotherapy), Asian countries are unavailable, which might point to
University Hospital Tübingen, Tübingen, Germany. the inability to differentiate between infectious diarrhoea
2
Wingate Institute of Neurogastroenterology, Barts and London School of Medicine and and IBS in tropical countries, especially in those nations
Dentistry, Queen Mary University of London, London, UK.
with poor health-care systems or limited patient access
3
Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, Bologna, Italy.
4
Department of Behavioural Medicine, Tohoku University Graduate School of Medicine, to medical care, or to less attention of the health-care
Sendai, Japan. system for functional disorders, once an acute ­infection
5
Oppenheimer Center for Neurobiology of Stress, Division of Digestive Diseases, has been excluded2.
David Geffen School of Medicine at UCLA, Los Angeles, California, USA. Gathering subtype-specific prevalence information is
6
Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, complex. IBS subtypes overlap considerably in terms of
Germany. symptoms, and patients vary over time in terms of their
7
Lynda K and David M Underwood Center for Digestive Disorders, Division of predominant symptoms, and thus switch subtype3. The
Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical few population studies that have differentiated between
College, Houston, Texas, USA. IBS subtypes suggest that, in countries with a total IBS
8
Department of Biochemical Engineering and Biotechnology, Faculty of Technology
prevalence of ~10%, IBS‑C and IBS‑D each account for
and Metallurgy, University of Belgrade, Belgrade, Serbia.
9
Department of Human Biology, Technical University Munich, Freising-Weihenstephan, one-third of the affected population4. Incidence rates of
Germany. IBS (that is, the annual occurrence of new cases) are not
10
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, reported for most countries, but a few long-term sur­
Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. veys (≥10 years) in the United States allow for an esti­
11
NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of mation of the annual incidence in the range of 1–2%5.
Nottingham, Nottingham, UK. At the same time, disappearance rates of 2% have been
reported6, indicating spontaneous disease remission.

assessments of clinical and molecular biomarker clus­ Association between IBS and other disorders
ters. The same heterogeneity is evident with respect to Not only do IBS subtypes overlap6 but population-based
clinical diagnosis and management. Indeed, medical studies also report a substantial overlap of ≥20% with
treatment, nutritional intervention and psychotherapy other functional gastrointestinal disorders of the upper
lack consistent and homogeneous efficacy, but can be and lower gastrointestinal system: functional dyspepsia,
effective in some subgroups. heartburn, gastroesophageal reflux disease and nausea
This Primer summarizes recent progress in our on the one hand7, and diarrhoea, incontinence, pelvic
understanding of IBS prevalence, comorbidities, floor dyssynergia and constipation on the other hand8.
QOL and the putative roles of inflammation, genet­ An overlap of IBS with inflammatory bowel diseases
ics, the intestinal microbiota and the brain–gut axis (IBDs; including Crohn disease and ulcerative colitis)
in IBS pathogenesis. Furthermore, we will discuss the during remission phases has been proposed9 but is not
current diagnostic approach and highlight the thera­ mutually agreed on10.
peutic options in IBS, including drugs, nutrition Other IBS-associated disorders (FIG. 3) include func­
and psychotherapy. tional non-gastrointestinal syndromes, such as uro­logical
chronic pelvic pain syndrome (this term includes inter­
Epidemiology stitial cystitis and chronic prostatitis), vulvodynia, over­
Global prevalence and incidence active bladder, prostatic pain syndrome, pre­menstrual
Prevalence rates of IBS vary between 1.1% and 45%, syndrome, sexual (including erectile) dysfunction,
based on population studies from countries world­ chronic pelvic pain, fibromyalgia syndrome, chronic
wide (FIG. 2; Supplementary information S1 (table)), fatigue syndrome, migraine, eating disorders, nutri­
with a pooled global prevalence of 11.2% (95% CI: tional intolerances and others11. All of these syndromes
9.8–12.8)1. Prevalence rates of 5–10% are reported for consider­ably overlap with IBS in population studies to
a degree that is often beyond what is expected based on
the prevalence rates of the individual diseases. Given that
many of these conditions are only diagnosed in special­
Box 1 | IBS definition and subtypes: Rome III criteria
ized centres, it has been questioned as to whether some
Diagnostic criteria* for irritable bowel syndrome (IBS) include recurrent abdominal of these conditions — for example, IBS and chronic ­pelvic
pain or discomfort‡ at least 3 days per month in the past 3 months associated with two pain — are one and the same disease12.
or more of the following: In addition, most epidemiological studies note the
• Improvement with defaecation presence of psychiatric comorbidities (such as anxiety,
• Onset associated with a change in the frequency of stool depression, somatization or neuroticism) not only for
• Onset associated with a change in the form (appearance) of stool IBS but also for these IBS-associated diseases. Again, the
*Criteria fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis. rates are above the expected levels for IBS and the popu­

Discomfort means an uncomfortable sensation not described as pain. In pathophysiological lation prevalence of these symptoms13. Thus, the entire
research and clinical trials, a pain or discomfort frequency of at least 2 days per week during disease entity (IBS, functional gastrointestinal disorders
screening evaluation for subject eligibility. Adapted with permission from REF. 119, American and other functional non-gastrointestinal dis­orders) has
Gastroenterology Association.
been included in the term ‘somatic symptom disorder’

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with a median prevalence from the luminal to the basolateral side of gut tissue NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 3 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . This association seems to differ with respect to epidemic infectious events that affect many people at the same time and individual infections. In addition to these putative bio­ not receive adequate attention with respect to their markers.82) across many population-based studies16. gut IBS (IBS‑M) and unsubtyped IBS (IBS‑U). . The most valid dis­ tinction may be a sudden onset that is well remembered IBS-U IBS-D by the patient and is associated with fever. Based on symptoms alone. and preceding gastrointestinal infections of bac­terial. A l l r i g h t s r e s e r v e d . and the percentage of time this bowel form has to be present to symptom generation is rapidly advancing. which has detected enlarged spaces Post-infectious IBS between epithelial cells and cytoskeletal condensation Several studies have shown an association between IBS in gut biopsies of patients with IBS-D26. as depression and anxiety. microbiota.7–11. Adapted with permission from REF.23. family meability is considered an early event in IBS that leads to aggregation has been reported18 that is driven by genet­ low-grade immune cell infiltration of the gut mucosa25. consultation behaviour and biological functions The epithelial barrier (for example. The epithelial gut lining represents an enormous sur­ The incidence of IBS decreases with advancing age face that is in constant contact with the environment (>50 years)1. Thus. but inflammatory biomarkers may. PRIMER 100 of ~10%22. our understanding of the potential mechanisms the four possible irritable bowel syndrome (IBS) subtypes according to bowel form at a involved in gut dysfunction. Patients with these factors might have a role as potential biomark­ IBS who were treated by psychiatrists frequently did ers of disease (BOX 3). ics19 as well as by social learning 20.1) for the development of IBS after sies. the epithelial barrier. In addition. 4). with explanations varying between sex-different health care. have been acknowledged and will be discussed 1. The pooled odds ratio is 7. hormonal regulation of gut functions). a median prevalence of 10% might better reflect the true prevalence of post-infectious IBS than the extreme values reported in individual studies. the brain–gut axis and Disorders 5th Edition (DSM‑5)14 and in psychiatric or the enteric nervous system (ENS) (FIG. BOX 2 lists the per­ Indeed. However. prevalence data are reported to be higher (15–30%) in epidemic events22 and lower (5–10%) 75 following travellers’ diarrhoea23. bloody stools and a positive laboratory stool test for an infective agent. younger age.67 (95% CI: down). the immune system. but is similar in children and adolescents and with billions of bacteria that constantly challenge compared with adults and does not necessarily trans­ the intestinal immune system. functions. have shown excessive passage of macromolecules infectious gastroenteritis24. A two-dimensional Nature Reviews | Diseasegraph of Primers mined. which are known to respond to abdominal symptoms (bottom‑up). presence of this remodelling in IBS has been provided by electron microscopy. in IBS‑D in particular. food antigens and bile acids elicit abnormal American Gastroenterology Association. such as travel­ lers’ diarrhoea. psychosomatic clinical management 15. disease.3 lial membrane properties on colonic mucosal biop­ (95% CI: 4. visceral sensation and particular point in time. 0 0 25 50 75 100 Mechanisms/pathophysiology Loose or watery stools (%) Although the aetiology of IBS remains largely undeter­ Figure 1 | IBS subtypes according to the Rome III criteria. although some reports have also although some of these factors have only been identi­ shown that IBS‑C and IBS‑M might also involve an fied in individual studies21 or have been found to vary increase in epithelial permeability 25. Ussing chamber experiments. post-infectious IBS cannot 25 be distinguished from IBS without an infectious origin. in IBS. 50 Risk factors for the development of post-infectious IBS are female sex. including the hypothalamus–pituitary–adrenal in the Diagnostic and Statistical Manual of Mental (HPA) axis. Evidence for the between countries and settings. responses in the key regulators of sensorimotor func­ tions. Increased intestinal per­ mit from childhood to adulthood17. and psychosocial Risk factors for IBS factors (‘stress’) that influence physiological (intestinal) The best-documented risk factor for IBS is female sex. psychosocial and social factors that have marily described in post-infectious IBS in general and been found to be associated with increased risk of IBS. Accordingly. increased epithelial permeability has been pri­ sonal. which measure epithe­ viral or other origin22. mixed-type evidence suggests that. Growing meet the criteria for IBS with constipation (IBS‑C).53–1. the severity of the initial IBS-C IBS-M infection and premorbid psychological conditions22–24. That is. in more detail. 119. psychological factors (‘psychomarkers’) such ­gastrointestinal symptoms before the release of DSM‑5. such as motility and visceral sensitivity (top- which is associated with an odds ratio of 1. these differences are presumably due to different reporting biases in these Hard or lumpy stools (%) populations. IBS with diarrhoea (IBS‑D).

Thus. which in turn influences bowel habit expression of tight junction proteins. outlined below. considerable role in some patients with IBS. including a reduc­ by acceler­ating colonic transit and inducing diarrhoea tion in the expression of occludin and zonula occludens and visceral hypersensitivity in IBS32–34. inflammatory mediators including in the pathophysiology of IBS based on the clinical obser­ eicosanoids. Of note. diarrhoea and pain severity 26. dysbiosis and food allergies25. . although both studies clearly indicated that intolerance showed epithelial breaks and increased inter­ subgroups. IBS. villous spaces.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . This may involve the participation of ENS for the development of IBS24. A l l r i g h t s r e s e r v e d .PRIMER IBS prevalence (%) <5 5–9 10–14 15–19 20–29 >30 N/A Figure 2 | IBS prevalence in population studies around the world. claudin 2 and cingulin. Tight junction changes are probably the result of both bacterial-mediated and proteasome-­ Immune response mediated degradation triggered by low-grade inflamma­ It has been argued that the immune system participates tion29. as junction proteins claudin 1. comes from the evidence that about one-third of patients Increased intestinal permeability has been linked to with IBD in remission experi­ence IBS-like symptoms35. N/A. ous factors could be involved. hence providing the func­ A subset of patients with features compatible with IBS‑D tional correlate for the described structural epithelial present with increased levels of total faecal bile acids barrier defects27. suggesting that this mech­ These inferential data have been subsequently enriched anism might have a role in symptom generation in IBS. genes protein 1 (REFS 25. Confocal laser with IBS demonstrated that the anti-inflammatory agent endo­microscopy of the duodenal mucosa of patients with mesalazine was not superior to placebo in alleviating IBS IBS after challenge with food to which the patients reported symptoms. by quantitative immuno­histochemistry data showing Although the exact causes underlying the ‘leaky’ gut barrier increased infiltration of T cells and mast cells in the mucosa in IBS remain elusive. as outlined below. including genetics. irritable bowel syndrome.38 in patients genetics. which may amplify these effects27.30.nature. not applicable. Pooled prevalence data perReviews Nature country are colour‑ | Disease Primers coded. Accordingly. in biopsies obtained from patients with IBS compared Bile acids with asymptomatic controls. particularly patients with post-infectious IBS. epi­ Two randomized controlled trials (RCTs)37. These studies suggest a causative effect of food ies confirm the hypothesis that immune activation has a in the increased epithelial permeability in IBS31. these stud­ ability. histamine and proteases increase intestinal vation that infectious gastroenteritis is a strong risk factor permeability. These findings have recently been involved in bile acid metabolism and function have been corroborated by genetic and epigenetic findings in tight reported to be associated with colonic transit in IBS‑D. caused by increased excretion and synthesis of serum C4 Morphological and functional changes in intestinal (7α‑hydroxy‑4‑cholesten‑3‑one. a surrogate for bile permeability are related to abnormal gene and protein acid synthesis). Additional clinical support neurons.28). indicative of increased intestinal perme­ had sustained symptomatic responses. 1 are supplemented by studies from another nine countries (see Supplementary information S1 (table)). 4 | 2016 | VOLUME 2 www. Data from REF. it has been postulated that numer­ of the small and large intestine of some patients with IBS36.

In addition. which have been implicated in the pathogenesis of sensory Although mucosal immunocyte numbers are not hyperalgesia. this was not observed if biopsy supernatants from patients with IBS contained control supernatants were used48.1% increase in mucosal neu­ that the microbiota might contribute to the observed rons and neuronal outgrowth. chronic For each of the listed disorders. For instance. mucosal mediators from n ce ic p era ros patients with IBS evoked higher activation of visceral l ta to ti and somatic pain pathways when applied to intestinal in a usea An N Hea tis n od preparations isolated from rodents42. given to animal models46. as indicated ctiv dy isor al Dia by the activation of human ENS neurons via mast cell-­ e bla tion IBS-U Eating d rrho derived histamine. overlap with IBS symptoms has been reported in the exposure to soluble mediators from patients with literature11. Colon tissue samples from patients with always increased in IBS. PRIMER Somatic symptom disorder Neuroimmune interactions Mucosal mediators isolated from biopsy samples from patients with IBS have been extensively studied to identify their effect on bowel physiology and sensory perception in isolated tissues or laboratory ­animals41. there is strong functional and IBS have increased levels of specific polyunsaturated molecular evidence of an increased state of activation of fatty acids. gastroesophageal reflux disease. Indeed. origin. The different components should be viewed as layers of complexity: the IBS IBS-D was shown to sensitize noci­ceptive neurons47.42 (FIG. mixed-type IBS. . including pro­ Recent data support the concept that the chronic teases and histamine36 as well as poly­unsaturated fatty release of factors with known effects on nerves in the acid metabolites40. prob­ e pa Pe ti nd lv ic fl Co ns r se ably pancreatic or bacterial. IBS-U. some of the serine and cysteine proteases that l d ysf ine are present at a higher level in the mucosa or stool of nc ia sy n xua tio patients with IBS than controls might be of other. sis factor (TNF) and TRPA1. respectively. In line with these rom eo oor dyssynergia findings. with IBS compared with healthy controls49. By contrast. importance of those visceral afferents that express TRPs grade immune activation in IBS36. suggesting that increased activation hypersensitivity of visceral afferents via tumour necro­ of mast cells is involved in the condition39. Mucosal immune intestinal milieu might not only have functional effects activation is coupled with altered gene expression but could also affect the ENS and sensory fibres in a of several components of the host mucosal immune structural manner. GERD. enteroendocrine cell-derived sero­ Func dder ea tonin (also known as 5‑hydroxytryptamine (5‑HT)) and protease-dependent mechanisms 30. nic pelvic pain Ch Chro ron Compared with controls. Attention has been directed to agonists of the tran­ IBS-M. serine proteases in faecal supernatants from e til hr individuals with IBS‑D evoked colonic hypersensitiv­ ec Er C on ic S ity to distension44. mucosal Functional non-gastrointestinal disorders IBS mediators from patients with IBS and visceral hyper­ sensitivity — but not from normosensitive patients Figure 3 | IBS-associated comorbidities. than controls. plasticity alterations. A model of irritable Naturebowel Reviews | Disease syndrome Primers (IBS) and with IBS — acutely activated spinal nociceptors when its associations with other clinical. premenstrual syndrome. Further work showed the implica­ tion of serine proteases that act on protease-­activated nociceptors located on intestinal nerves convey­ing Psychiatric disorders Functional gastrointestinal disorders pain stimuli to the brain 43. subtypes are part of the group of functional bowel disorders. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 5 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . in patients immune activation36. IBS with constipation. sient receptor potential cation channels (TRPs). which stimulate sensory neurons from immune cells in about half of patients with IBS36. IBS with diarrhoea. Data mice via the activation of TRP subfamily V member 4 from several studies point to the importance of mast cells (TRPV4) and generate visceral hypersensitivity 40. The as key components of inducing and maintaining low.7% and 56. faecal cysteine protease fat M ig u s P activity was augmented in some patients with IBS‑C e sy ndrome d ro me Pain sy n compared with controls and increased protease activity correlated with abdominal pain and impaired epithe­ S o m at i z a t i o n lial permeability 45. higher in IBS symptomatology is underscored by the finding proportions of mast cells were found in a degranulating that peripheral blood mononuclear cell (PBMC) super­ state in colonic biopsies from patients with IBS than in natants from patients with IBS‑D cause mechanical control samples. IBS-D. PMS.43. Mast cells and sio rtb xie sia Fo Ov ur ep res n enteroendocrine cells have been suggested to partici­ ty era p s s der Dep pate in this abnormal neural signalling. For example. intestinal. these are part of all kinds of implying that c­ hronicity is associated with long-lasting functional disorders and these again are part of a ‘layer’ of psychiatric disorders. unsubtyped IBS. In the same model. immunohisto­chemistry response to microbial pathogens (see below). u n cti o n Fibromyalg IBS-C IBS-M IBS-D GERD In co nt Although most of the proteases are secreted by mast cells. Importantly. suggesting showed a 57.  5) . A l l r i g h t s r e s e r v e d . higher amounts of mast cell mediators. IBS-C. extra-intestinal and psychiatric conditions.

and bacteria related Personal factors to Ruminococcus torques (a species belonging to the • Sex (female) Lachnospiraceae) are profoundly enriched in patients • Age (>50 years) with IBS51. Given the provided evidence. but the aetiological role remains uncertain. REF. for example. Two groups of uncultured Clostridiales are significantly depleted in IBS51. An important • Family history of substance abuse role of the microbiota is degradation of non-­digestible • Family history of mental illness dietary components 62. monosaccharides and poly­ • Abdominal obesity ols (FODMAPs. at least in a subset of patients51 (for a recent review • Birth weight (low)* see REF. Experimentally.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . impair intestinal perme­ • Stressful life events ability and alter gastro­intestinal transit time59 — indi­ • Sexual or physical abuse history cating the importance and the possible aetiological role • Anxiety. or the addition of sweeten­ers • Diverticular disease (left side) (fructo-oligosaccharides) or fibre (psyllium)) can • Antibiotic use improve symptoms of some but not all patients with • Abdominal surgery IBS.52.PRIMER the intestinal mucosa of patients with IBS contains Microbiota increased levels of nerve growth factor (NGF). the • Childhood war exposure* presence of the resistant carbohydrates FODMAPs can Less well-established factors are marked (*) and are based on provoke IBS symptoms64. the microbiota is still in large part undefined and protein and mRNA expression of growth-associated regarding the scope of its contribution to human physio­ protein 43 (GAP43. the dietary change has • Gastrointestinal infection to be dramatic (for example. variability. Experiments with a­ nimal mod­ • Illness behaviour els have shown that colonization of germ-free a­ nimals • Low quality of life with microbiota from patients with IBS can induce • Acute psychological stress ­visceral hypersensitivity 58. A l l r i g h t s r e s e r v e d . joint pain fat and high-protein diets61). 56). 21).55. The most prominent markers of IBS are derived from uncultured Box 2 | Risk factors for IBS bacteria. for example. the dysbio­sis of • Body mass index (low)* microbiota in IBS has been acknowledged by the Rome Foundation Working Team57 as a plausible contributing Psychological factors factor to the disorder. IBS pathophysiology has been accumulating (BOX 4).54 and levels positively correlate with bowel • Birth cohort* symptoms51.53. a • Number of family members (with more members decrease in inflammation and improvement in gut increasing the risk)* barrier function63. in patients with IBS. whereas all others have production or underproduction of relevant metabolites been shown in more than one study.52. depression or somatization of the microbiota in IBS. In addition. • Intimate partner violence* Although diet changes have an effect on the abun­ • Addictive behaviour* dance of particular microbial groups. vegans switching to high- • Somatic symptoms (pains. BOX 5). increased Firmicutes to • Breast feeding (<6 months)* Bacteroidetes ratios have been observed at the p ­ hylum • Herbivore pet in childhood* level. The evidence for an to supernatant obtained from mucosal biopsies of involvement of altered gut microbiota composition in patients with IBS49. It is generally accepted that • Working conditions (insufficient autonomy)* fermentation of carbohydrates is desirable because • Shift work* of the beneficial effects of the main fermentation products — short-chain fatty acids (SCFAs) — including • Marital status (never married)* energy supply to gastro­intestinal epithelial cells. Dietary interventions and migraine) (such as low dietary content of fermentable oligo­ • Endometriosis saccharides. also known as neuromodulin) — a logy and tolerable compositional variations under which key neuronal growth protein — following exposure normal functions are preserved50. Owing rat myenteric plexus and the neuroblastoma cell line to its enormous complexity and high interindividual SH‑SY5Y. disacchar­ides. Social conditions • Socioeconomic status (childhood) Fermentation of non-digestible foods.nature. the effect of ous ecosystem that inhabits the entire gastrointestinal NGF was demonstrated in primary cell cultures of the tract and has a systemic influence on our health. Future studies should evaluate the relevance of • Spicy food consumption* these microbial groups for IBS and could contribute to a better understanding of the role of the microbiota in the • Sleep problems* pathophysiology of IBS that is currently acknowledged • Low exercise level* for the following contexts. which showed an increase in neurite growth. However. owing to the disturbed microbiotic balance. the microbiotic signature (in terms of present species) is very stable60. primar­ The gastrointestinal microbiota is a diverse and numer­ ily in mucosal mast cells. Somatic issues To observe a profound effect. This might be a result of over­ single studies (for example. . 6 | 2016 | VOLUME 2 www.

66. the brain–gut axis (spinal. PAR2. PRIMER Gut microbiota and proteases healthy controls. CGRP. However. glial cell-derived neurotrophic factor. those in parentheses denote actions established in animal models lism81 and can be further converted to tetrathionate. decreased abundance of gas-­utilizing micro­organisms. Another potential pathway for microbiotic involve­ Mast + Proteases IL-4. 5‑HT is an important metabolite differs between patients with IBS and healthy con­ that. and altered Schaedler flora of several SCFA-producing bacteria  —  including (a community of eight bacterial strains). increased compared with the levels of these bacteria in The majority of these spore-forming bacteria belong NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 7 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . The depletion of bifido­bacteria has been noted in both faecal and Figure 4 | Overview of the pathophysiology of IBS. which seem to be depleted in patients with IBS51. Although the aetiology Nature Reviews of irritable | Disease Primers mucosal ­samples of patients with IBS51. which stimulates the growth of tetrathionate-utilizing 5‑HT. but could also be due to insufficient endo­genous Spinal. in Finally. permeability Intestinal gases are efficiently removed by methano­ genic archaea74. including composition of the gut microbiota. The role. Serine protease inhibitors are produced by many bacteria. that are capable of 5‑HT synthesis have shown that. among other functions. Blautia and Veillonella 70 — is significantly spore-forming commensal bacteria have this feature.83. Microbiota Other carbohydrate-utilizing gastrointestinal bac­ teria — namely. The excessive production of gas can also cause faster colonic transit in patients with IBS-D. The luminal con­ cell IFNγ and TNF) tents of patients with IBS contain increased levels + Histamine Lymphocytes of proteases30. Attempts to identify microorganisms inflammation as observed in patients with IBS 68. Lamina + Mast cell tryptase propria whereas the degree of the methanogenic activity could (+) TNF be correlated with the severity of constipation in those Extrinsic visceral with IBS-C76.69. The figure highlights those mediators that are probably sulfide is a relevant toxin that impairs epithelial metabo­ involved in IBS pathology. IL-10. regulates gastrointestinal trols. these are the main Food particle gas-producing bacteria in the human gastrointestinal tract 71. 5‑hydroxytryptamine (also known as serotonin). IL-6. although the available data are not always in motility. The abun­ peptide. tumour necrosis factor. and it has been recently shown that inflammatory mechanisms67. disturbed levels of 5‑HT seem to be relevant agreement 65. immune cell fermentation of proteins generates numerous health-­ reactivity and sensitivity of the enteric nervous system.79. 51) that are typically due to an increased abundance of gas-­producing and increased in IBS54. the production of microbial for IBS pathology 84. The overproduction of gas is associated with Lumen Intestinal epithelium IBS72 and this phenomenon could underlie flatulence and abdominal pain.52. Immune and their activity could prevent the excessive proteo­ Visceral sensitivity Glial + GDNF response cell lytic activity of intestinal content in IBS. TNF. calcitonin gene-related pathogens from Gammaproteobacteria82. Dorea spp. A l l r i g h t s r e s e r v e d . hydrogen pelvic pathways) or the brain. GDNF. As much as 90% of 5‑HT is pro­ SCFAs stimulates regulatory T cell differentiation and duced in enteroendocrine cells present in the gastro­ affects the balance between pro-inflammatory and anti-­ intestinal tract. vagal or compromising substances80. ment in IBS is protein degradation. interleukin. and those without parentheses are effects demonstrated in humans (human tissue). suggesting that inade­quate intestinal bacteria are needed for the stimulation of levels of SCFAs could provoke low-grade intestinal 5‑HT synthesis. dance of several Gammaproteobacteria significantly proteinase-activated receptor 2. IL. various factors have a an important role for this bacterial genera in IBS. intestinal permeability. and also with the levels of the inflammatory markers inter­leukin 6 (IL‑6) and IL‑8 (REF. The plus symbols indicate whether a mediator activates or inhibits its target cell. afferent + Histamine Cytokines (IL-1. studies of microbiota show that the abundance contrast to Bacteroides spp. a significant increase (+) (+) 5-HT PAR2 in the abundance of this microbial group is character­ istic of patients with slow transit and constipation75. suggesting bowel syndrome (IBS) has not yet been completely elucidated. which could be due to the increased + Proteases secretion of endogenous and microbial proteases in + CGRP response to protein-rich nutrition (typical of western Enteric + neuron Substance P diets). Moreover. including bifidobacteria78. providing a potential ­mechanistic basis Bile acid for the development of IBS symptoms. corre­lates with bowel symptoms in patients with IBS51. as the colons of these patients are more sensitive Enteroendocrine Tight cell junction Intestinal to increased intestinal volume than healthy controls73. The quantity and composition of SCFAs in the gut Microbiota and 5‑HT.52 and are negatively correlated with the pres­ ence of loose stools52. — show significant increases in abundance in patients with IBS51. only specific Roseburia. vagal and pelvic Macrophage protease degradation by the disturbed gastrointestinal pathways to the brain + Proteases microbial community 77. . Among these.

Cross-sectional correlations of brain networks with sev­ ‡ In stool. peptide YY. TLR. SERT. via the autonomic • Increased nerve mast cell association in the lamia propria region§ nervous system and the HPA axis. One of the best-studied • PBMC supernatants evoke mechanical hypersensitivity involving cytokines and TRPA1 behavioural aspects of IBS-related central processing of gut-related information involves a coping strategy Serotonin metabolism and signalling referred to as catastrophizing. a comprehensive IBS pathophysio­ the Clostridiales class within the Firmicutes phylum logical model can be formulated (FIG. 244. the gut and its microbiota and the immune • Increased numbers of intraepithelial CD3+ lymphocytes§ system show reciprocal associations in health and dis­ • Increased mucosal cell density and reactivity§ ease. On the one hand. PBMC. given that IBS is nearly always Mucosal permeability associated with increased anxiety and patients often show comorbidities with other chronic pain and psychi­ • Reduced epithelial resistance§ atric conditions. nerve growth factor. a history of to the Clostridales class within the Firmicutes phy­ early adverse life events93. the brain plays an essential part in • Mostly visceral hypersensitivity. gene expression profiles in PBMCs98 and an increase of the Firmicutes phylum members on the gene polymorphisms99. all of which have been reported to • Increased levels of the pattern recognition receptors TLR2 and TLR4§ be dysregulated in IBS. Given that biological findings. determining how much • Mucosal biopsy supernatants activate the enteric nervous system independent of of this information is amplified or tuned down. IBS with attention. the brain. it is not clear if the observed feature interoceptive signals (salience and attentional network). ||In blood. Two recent comprehensive studies51. TNFSF15. Others Multimodal brain imaging has made it possible to identify differences in functional (evoked and resting • Increased levels of cysteine and serine proteases‡ state) and structural (grey matter and white matter • Increased levels of mucosal PARM1§ tracts) aspects of specific brain networks that provide • Increased levels of BDNF and NGF§ a neurobiological substrate for previously observed • Increased levels of rectal PYY and somatostatin cell count§ affective and cognitive features of IBS (reviewed in • Altered microbiota diversity and composition‡ REFS 92. BDNF. These networks include the salience.|| permeability 25. §Intestinal biopsy. but this possible link should certainly (sensorimotor network) and engagement of emotional be further investigated. zonula occludens 1. IL‑1β. TH2. ZO1. prostate androgen-regulated works. 96). a term that refers to a • Increased plasma levels of serotonin in IBS‑D|| bias towards prediction of a high likelihood of worst • Increased enterochromaffin cell density§ outcomes95.nature. *Based on data available in REF. intestinal epithelial • TNFSF15 and TNF polymorphisms§. . arousal associated with experience and expectation of 8 | 2016 | VOLUME 2 www. factor.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . tumour necrosis individuals and patients with IBS (reviewed in REF. a more widespread dysregulation of the • Reduced expression of ZO1§ nervous and immune systems is probably implicated86. to what stool behaviour or visceral sensitivity§ degree it is modulated by affect 94 and how much of this • Mucosal biopsy supernatants activate sensory fibres and dorsal root ganglion neurons interoceptive information from the gut is consciously (mostly hypersensitive IBS) perceived (visceral sensitivity). PPY. Immune imbalance The brain. TRPA1. 6). Profound sex-related differences in these mucin-like protein 1. On the other hand. of the IBS microbiota is associated with 5‑HT-mediated central sensory processing of interoceptive information pathophysiology. can influence intes­ • Increased levels of TH2 cytokines in the blood|| tinal motility and fluid secretion87.85 revealed composition97. gut metabolite and microbial lum. 6). A l l r i g h t s r e s e r v e d .88. Toll-like receptor. Neural plasticity In addition to its role in the bidirectional communi­ • Increased nerve fibre density in the epithelium and lamina propria§ cations with the gut. several of • Increased levels of anti-flagellin autoantibodies|| these peripheral alterations can influence brain structure • Increased levels of histamine and proteases in biopsy supernatants§ and function either developmentally or in response to • Increased production of IL‑1β and TNF by PBMCs|| acute perturbations. but ≤40% of patients are normosensitive or assessing the salience of received or expected intero­ hyposensitive ceptive (sensory) information93. TNF. This measure strongly correlates with the • Altered SERT expression and polymorphism§ severity of pain symptoms and is a primary treatment • Serotonin receptor and transporter polymorphisms§ target in cognitive–behavioural therapy.PRIMER Box 3 | Structural and functional biomarker candidates in IBS* Brain and behaviour IBS is narrowly defined by recurrent abdominal pain Altered motility and stool behaviour and discomfort associated with altered bowel habits • Altered colonic transit time in the absence of an organic origin and/or explanation • Impaired bile acid transport‡ of symptoms. networks have also been identified in both healthy serotonin reuptake transporter. NGF. which includes are the most diverse and the most abundant group of alterations in the appraisal of and selective attention to the microbiota70. irritable bowel syndrome.89. PARM1. TNF superfamily member 15. T helper 2. On the basis of these neuro­ account of the Bacteroidetes members in IBS. setting up circular regulatory loops • Increased levels of β‑defensin 2 antimicrobial peptide‡ between the gut and the brain92. However.96) (FIG. peripheral blood mononuclear cell. interleukin 1β. transient receptor potential cation channel subfamily A member 1. immune function90 and gut micro­ bial composition91. IBS-D. sensorimotor and emotional arousal net­ diarrhoea. IBS. brain-derived neurotrophic factor. eral clinical and non-brain biological parameters show a relationship between some of these brain signatures with IBS symptom severity and duration.

PUFA. polyunsaturated fatty acid. is probably caused by the release of CGRP and substance P to cytokines and mast cell mediators. Functional signalling between effect is the activation of mast cells through the release of calcitonin nerves and immune cells mostly happens in the epithelial and sub­mucosal gene-related peptide (CGRP) from extrinsic visceral afferents or enteric layers where there is a high density of immune cells — in particular. enteroendocrine cells). mech­ The correlation of gut microbial signatures and PBMC anistic and longitudinal studies are required to expression profiles with structural alterations in the Lumen Microbiota Food particle (+) Polysaccharide A Intestinal Epithelium Lumen epithelium Enteroendocrine (+) TRPV1 cell receptor (+) TRPA1 receptor TRPV4 receptor 5-HT Lamina + Antibody (+) PUFAs propria (–) Adenosine + ATP + Histamine + H+ + TLR (+) Prostaglandin + 5-HT (+) Leukotrienes Extrinsic (+) CCK + Proteases visceral NGF afferent Submucous plexus Cytokines T lymphocytes (+) Adipokines Circular muscle Myenteric plexus Mast Spinal. which is sometimes observed in are bidirectional. PRIMER gut sensations. The best-documented neuroimmune interactions in the gut wall. adipocytes in the lamina propria nestle against nerve fibres. 5‑hydroxytryptamine (also known as serotonin). those in parentheses denote actions established in animal pathways involving neuronal Toll-like receptor 3 (TLR3). This disease model not only identifies determine the causality between these factors. syndrome (IBS) have circulating autoantibodies against neuronal structures In addition. . acetylcholine (ACh) inhibits the activation of T lymphocytes. immune and nerve cells. terminals from the gut wall under inflammatory or stress conditions. A l l r i g h t s r e s e r v e d . TLR4 and TLR7. CCK. transient (in particular. nerves extrinsic nerves and cells of the enteric immune system is the basis for release factors that affect epithelial or immune cells. neurons through polysaccharide A. interleukin 10. are central sensorimotor alterations a conse­ and behavioural features of IBS but also provides a plau­ quence of increased signals from the gut. IL‑10. They also respond to antigens through target cell. vagal and pelvic cell (+) CRF pathways to the brain Macrophage Figure 5 | Neuroimmune interactions in the gut. extrinsic nerves and glial cells respond animal models. mast cells and macrophages. Some patients with irritable bowel from extrinsic fibres followed by permeabilization of blood vessels. Nature both Reviews molecules | Disease Primers are released in and functional association between enteric neurons. ically determined trait that predisposes individuals to Although these findings have identified disease-­ IBS and might be present in asymptomatic relatives100? relevant brain alterations in patients with IBS. For neurobiological correlates of well-characterized clinical example. vagal Adipocytes cells and pelvic IL-10 (+) Substance P pathways to the brain ? (+) CGRP Longitudinal Extrinsic muscle visceral afferent Enteric (–) ACh Glial neuron Spinal. Neurogenic inflammation. corticotropin-releasing factor. Reciprocally. Neurons can respond directly to antibodies through direct plus and minus symbols indicate whether a mediator activates or inhibits its activation of channels or receptors. are they the sible explanation for the common coexistence of IBS consequence of dorsal horn sensitization by increased with other chronic pain conditions and with increased descending pain-­facilitating signals or are they a genet­ trait anxiety. are very likely to be outnumbered by signalling between epithelial NGF. The neuroimmune interactions macrophages. TRP. CRF. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 9 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . An intimate anatomical express receptors for adenosine and ATP. neurons. The the lumen. Neurons also receptor potential cation channel. Enteric neurons. and and antibodies that are generated as a response to antigen exposure from release of their pro-inflammatory mediators modulates nerve activity. models and those without parentheses are effects demonstrated in humans Direct signalling between microbiota and the host involves activation of (human tissue). Conversely. nerve growth factor. These direct effects of luminal factors cholecystokinin. 5‑HT.

encod­ • Dorea ing cytokines and neuronal signal transduction) and • Blautia others (such as neurexophilin 1 (NXPH1) and sodium voltage-gated channel α-subunit 5 (SCN5A)) have been • Roseburia replicated in several studies101. §Mixed-type IBS. genetic variants miR‑103. Even less insight into the role of epi­ Genetic data. the (mir‑29) family or amplifying mir‑199a expression might United States and Australia112. irritable bowel syndrome. Regardless of enlarged sample sizes. TNF • Streptococcus* and TNF superfamily member 15 (TNFSF15.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . 6). claudin 1 (CLDN1) and 10 | 2016 | VOLUME 2 www. In 2014. miR‑29b. immune response and neuro­ (KDELR2) and GRID2‑interacting protein (GRID2IP) nal signal transduction101 (FIG. • Enterobacteriaceae such as cadherin 1 (CDH1) and cell division cycle 42 • Veillonella (CDC42). silencing the microRNA‑29 Sweden) and all replication cohorts in Europe. as well as emotional and in bile acid synthesis regulation (the Klotho-β (KLB) autonomic nervous system responses? Future studies gene. miR‑16. HTR3E and HTR4 • Clostridiales (REF. the under­lying have important therapeutic implications for selected molecular cause for this association finding has not patients with IBS and symptoms caused by increased been elucidated. To date. 5‑HT receptor 3A (HTR3A). Mutations in the following genes encod­ • Streptococcus‡ ing proteins involved in the serotonergic system have also • Faecalibacterium been shown to be associated with IBS: solute carrier fam­ ily 6 member 4 (SLC6A4. Similarly. These variants also of early adversity.111. also known as 5-HTTLPR or • Christensenellaceae SERT). These studies reported on (GWAS).108. patients with a history transit in patients with IBS-D107. Genetic studies to date range from fam­ genetics in IBS pathology is available compared to ily and twin studies to candidate gene approaches the genetic implications. IL10. statistical power and meta-analyses. For example. deoxycholic acid (a bile acid used to treat constipation) in IBS-C109 and to colesevelam (a bile acid sequestrant Genetic and epigenetic data used to treat diarrhoea) in patients with IBS-D110.PRIMER Box 4 | Dysbiosis in IBS Polymorphisms or variants in several genes have been found to be associated with IBS. 101). Upregulation of been replicated in independent cohorts. These findings underline the sensorimotor network suggests a possible role of these effect of polymorphic serotonergic and other genes in peripheral factors in influencing the brain. a small pilot study • Ruminococcus reported an association between IBS and a locus on chro­ • Methanobrevibacter‡ mosome 10 (containing the protocadherin 15 (PCDH15) Microbiota species decreased in IBS gene) in a discovery sample from Australia that could not • Bifidobacterium be replicated in additional cohorts from Sweden and the • Collinsella United States104. intestinal permeability or hypersensitivity 102. Epigenetic data. a locus at 7p22. *IBS with diarrhoea. the immune system.1 in which the genes KDEL rent models of IBS pathogenesis that suggest disturbed endoplasmic reticulum protein retention receptor 2 intestinal barrier function. the fibroblast growth factor receptor 4 (FGFR4) will need to address the question of whether these brain gene and the G protein-coupled bile acid receptor 1 signatures differ between subgroups of patients with IBS. anxiety and increased symptom score in IBS106. The data even point localize was significantly associated with IBS risk in towards potential diagnostic biomarkers or therapeutic the index GWAS (a large twin discovery sample from options (BOX 3). salience and somatosensory and emotional central ception of visceral signals or are they a primary abnor­ ­networks (FIG. polymorphism in HTR3A could be associated with altered amygdala responsiveness. genome-wide association studies studies have been performed. ‡IBS with stimuli in patients with IBS105. mality that is responsible for the generation of aberrant Variants of genes encoding proteins that are involved endogenous pain modulation. more recently. visualized • Methanobrevibacter§ through functional brain imaging following visceral pain IBS. tamine synthetase (GLUL)102. increased the differential expression profiles of miR‑29a.nature. 6). a functional constipation. patients with different durations of correlate with the colonic transit response to cheno­ symptoms and patients with post-infectious IBS. are modulating gut-­derived brain response in areas that the altered salience and attention network alterations a process visceral perception and integrate autonomic con­ secondary response to the chronically increased per­ trol. A l l r i g h t s r e s e r v e d . However. A recent paper miR‑29a and miR‑29b was reported to accompany summar­izes all currently available genetic data that have downregulation of the target genes encoding glu­ been replicated101.103. such as IL6. The latest genetic and epigenetic findings support cur­ Finally. Furthermore. . Genes encoding proteins Microbiota species increased in IBS involved in homeostasis of epithelial barrier function. A polymorphism in SLC6A4 has been found • Uncultured to be associated with altered brain responses. miR‑125b and miR‑199a in the intes­ associated with IBS are still scarce and/or have not tinal mucosa of patients with IBS‑D. only a few miRNA and. (GPBAR1) gene) are associated with accelerated colonic such as male and female patients.

cucumber. constipation (hard and infrequent stools) ditions varies depending on the clinical situation and or alternating constipation and diarrhoea). cold cuts. several symptoms were further indicated increased levels of circulating miR‑150 shown to be more common in patients with IBS than in and miR‑342‑3p in the blood of patients with IBS117. passion fruit. oats. pineapple. In this publication. 122). miR‑16 and gations. One recent study found that variations • Dairy and non-dairy alternatives: lactose-free milk. kumquat. Clinical features mandarin. orange. with symptom (lactose present in milk and milk products).*61T>C — were found to be associated with IBS‑D. pork. among others of IBS. and low FODMAP fruit or vegetable juices.174. fish. ments per week). of these criteria is suboptimal to distinguish the different leafy greens. egg. abnormal stool frequency corn flakes. among others Besides the symptoms included in the diagnostic criteria. egg whites. exclusion of other diseases. IBS could be discrimin­ IBD and pain. The updated Rome IV criteria diagnostic criteria for IBS119 in conjunction with nor­ are expected in May 2016.  7). PRIMER NF‑κB‑repressing factor (NKRF). the sensitivity and specificity • Vegetables: bamboo shoots. published in 1978 miR‑510 and miR‑16. respectively. However. coffee and tea. yam.126. combination of symptoms have been developed. A l l r i g h t s r e s e r v e d . lettuce. cantaloupe. carrot. CLDN1 and NKRF only a limited number of laboratory tests are recom­ correlated with increased gut permeability 103. squash. it should be noted that patients with some cauliflower. tomato and courgette (zucchini). a diminished ­putative pathophysiological mechanisms. rice milk and rice-milk ice-cream). as such. Moreover. experience from the Manning criteria was then used to colonic motility and smooth muscle function118. quinoa and rice. In addi­ mended without any need to perform invasive investi­ tion. miR‑150 has been described to be associated with By combining these symptoms. grits. pumpkin. nuts and seeds. potato. One pilot study (REF. There is currently teria is abdominal pain and/or discomfort associated no valid biomarker for IBS121.116. pastas. cream cheese. was published in The diagnosis of IBS relies on the patient fulfilling 2006 (REFS 119. even though none of them is mandatory for an IBS diagnosis. the Rome III criteria. but a problem reasonable certainty (FIG. among others bowel pattern (‘irregularly irregular’) could be used to discriminate IBS-D adequately from organic gastro­ • Grains: wheat-free grains or wheat-free flours and products made with these (for example. there are other clinical features that support a diagnosis • Protein: beef. The first attempt tion and to lead to disturbed expression regulation of was the so‑called Manning criteria. Of patients with another organic gastrointestinal disease. All of these the symptom profile of the patient. chicken. tory the presence of a combination of these symptoms for onion and garlic chicory. given the get genes encoding the tight junction proteins claudin 2 hetero­geneity of the disease and the multiplicity of (CLDN2) and cingulin (CGN)113. Moreover. Thus. the practical clinical use of the diagnostic criteria Box 5 | FODMAPs and a low FODMAP diet* for IBS involves demonstrating through the clinical his­ FODMAPs stands for fermentable oligosaccharides (fructans present in wheat. note. urgency (having to rush to the toilet). The sensitivity and specificity mal results on a limited number of additional tests and of the Rome criteria have been found to be 69–96% and investigations used to rule out other diagnoses with 72–85%. In the majority of criteria require a certain duration and frequency of cases with a typical clinical history compatible with IBS. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 11 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . kiwifruit. develop the Rome Foundation criteria. artificial sweeteners) and polyols (sugar alcohols present in apples. respectively 115. mozzarella and sherbet (almond milk. grapefruit.123. miR‑199 level correlated with an upregulation of TRPV1 and increased visceral sensitivity 114. in different studies. Diagnosis. A low FODMAP diet may include reasonable organic gastrointestinal disease also meet these diagnos­ amounts of: tic criteria125 and. pancakes. lamb. . pears. The choice of the tests or with abnormal bowel habit (diarrhoea (loose and fre­ investigations deemed necessary to rule out other con­ quent stools). mushrooms and sweeteners). stone fruit. parmesan and Swiss). noodles. similar Both variants were reported to impair miRNA regula­ to the DSM system within psychiatry. cream of rice. that is. excessive straining during defaeca­ among others tion. In turn. lime. rhubarb and tangerine. disease entities125. pawpaw. the current recommendation The common feature in all of these diagnostic cri­ is to base diagnosis on symptoms119. II and III). among others • Fruits: banana. disaccharides ≥3 days per month in the past 3 months. shellfish. crackers. bagels. feelings of incomplete evacuation and mucus with bowel move­ *See REFS 171. canned tuna. the symptoms to fulfil the diagnostic criteria for IBS. Screening for IBS risk and for prevention of miR‑125b correlated with the upregulation of the tar­ IBS develop­ment is currently not applicable. and galactans present in legumes and beans). pretzels and waffles). turkey. c. grapes. the symptoms should be chronic and recurring. decreased expression of miR‑103. whereas miR‑342‑3p has been predicted ated from other organic gastrointestinal diseases. with three differ­ ent versions over the past 15 years (Rome I. rye. aubergine (eggplant). breads. hard cheeses in stool consistency and frequency or an unpredictable (cheddar. intestinal disease127. but are nonspecific124. screening and prevention the latest criteria. variants Diagnostic criteria
 residing in miRNA target regions of the 5‑HT receptor As individual symptoms have poor sensitivity and speci­ genes HTR3E and HTR4B — namely. Although a substantial with these studies is how to define the gold standard for proportion of clinicians120 prefer a process of thorough an IBS diagnosis121. lemon. monosaccharides (fructose present in onset ≥6 months before the diagnosis (Rome III cri­teria).*76G>A and ficity to diagnose IBS. diagnostic criteria incorporating a c. ments support an IBS diagnosis. corn.124). The to target genes that are relevant for pain signalling. among others (>3 bowel movements per day or <3 bowel move­ • Beverages: water.

 GRID2‑interacting protein. adrenoceptor-α. KLB IL6 IL10 On the basis of the existing literature. A recent systematic review Altered immune demonstrated that C‑reactive protein (CRP) levels of Impaired bile function ≤0. catechol-O-methyltransferase. aINS sgACC • CRHR1 but the absence of objective findings on a physical mPFC Hypo • NR3C1 PAG examin­ation has been found to support a diagnosis of OFC Female sex hormones LCC IBS132. interleukin. . Stool analyses immune function. medial prefrontal cortex. orbitofrontal cortex. locus coeruleus complex. cell division cycle 42. GLUL. sodium voltage-gated channel α-subunit 5. aMCC. microRNA. Serotonergic signalling axis • HTR3A SLC6A4 HTR3A Laboratory tests HTR3E Impaired intestinal From the existing literature. improves the performance of diagnostic criteria for IBS sgACC. nuclear receptor subfamily 3 group C member 1. A digital rectal examination is an important part • PGR Catecholaminergic signalling of the physical examination and a useful tool to identify Amygdala Medulla • ADRA1D patients with dyssynergic defaecation. those in black are mended in patients with non-constipated IBS and — if currently not seen as potential pharmacogenetic targets101. mPFC. FGFR4. rather than IBS. Alarm features for IBS are symptoms that should raise LCC. Only serological tests for GRID2IP CDC42 ↓GLUL coeliac disease seem to be more likely to be abnormal in CGNA ↓NKRF ↑CLDN2 ↑mir-29a/b patients with symptoms compatible with IBS than in the Visceral ↑CGN ↓mir-199a general population135. presumably contributing to psychological conditions such as anxiety. Alarm features HTR. OFC. that certain biomarkers or biomarker assays (BOX 3) for COMT. as these are inexpensive and can be used to reassure Figure 6 | Summary of the genetic findings associated Nature Reviews | Disease Primers with different the health-care provider and the patient. are all presence of other functional gastro­intestinal diagnoses ­common and support an IBS diagnosis. 5‑hydroxytryptamine receptor. A l l r i g h t s r e s e r v e d . abdominal tenderness is present in various diseases). an abdominal examination. Various pathways might be there is suspicion of an inflammatory process — a faecal affected in specific subgroups of patients with IBS: epithelial barrier (permeability). corticotropin-releasing hormone clinical use might prove to be valid following further receptor 1. muscle and joint pain bation of symptoms. IL. hypothalamus–pituitary–adrenal. a serological test for coeliac disease can be recom­ genetic findings and in blue when based on epigenetic findings.5 mg per dl or faecal calprotectin levels of ≤40 μg per g acid metabolism and function TNFSF15 essentially exclude IBD in patients with IBS symptoms137. SLC6A4. which is important Brainstem NTS • ADRA2B to exclude in patients with constipation133. hypothalamus. Irritable bowel syndrome (IBS)-related can be included if the clinical suspicion of thyroid disease pathways that are potential pharmacogenetic targets are marked in red when based on is high. CRHR1. calprotectin measurement can be added. neuronal processing and to detect gastrointestinal infections can be considered if signal transduction via spinal afferents from the periphery to the central nervous system in diarrhoea is predominant and difficult to treat. TNF superfamily member 15. Admittedly. However. PAG. tumour necrosis factor. NTS.141.nature. anterior midcingulate cortex. from a clinical point of TNF. depression and somatization. Whether the use of alarm features (BOX 6) PGR. Klotho-β. GPBAR1. aINS. anterior insula. impaired bile acid metabolism and function. (such as functional dyspepsia)129. there is currently no valid diagnostic ADRA. Brain networks in regions where infectious diarrhoea is common138.PRIMER The same is true for postprandial worsen­ing or exacer­ uro-gynaecological symptoms. CLDN. KLB. as well as reporting numerous functional non-gastrointestinal symptoms Physical examination and syndromes (such as chronic fatigue. subgenual anterior cingulate cortex. SCN5A. However. rarely discloses a specific diagnosis (that HPA axis regulation is. solute carrier family 6 member 4. biomarker. claudin. it seems reasonable to use these to select patients receptor potential cation channel subfamily V member 1.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . the clinical concern of another gastrointestinal disease NKRF. cadherin 1. CGN. NR3C1. it seems reasonable FGFR4 to perform a complete blood count and CRP measure­ GPBAR1 TNF ment. HPA. it is not obvious which HTR4 barrier function labora­tory test to recommend in the diagnostic work‑up SCN5A CDH1 ↓CLDN1 of patients with IBS symptoms. CDH1. (also known as glutamine synthetase). solitary nucleus. TRPV1. periaqueductal grey. transient view. for further diagnostic testing. even though preliminary data have suggested CDC42. nuclear factor-κB-repressing factor. As that have been associated with structural and functional alteration in IBS are depicted. especially addition to the bidirectional crosstalk via the brain–gut axis. The bidity (such as anxiety and depression) 131. GRID2IP. glutamate-ammonia ligase ­scientific investigation139. A physical examination should be part of the evalu­ ation to reassure patients and also to help exclude another organic cause of the symptoms. which is part of the ­routine aMCC Altered central processing examin­ation. hypo. which is common in IBS128. mir. but and sleep disturbances)11. is not totally clear 125.140. even though a large multi­centre sensitivity HTR4? ↓mir-16 trial failed to confirm this136. even though these may be 12 | 2016 | VOLUME 2 www.134 as well as to Spinal • COMT exclude rectal cancer. TNFSF15. stated previously. progesterone receptor. A thyroid profile pathophysiological mechanisms underlying IBS. fibromyalgia.130 and psychological comor­ is also observed in other gastrointestinal diseases. cingulin. few studies have TRPV1 ↓mir-125b systematically evaluated the usefulness of laboratory tests in patients with potential IBS. fibroblast growth factor receptor 4. G protein-coupled bile acid receptor 1. Perianal inspection should also be cord Inflammation-related genes • IL1B part of the examination to rule out perianal fistulas and Brain–gut other relevant anal pathology.

refractory symptoms • Normal physical examination specificity are lacking. whereas nutritional interventions and of an inflammatory condition in the gastrointestinal tract ­psychotherapy can be used in all subtypes. ary alterations. disease before an IBS diagnosis can be recommended. Most of these patients • Type of alarm symptom • Explain will initially consult primary care physicians for their • Abnormal laboratory test or physical • Treat according to the predominant finding symptom symptoms. the predominance of diarrhoea. Once a positive diagnosis of IBS has been indicating a serious underlying condition in the gastro­ established. Moreover. especially pain.157. loose stools32. Owing to the fact that Invasive investigations ~50–70% of patients with IBS report additional somatic In the majority of patients with symptoms compatible and psychological symptoms when they are asked161. This diagram gives a schematic of alarm symptoms (BOX 6) and concerns that symp­ Nature Reviews | Disease Primers overview of the sequential approach to irritable bowel syndrome (IBS) diagnosis144. clinical management can be carried out intestinal tract 142. example. Figure from REF. mediated food allergy (which involves activation of the NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 13 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . intestinal specialist care is needed to exclude diseases that can mimic IBS symptoms — for example. C-reactive protein. Management of IBS involves an integrated approach. toms might indicate an underlying severe disease — for CBC. Postprandial symp­ the predominant symptom. based on history or laboratory parameters (increased CRP or faecal calprotectin levels)137. in many cases. . Up until recently. the occurrence Figure 7 | A diagnostic algorithm for patients with IBS.146. an upper gastro­ intestinal endoscopy with duodenal biopsies should be performed. Therefore. antidiarrhoeals for IBS‑D and lax­ tures prompt an investigation and when there is suspicion atives for IBS-C. and laboratory tests Management Further investigations based on: • Make a confident IBS diagnosis Only a fraction of patients with IBS-like symptoms • Predominant symptom • Reassure (~50%) seek medical care158. and a diagnos­ of usually non-validated and untested diagnostic tests tic test should be considered (75‑homocholic acid taurine and diet­ary regimens. 144. factors that results in the exacerbation of symptoms When the patient complains of watery diarrhoea as among patients with IBS 163. gastro­ Nature Publishing Group.162. diet­ consider alternative diagnoses143. and the factors that drive this consultation are symptom severity. and lactose or • Other clinical features fructose hydrogen breath tests can be considered154. A l l r i g h t s r e s e r v e d . but far from perfect. Moreover. importantly. education. should alert the clinician to provider relationship.155. leav­ very important differential diagnosis in patients with IBS ing patients to find their own way through the plethora symptoms with frequent.148. supporting a diagnosis of IBS or physical examination especially as valid tests with adequate sensitivity and • No alarm symptoms • Severe.164. these tests are not available in all centres. or based on the indi­ Nutrition cations for colorectal cancer screening in countries with Food ingestion is one of the most commonly reported population screening programmes147. CRP and serological test for coeliac disease) Consider: thyroid profile.33. Unfortunately. therefore a It has become evident that food intolerance (a physio­ therapeutic trial with a bile acid-binding agent is often logical reaction to food allergens that is not associated used as an indirect. pharmacotherapy and behavioural and psychological treatment 161. no additional invasive investigations are tive and interpersonal therapy is most appropriate15. especially including the establishment of an effective patient– when watery and frequent. complete blood count. CRP. based on a positive on clinical presentation serological test or the clinical history. food-related symptoms had acid-induced diarrhoea has recently been found to be a received scant attention from clinical scientists. by present in a substantial proportion of patients without endoscopy. performing investigations does The i­ nitial treatment strategy should be based on pre­ not seem to improve patient satisfaction or QOL145. PRIMER Carbohydrate malabsorption is another differential Initial evaluation • Diagnostic criteria for IBS* diagnosis in patients with IBS-D151–153. needed and. ­relevant nutritional deficits165. assessment of with an immune response). Alarm symptoms can necessitate fur­ as well by ­primary care physicians and at substantially ther investigations to rule out another gastrointestinal lower costs160. with IBS and normal routine laboratory tests but without a stepped-care approach including aspects of cogni­ alarm features144. • Alarm symptoms present? but a trial period with dietary exclusion of the suspected • Physical examination carbohydrate for several weeks is often used instead. but its preva­ diagnostic criteria for IBS lence and clinical importance is uncertain. which could result in clinically (75SeHCAT) test or serum C4 levels)150. bile IBS128. Small intestinal bacterial overgrowth has • Positive symptom-based been proposed to be common in IBS. faecal calprotectin and stool analyses based If coeliac disease is suspected. cancer 159. dominant symptoms and includes antispasmodics for Colonoscopy should be performed when alarm fea­ abdominal pain. and not classical IgE- bile acid-induced diarrhoea. therefore • Alarm features • Other clinical features • Abnormal laboratory tests ­routine clinical testing for this cannot be advocated156. a colonoscopy with biopsies toms per se and fear of their occurrence (anticipatory should also be considered to rule out microscopic colitis. • Routine laboratory tests (CBC. reassurance.149. anxiety) contribute profoundly to reduced QOL in especially in women >50 years of age143.

Food-related symptoms could also and contentious issue with some studies reporting that. Another study also reported local immune ician and involve the elimination of many food items responses to gluten among a group of non-coeliac commonly regarded as components of a ‘healthy’ patients with IBS166. but not in complex. anti­ Fibre and fibre-based supplements accelerate colon oxidants and essential oils. such as bifidobacteria174. r­ epresented by bran. yielded mixed results179. as commonly gastrointestinal functions. blinded food chal­ gluten-­free diets are currently enjoying consider­able lenge studies169. precipi­tate symptoms. species commonly regarded as important components immunological response to certain dietary components. gluten did induce products of digestion and the gut microbiota. Taken together. postprandial pain and rectal used challenge tests. RCTs have confirmed some beneficial effects of low FODMAP diets on IBS immune system). the rationale for gluten notwithstanding. such as deconjugated bile salts. Predicting responders is difficult. some patients with IBS How does one explain food-related symptoms in IBS? may benefit from the removal of one of these substances Given the primacy of food ingestion as a stimulus to most alone175. Prebiotics (non-­ resulting in an increase in stool frequency.PRIMER Box 6 | Alarm features for IBS and distension). Results of clinical trials assessing the speci­fic food items as those that are especially likely to role of gluten exposure in IBS pathology have therefore. more problematic: wheat. the when tested in a blinded manner. but that fructans (FODMAPs contained physiology and thereby induce symptoms. There to say that immune responses to food or food compo­ are some limitations. Current Patients with IBS commonly consume any one or enthusiasm for diets low in FODMAPs is ­consistent with combinations of a wide variety of dietary supplements these observations. RCTs found that not all patients benefit) have also been used for decades in IBS in the gained relief and some even complained of exacer­ absence of supportive data. fruit and vegetables170. This remains an ­unsettled symptoms in IBS168. Indeed. in wheat). fructose and sorbitol. lactose. as has been the case with many studies of dietary demonstrated that exposure of the small intestine to cer­ interventions in IBS. one study and. Products the usual IBS symptoms in some patients with IBS178. and not gluten. A l l r i g h t s r e s e r v e d . Few. This is not tional diet­ary advice when directly compared172. such as immune system. Although identified when confirmed in formal. Recent meta-­analyses and systematic reviews have shed some light on this issue by showing • Unintended weight loss (>10% in 3 months) that fibres are heterogeneous and the consumption of • Presence of blood in the stools not caused by haemorrhoids or anal fissures soluble fibres such as psyllium. For example. may require supervision by a qualified diet­ controls31. of bacterial metabolism. as they might 14 | 2016 | VOLUME 2 www.180. the 5‑HT precursor. . of healthy micro­biota. However. studies to date have been small nents are irrelevant for IBS. whereas • Fever in association with the bowel symptoms ­insoluble fibres. suffer from some method­ological tain food antigens led to subtle ultra­structural changes limitations173. of a normal physiological phenomenon.176. positive serology and appropriate changes in small late psychological comorbidities and gastro­intestinal intestinal morphology)177. have been advanced to explain instances of IBS-type symp­ also been demonstrated in the small intestine in IBS167. especially to lipids. such as the lactose or fructose urgency in IBS could simply reflect an exaggeration breath hydrogen test. these observations diet.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . of these have transit. only 11–27% of those are correctly not surprisingly. and nostic criteria for the diagnosis of coeliac disease (that related compounds present in some foods could modu­ is. Prebiotics and probiotics are bation of their symptoms (including pain. some food items are reported as being ­exclusion in IBS has yet to be firmly established. increase stool bulk and facilitate its passage. toms that develop in individuals who do not satisfy diag­ Furthermore. be mediated through interactions between our diet. Furthermore.nature. if any. been subjected to rigorous study. tryptophan. bloating now subjected to more-rigorous studies. Some ­initial investigations suggest that the low leave the door open to the possibility that at least some FODMAP diet may suppress the growth of bacterial patients with IBS may mount an. inflammatory bowel disease or coeliac disease patients with IBS169. is the major mechanism responsible symptoms171. are the culprits of wheat-­ Although patients with IBS readily incriminate related problems. Exaggerated The concept of ‘non-coeliac gluten sensitivity’ has motor responses to food and. but they were not superior to conven­ for symptomatic responses to certain foods165. could exert potent effects on colonic tomatology. Included a response that seems to be confined to the mucosal in the FODMAP category are some molecules. do not seem to be of value175. Others argue that gluten contributes little to IBS symp­ SCFAs and gases. calcium polycarbophil • Symptoms that awaken the patient in the night and i­spaghula bring symptomatic benefits. ranging from vitamins to ‘digestive enzymes’. as yet to be defined. low FODMAP diets are in the duodenal mucosa of patients with IBS. of one species or a limited number of species of bac­ fibre and products based on synthetic fibre-like sub­ teria in the colon) and probiotics (live microbial food stances became a cornerstone in the management ingredients that alter the microflora and confer health of IBS. are ineffective in • Family history of colorectal cancer. These digestible food ingredients that beneficially affect the effects translate into clinically meaningful benefits for host by selectively stimulating the growth and activity people with chronic constipation and IBS‑C. The limitations of dietary surveys and popularity among patients with IBS and the population the poor reproducibility of reported food intolerances at large in the United States. • New onset of irritable bowel syndrome (IBS) symptoms after 50 years of age Interest in the use of low FODMAP diets (BOX 5) in patients with IBS is increasing.

Antidepressants. atives have failed in patients with IBS‑C and symptoms NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 15 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . Some studies CIC2 have demonstrated a beneficial effect of otilonium bro­ channel GC-C Lumen receptor CFTR mide and hyoscine over placebo. The plus and minus symbols indicate whether a mediator activates or inhibits its target cell. and central. (+) (+) plexus 5-HT (+) Spinal. 8). CIC2. with smooth CI– Linaclotide CI– muscle relaxation as a consequence186. VIP. to modulate signal transduction at the neuromuscular junction or alter motility by direct the use of lactulose is not recommended as it is often myogenic actions. result of smooth muscle spasms. Adverse effects such as constipation. those in parentheses denote actions established in animal models poorly tolerated by patients with IBS because of wors­ and those without parentheses are effects demonstrated in humans (human tissue). via alterations of (+) Perception (+) histaminergic and/or cholin­ergic transmission within the gastrointestinal tract. PRIMER contribute to altered microbiota in IBS181. via modula­ Antispasmodic Alosetron tion of both ascending visceral sensory afferents and drugs Muscarinic receptor Ramosetron 5-HT3 receptor central transmission191. target nerve activity. but are less suitable for patients Drugs currently used for the treatment of irritable bowel syndrome (IBS) (orange boxes) who have IBS‑C. dry mouth. mation to assist the consumer in choosing a particular product to alleviate symptoms184 or to make a recom­ Antispasmodic drugs. the rationale for using Myenetric such drugs should be discussed in detail with patients. guanylyl cyclase C. Finally.182. However. The mode of action of antispasmodic drugs is probably their ability to antago­ nize the binding of acetylcholine to the muscar­inic Lubiprostone receptor at the neuromuscular junction. Given neuron Antidepressants the lack of licensed indication. is beneficial in reducing Mucosa + ACh (+) Intestinal IBS symptoms188. high-quality RCTs remain habits and/or visceral pain. GTP cGMP which also inhibits smooth muscle contraction albeit 5-HT (–) by calcium channel blockade. with a number needed to treat (NNT) of four patients187. a min­ 5‑HT. An adverse effect of anti-muscarinic agents is constipation because of their Enteroendocrine strong inhibition of intra­luminal fluid secretion186. vasoactive intestinal peptide. TCAs may be particularly effective for treating pain in Figure 8 | Mechanisms of action of different drugs used NatureforReviews the treatment | DiseaseofPrimers IBS. Peppermint oil. simple laxatives such as senna and docusate include modulation of visceral sensitivity at a central or peripheral level. drugs act are often effective in managing symptoms. patients with IBS‑D. Although Drug therapy these studies must be interpreted with care. Other mechanisms of action stipation. these drugs are best used in patients with­ out constipation and should be taken 20 minutes before meals to ease postprandial symptoms. However. CFTR. Loperamide μ-opioid receptor Prucalopride 5-HT4 receptor drowsiness and fatigue are reported with TCAs. vagal The exact analgesic mechanism of action of low-dose and pelvic anti­d epressants is incompletely understood but is pathways (–) (+) to the brain considered to be both peripheral. and is in part the of a prebiotic and a probiotic) in IBS185. In those with con­ secretion into the intestinal lumen as a consequence. (FIG. acetylcholine. . designed to cause a sustained release + within the small bowel. Several drugs act by enhancing the activity of chloride channels to increase fluid Laxatives and motility accelerants. the current therapeutic armamentar­ meta-analysis does suggest efficacy for probiotics (as a ium in IBS aims to alter predominant problematic bowel category) in IBS183. ening of bloating and discomfort. cystic imally absorbed guanylyl cyclase C agonist peptide fibrosis transmembrane conductance regulator. are recommended by existing guidelines for the treatment of pain in + patients who are refractory to antispasmodics and – NO dietary alterations190. cell Accordingly. chloride channel protein 2. A recent RCT in patients with IBS‑D VIP epithelium and IBS‑M demonstrated that a novel formulation of pepper­mint oil. an emerging area few in number and available data provide scant infor­ is manipulation of the gastrointestinal microbiota. such as muscle cell + afferent tricyclic antidepressants (TCAs) or selective sero­ tonin reuptake inhibitors (SSRIs). Linaclotide. However. was superior to placebo in 5-HT ­causing a reduction in total symptoms189. ACh. However. Submucous (–) plexus Extrinsic Smooth + visceral Low-dose antidepressants. these drugs are not ACh licensed anywhere in the world for the treatment of Enteric patients with IBS. a recent Broadly speaking. and their use is off-label. epithelial functions or the contractile state of the smooth muscle layers. A l l r i g h t s r e s e r v e d . SSRIs are generally well toler­ Ondansetron ated. Pain in IBS is mediated through mendation on pre­biotics or synbiotics (a ­combination central and peripheral mechanisms. can be used as second-line therapy after lax­ GC-C. 5‑hydroxytryptamine (also known as serotonin).

5‑HT and have been shown to be effective in increasing com­ opioid receptors in the gastrointestinal tract207. tion of gut function. In addition. such as psycho­dynamic (interpersonal) approval in Europe. again. are effective in the reducing psychological distress. a minimally absorbed. but is considered to pro­ patient education and a target for effective treatments. tic physician–patient relationship have fewer IBS-related both antibiotics and probiotics have been evaluated. improved abdominal pain and QOL in a tinal symptoms in IBS-C195. 16 | 2016 | VOLUME 2 www. ­μ‑­opioid receptor agonist and δ‑opioid receptor antago­ Treatment concepts that target these psycho­ nist. 5‑HT3 receptor antagonists have been investigated. Such models might be helpful as a basis of incompletely understood. rifaximin. we have to component of the peristaltic reflex and of the high learn more about IBS-specific interactions and the role amplitude propagating contractions within the gastro­ of stress and visceral sensitivity for clearer evidence intestinal tract 199.194. locally active. which is a mixture of nine Lubiprostone has been shown to improve global intes­ plant extracts. A l l r i g h t s r e s e r v e d .nature. including general management of IBS‑D symptoms. although National Institute of Health and Care Excellence it is not clear whether repeated courses of treatment (NICE) guidelines advise that patients whose symp­ are needed204. Eluxadoline. which subsequently led to functional s­ ymptoms. lished. fur­ chronic constipation196. micro-inflammation. Although plete spontaneous bowel movements in patients with herbal remedies represent a promising intervention. patients report being poorly understood by their physicians. However.213. a central effect of 5‑HT3 on which group of patients might benefit from which receptor antagonists on pain cannot be excluded200. it should be noted Safety concerns. Four weeks of apical membrane. ther rigorously designed larger RCTs in the subtypes of IBS are needed. Consequently. sensory threshold and stress reactivity of the gut ing the consistency of the stool197. and improv­ tion. Rifaximin is approved for use in hypno­therapy (gut-directed hypnosis) or other psycho­ the United States. Lubiprostone. but has not yet received regulatory logical therapy. As lopera­ abdominal symptoms secondarily influence anxiety mide does not cross the blood–brain barrier. Given the burgeon­ friends210. 5‑HT4 receptor agonists double-blind RCT of 208 patients with all types of IBS206.184. p ­ ointing to the complexity of restrictions in its prescription201. altered brain–gut signalling and ramosetron and ondansetron. The with a NNT of approximately 11 patients. has been evaluated in a Phase III RCT. fearfulness and embarrassment is well estab­ in RCTs203.205. but also direct effects on local for referral to cognitive–behavioural therapy (CBT). Its main benefit is reducing influence physiological factors. components into account: altered peripheral regula­ 5‑HT3 receptor antagonists. indirect symptoms in two well-designed Phase III RCTs193. although recent meta-analyses have through increasing intraluminal fluid secretion thereby highlighted that inconsistencies in study design render giving its laxation effect but also an analgesic effect via definitive recommend­ations problematic183. ceed through inhibition of the ascending excitatory To further improve treatment programmes. acti­ Others. Probiotics can reduce pain and therapy and m ­ indfulness-based therapy 190. it is probably multifaceted via acetylcholine. Patients who experience a positive therapeu­ ing evidence of the role of the microbiota in IBS. a mixed (top-down)208. as well as by their family members and Manipulation of the microbiota. and its effects it is unclear whether pro­biotics act on IBS symptoms caused reduced abdominal pain.PRIMER have lasted for >1 year. through the activation of the serotoninergic pathways. Antidiarrhoeals. central and depression (bottom‑up) and psychosocial factors adverse effects are limited. advocated for a graded treatment approach212. The μ‑opioid receptor agonist lopera­ mide is frequently used as a first-line agent in IBS‑D Psychotherapy and improves diarrhoea by inducing peristalsis. A proportion of patients use herbal supplements vates type 2 chloride channels on the enterocyctic either as single herbs or in combination. follow‑up visits211. such as alosetron. with The effect of IBS symptoms on patients’ feelings of ondansetron202 and ramosetron demonstrating efficacy shame. bloating and bowel through direct modulation of the microbiota. which promote gut motility Although the mechanism of action is poorly understood. Linaclotide has a dual action symptom severity. with respect to ischaemic colitis. other the condition15. thereby stimulating fluid secretion. treatment with iberogast. treatment approach. such as motor func­ stool frequency and defaecation urgency. The mechanisms by which rifaximin toms do not respond to pharmacological treatments exerts its positive effects on IBS symptoms are incom­ after 12 months and who develop a continuing symp­ pletely understood and may include modulation of tom profile (refractory IBS) should be considered the gut microbiota. The mechanism of hypervigilance and a general mindset of catastro­ action of 5‑HT3 receptor antagonists is complex and phizing 209. bicyclic fatty acid derivative of prostaglandin E1. has been International treatment guidelines for IBS have demonstrated to cause a reduction in symptoms. (such as prucalopride). The non-­absorbable antibiotic. which The biopsychosocial model of IBS suggests that prolongs the gastrointestinal transit time. via the gut immune system or otherwise. . although social factors of patients with IBS should be based on safety concerns have been expressed concerning the evidence-­based models that take the following three excess rates of pancreatitis198. modulation of colonic nociceptors192. have that patients with IBS often experience additional been confined to alosetron.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d .

gut-directed hypnosis and mindfulness-based have been performed in the field of psychological and therapy  (BOX 7) has only been done in a very limited behavioural therapies (including studies in stress reduc­ number of tertiary treatment centres and the general­ tion and relaxation) that took 45 RCTs into account with ization of these treatment approaches is limited. Psychological an effective treatment option for all subtypes of IBS250. All subscales of SF‑36. The NNT for CBT is only ment that can evaluate physical functioning. On the basis of these findings. Nevertheless. GDH differs from other forms of psychological IBS-QOL in patients with IBS‑D or IBS‑M. there is a lack of reports of adverse effects of patients). vitality. Patients are encouraged to discuss their symptoms in depth. than non-consulters with IBS (individuals who do not Gut-directed hypnosis seek treatment)221. a study has shown that patients with IBS with key people.219. which consists of the explanation of IBS another study 221. mindfulness-­based therapy for IBS shows some prom­ Overall. Very limited data on multi­ majority of drugs214. role. . physical role and emo­ behaviour and an inappropriate attribution of symptoms. Several meta-analyses apy. both gastrointestinal symptoms and stress reduction programme. large effect size on increased patient’s QOL. A l l r i g h t s r e s e r v e d . Finally. In gut-directed hypnosis (GDH). maladaptive (except physical functioning. General QOL is a measure of the There are medium-to-large significant pooled effect entire health perception of a person. emotions and actions. physi­cal three patients. After than in patients with IBS‑C in one study 222. Although Quality of life CBT is not routinely available in primary care. Finally. QOL in patients with IBS is greatly disturbed. CBT aims to modify these tional role) than in healthy controls were observed in behaviours and thoughts through education. thus. Another study revealed that cognitive techniques. as opposed to standard hypnotherapy. particularly in the subgroup of patients (95% CI: 3–5) and. are made on how to control and normalize gastrointestinal function and metaphors are However. with a limited variance between the RCTs. emotional role and mental health216. 9). ­easily. general health perceptions and social functioning are identified246. had more disturbed general QOL in physical role. IBS‑M may have been responsible for the lower QOL222. Finally. Mindfulness-based therapy but there are controversial reports218. diabetes mellitus or severe chronic kidney dis­ Psychodynamic (interpersonal) therapy (PIT) aims to obtain insights into symptom development as a consequence of interpersonal conflicts or difficulties in relationships ease220. was worse treatment in which therapy is provided to patients in a conscious state. whereas Cognitive–behavioural therapy (CBT) is based on the assumption that irritable bowel lower values on the SF‑36 subscales in patients with IBS syndrome (IBS) symptoms are a response to stressful life events. a psychology-based self-aid (educational) psychological and behavioural treatment approaches and approach has been shown recently in a meta-analysis as treatment resistance in patients with IBS. Patients with IBS showed impaired general QOL with Box 7 | Evidence-based psychological treatments lower values on all SF‑36 subscales except physical func­ Cognitive–behavioural therapy tioning than healthy controls in one study 220. In a stepped-care approach (begin­ component thera­pies and on the combination of anti­ ning with the least intensive or invasive treatment and depressants and psycho­logical treatments are available169. therapies have also regularly not distinguished between Compared with control treatments. information on the effects of hypnosis is given. the feeling that there is something NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 17 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . Representative gen­ sizes for an improvement of IBS symptoms using CBT eral QOL can be assessed using the Medical Outcome with a medium significant pooled effect size for QOL Study 36‑item Short-Form Health Survey (SF‑36)216 or and a small-to-medium pooled effect size for psycho­ the EuroQOL survey 217. stress management) is applied245.325 patients with IBS of all subtypes (TABLE 1). suggestions QOL seems to be the same among IBS subtypes. participants are provided with a increased food avoidance in patients with IBS‑D and compact disk (created by hypnotherapists) for practicing at home on a daily basis247. to date there is no evidence of a superiority social functioning. SF‑36 is the most popular instru­ logical comorbid symptoms. The basic course emphasizes the relevance of mindfulness psychiatric comorbidity independently contribute to in coping with IBS-related symptoms and perceptions. QOL are distinguished. The degree of disturbance of general QOL in (for example. as measured with the used to bring about improvement. bodily pain. bodily emotional factors are explored and links between symptoms and emotional factors pain. the NNT for psychological therapies is four ising initial results. patients and therapists work together to identify the potential associations between IBS patients with IBS than in healthy controls regardless of symptoms and their thoughts. and by identification of the psychological factors that cal functioning and physical role domains. In this study. it can be In the field of medicine. of CBT ­compared with other psychological treatments Disease-specific QOL is a measure of life disturbance that in IBS. low in energy. With a range of behavioural and disturbed QOL223 (FIG. stepping up or down depending on the needs of the Overall. The best evidence is available for CBT. disease-specific QOL. PRIMER BOX 7 describes the four major psychological-based Validation of psychodynamic (interpersonal) ther­ therapies for patients with IBS. Mindfulness-based therapy (MBT) for IBS has been adapted from the mindfulness-based In severe IBS. therefore. a medium effect size IBS subtypes and. were lower in are interacting with their physical symptoms. patients with IBS has been shown to be worse in several subcategories than in those with gastroesophageal reflux Psychodynamic (interpersonal) therapy disease. general QOL and disease-­specific accessed in some local hospitals and health-care systems. a total of 3. except the physi­ symptoms and the CBT model. MBT promotes sensory versus emotional processing of the QOL of patients with IBS was more influenced interoceptive signals and counteracts catastrophizing as a maladaptive cognitive by  the extraintestinal symptoms  —  such as tiring coping style215. is specifically caused by the disease218. general health perceptions. might have missed differential was demonstrated on decreased symptom severity and a indications and advantages and disadvantages. better than the female patients with IBS215. behavioural therapy culture222.

a moderate effect size on • GSHs might be an easily accessible and symptom severity (0. Cohen’s d): effect sizes of 0. 18 | 2016 | VOLUME 2 www.001) stress reduction group was not • Changes in QOL. Even if primary end points based on cardinal symptoms The psychological and psychosocial dimensions of food of IBS are similar between treatments. QOL. Although the SF‑36 can also detect the efficacy of long-term treat­ Patient stratification and biomarkers ment (>1 year). randomized controlled trial. there is a wide heterogeneity and variance in its performance The NNT data are based on Ford et al. especially long-term therapies226. differences from placebo187. 245. A therapeutic gain of ≥14 points nervous. basic (1. . These small differences QOL is sensitive enough to detect efficacy for mid-term conceal the fact that some patients benefit from the drugs. no benefit of relaxation training or therapy in IBS was • The field of studies on relaxation detected in the RCTs techniques is diverse GSHs250 10 RCTs (886) • Compared with control conditions.nature.76–4. but IBS. OR. CBT. patients’ QOL (0. §Methods and techniques applied are progressive muscle relaxation.21) to other psychological treatments • NNT for CBT was 3 (95% CI: 2–6) PIT249 2 RCTs (273) Both studies compared PIT with ‘supportive listening’ applied by the • PIT is less well standardized in terms same therapist.48) support or medical treatment alone at • Psychological distress (depression and anxiety): small-to-medium the end of treatment but not superior pooled effect size (0. difficulty sleeping and low in IBS-QOL denotes a clinically meaningful change. urgency. feeling hopeless. distress and anxiety were not different between retained at 6 months follow‑up groups immediately after treatment • Significantly greater improvement in the MBT group than in the control group evident at 3 months follow‑up • The beneficial effects persisted for ≥3 months Relaxation214§ 6 RCTs (255) • Overall.214. Compared with controls: of its performance (that is. odds ratio. between 0.8 as moderate and >0. Many classes of drugs have been evaluated by RCTs in Both measures struggle to detect drug or psycho­therapy IBS and these have often produced disappointingly small efficacy in the short term (<1 month)226.4% versus 6.05) in overall • Very few professionals are trained for gastrointestinal symptoms compared with supportive therapy only the specific implementation of GDH • Response rates ranged between 24% and 73% and therefore their services can be • Efficacy was maintained long term in four of five studies difficult to access • NNT was 4 (95% CI: 3–8) • The mechanisms by which GDH exerts its effect are poorly understood MBT215 2 RCTs (79) • Women showed greater reductions of symptoms compared with a • In another RCT. mindfulness-based therapy.92 (95% CI: 1. feeling tense. An inability to participate in such a fundamental component of social intercourse Outlook because of a fear of pain. guided self-help intervention. duration.5 (95% CI: 2–25) GDH247 7 RCTs (452) • 6 of 7 RCTs reported a significant reduction (all P < 0. quality of life. *See REF. treatment. irritable bowel syndrome.2%. cognitive–behavioural therapy. biofeedback and transcendental or yoga meditations.2% compared with 11. setting and phases) • PIT significantly improved symptoms • PIT showed a large cost-effectiveness • PIT was widely acceptable • PIT significantly improved QOL • PIT significantly reduced costs • The calculated OR for benefit was 2. P = 0.83) • NNT for dynamic psychotherapy was 3. a treatment result­ ingestion might also have a role. gut-directed hypnosis. in part be devastating and can result in social isolation210.380) • QOL: medium significant pooled effect size (0.227.5 are regarded as small. RCT.8%. P = 0. A l l r i g h t s r e s e r v e d . Eating with family and ing in better QOL may be preferred by patients over friends is probably the most common form of social another treatment that does not improve QOL. diarrhoea or disten­ The field of research into IBS has expanded consider­ sion occurring during or immediately after a meal can ably over the past decade with many new studies. the IBS symptom control group immediately after training (26. Table 1 | Evidence-based psychological treatments for IBS Psychological n of studies Main findings Comments treatment (n of approach* participants) CBT248 18 RCTs • Symptom score: medium-to-large significant pooled effect size‡ (0. MBT.214. NNT.72) and a large effect size on the increase of a cost-effective treatment alternative. feeling (3 months) treatment203.228.8 as large.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . driven by the development of new therapeutic agents. sexual interest — than by gastrointestinal symptoms224. Systematic reviews have clarified that improvement This trajectory seems likely to continue as patients with of IBS-related pain by treatment results in better QOL in IBS account for a substantial proportion of all gastro­ patients with IBS225.2–0.006) severity in the mindfulness-based and at 3 months follow‑up (38. PIT. The disease-specific IBS-QOL and intestinal consultations. it is less sensitive than the IBS-QOL.5 and 0.PRIMER seriously wrong with their body. interaction worldwide. GSH. number needed to treat. and many questions in the field IBS-QOL questionnaires can measure the efficacy of remain unanswered (BOX 8). ‡Effect size (for example. psychodynamic (interpersonal) therapy.84) was found However.67) • CBT was superior to waiting lists. GDH. IBS.

RCTs rarely measure transit as a requirement at least in the case of lactose malabsorption. capsule endoscopy 232 and the pressure-­sensitive. somatization question­ ers that reflect the targets of ‘older’ drugs has been a naires concerning non-gastrointestinal symptoms considerable limitation. changes in autonomic and neuroendocrine function. which depends on symptoms recorded in no trial of lactose exclusion in IBS has used measures daily symptom diaries. However. notion such that the dose can be tailored to individ­ which might lead to many of the clinical manifestations observed in irritable bowel ual patients. those involved in 5‑HT reuptake via the 5-HT transporter (SLC6A4) and polymorphisms in the 5‑HT3 receptor genes (which alter sensitivity).230. emotion. dyspnoea and palpitations example of such drugs that have fallen out of favour have been shown to correlate. alternatives to test to show a significant difference from placebo. these studies are underpowered and have not yet been reproduced202. These gastrointestinal influence colonic transit and should be explored to see symptoms and other extra-intestinal manifestations (such as multiple somatic symptoms and psychiatric comorbidities) impair the quality of life (QOL) of patients with IBS. with rectal because we cannot reliably identify those with excessive ­distension pressure thresholds for pain239. However. therefore many Dietary restrictions such as low FODMAP diets (BOX 5) trials use unselected patients with IBS. independent of are another example in which implementation of an the underlying disease mechanisms and clinical presenta­ effective treatment is hampered by lack of biomarkers tions. Antispasmodics are a good such as headache. The|genome may be limited but combining polymorphisms that pre­ Nature Disease and Primers epigenome partially determine (‘filter’) the response of an individual to external stressors dict low 5‑HT production with rapid uptake and low (psychosocial factors) and internal stressors (ingested food or microbiota). Proper stratification of patients by relevant underlying Mode of action of food intolerances disease mechanism has been an issue. alosetron. hold the possibility of ­identifying such patients in the future. Although poorly absorbed fermentable improved their effectiveness with significant differences carbo­hydrates can undoubtedly cause symptoms in from placebo229. These. for trial entry. 234) and to (food and extra-gastrointestinal microorganisms) manifestations another 5‑HT3 receptor antagonist. More remotely. individ­uals experience symptoms and some do not 237. albeit weakly. polymorphisms in the FGF19– syndrome (IBS). coping and social support Future novel non-invasive motility assessments. A l l r i g h t s r e s e r v e d . This response might tion. PRIMER Genetics and motor activity who might be expected to respond. However. This finding may be due to a combination of important functional polymorphisms in genes involved in 5‑HT synthesis (tryptophan hydroxylase 1 (TPH1)). emotion and coping behaviours against stressors. which controls bile acid synthesis107. The use of more-objective bio­ of sensitivity to stratify patients. stressors temperature-sensitive and pH‑sensitive SmartPill (psychosocial factors) (Given Imaging Ltd. The use of 5‑HT receptor-modulating drugs has to predict response or reliably identify the key com­ taught the research community that restricting 5‑HT3 ponent (or components) of food that are responsible receptor antagonists to patients without constipation for symptoms. receptor sensitivity would be expected to be associated together with social support. although improve the effect size and reduce the number needed not impossible to standardize across centres. owing to the fact that 5‑HT3 recep­ some patients. stressors Gastrointestinal and according to polymorphisms in TPH1 (REF. By analogy with other complex dis­ orders236. Similarly. visceral sensitivity is the key to why some tor antagonists slow transit and aggravate constipation. the effect of any one individual polymorphism Figure 9 | Concept of multifactorial quality-of-life effects inReviews IBS. ramosetron. alteration in gastrointestinal motility. widely available biomark­ stimulation238. epigenetics Appraisal. While rectal barostat markers to select patients for RCTs would be expected to tests to assess visceral sensitivity are difficult. might be to use simple cutaneous pressure or thermal The lack of reproducible. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 19 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . with higher odds ratios for success of 5‑HT manipula­ determine the stress response affecting the brain–gut interactions. such as External MRI231. increased mucosal permeability and low-grade inflammation. they might be important predictors of drug sen­ sitivity in particular pathways. Future studies should be powered to examine this involve regional brain activation. Yoqneam. 5‑HT3 receptor antago­ Brain–gut Stress Impaired nists are good examples of drugs with a wide range of axis response QOL sensitivities such that effective doses for one patient can produce unacceptable constipation in another. if different combinations alter sensitivity to bile acid sequestrants or bile acid transporter inhibitors. Israel)233 (which can measure intestinal contractions). appraisal. Several small studies have suggested signifi­cant differences in responder Internal status to one 5‑HT3 receptor antagonist. FGFR4 pathway. . including visceral hypersensitivity. 235).108. accord­ ing to polymorphisms in SLC6A4 (REF. backache. Brain activation and neuroendocrine Although individual genetic markers seem likely to modulation be associated with only quite modest increases in risk for IBS.

subjects. Joustra. World J.. P. more widely adopted than at present. Can we characterize the functional effects of changes in microbiota to improve efficacy Analysis of urine and stool metabolites. U. C. T. developing countries — a disorder of civilization or 312–321 (2014). 105. G. including bile of manipulation of the microbiota as a novel therapy? Possible studies are: acids and endogenous tryptase.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d .. Gastroenterol. Gastroenterology 133. somatic symptom disorder. B. Management This meta-analysis covers epidemiological reflux disease and irritable bowel syndrome: increased of functional somatic syndromes. chronic fatigue syndrome. A. & Ford. a slower delivery in a solid matrix • Immune activation may be better tolerated. D. focusing on function may be more helpful than • MRI studies of intestinal volumes and gas or water content of the stool just ­identifying the species present. 13. Lovell. may provide simpler bio­ • Randomized controlled trials of fermentable oligosaccharides. 32. A. et al. L. Inflammatory bowel & Clark. 16. irritable bowel syndrome. A. 77. White. disease. et al. fibromyalgia. A.. Life course study of the etiology of 317–324 (2005). C. Ford.. Gastroenterol. these results need to be replicated and duo­denum more slowly after trituration by antral con­ studied in more detail to enable dissection of the extent tractions. Med. (2016). 33 countries worldwide and reports not only the 1232–1238 (2010). 1796–1798 (2010). Am. S. Gastroenterol. 2767–2776 anxiety or depression. (2013). a in microbiota SCFA. Whorwell.. which probably stimulates substrate provided in the diet. J. 17. hence. P. & Drossman. Overlapping gastroesophageal 15. Identification of early 6. 39. E. Pharmacol. M. M. Gastroenterol. Matheis. D. 16. Can we identify the mode of action of food intolerances to allow rational designs of diets? Given the very large number of different species that Possible tests are: have overlapping metabolic capabilities and functional • Nutrient challenge meals effects..nature. R. P. M. K. J. Psychosom. Co‑occurrence of IBS and symptoms of The prevalence. & Mearin. although. A. 712–721. J. Can we assess the role of genetic markers in irritable bowel syndrome? Possible factors that should be taken into account are: Functional effect of changes in microbiota • Gene and environment interactions Many studies have found profound differences in the • Biomarker discovery — for example. 78. 670–680 a real association or reflection of occult inflammation? Am. parents to children.. Yarandi. Better insight might also enable lactose in a patient with lactose malabsorption240. L. J. Lancet 369. Ther. 105. K.. patterns and impact of irritable syndrome. Bailey.. 75. Mostajabi. 7. Gastroenterol. low levels of butyrate. L. S. Saito. 449–457 (2015). Mood and anxiety disorders in 21. L. Aliment. P. Am. Gastroenterol. 3446–3455 (2007). Koloski.. Motil. 11. Lovell. 105. Thus. Pharmacol. Axon. Gastroenterol. J. colonization? Neurogastroenterol. F. S. A. A l l r i g h t s r e s e r v e d . Hungin. mainly Can we develop clinically applicable biomarkers to stratify patients to disease hydrogen. Pharmacol. Gwee. et al. Jonsdottir. H. Nasseri-Moghaddam. M. • Mucosal serotonin availability which would allow a less restrictive diet that may be easier to follow and. mannitol in healthy volunteers241 result in a rapid influx of based on their metabolic capabilities and response to a water into the small intestine. J. but the agree­ • Pharmacogenetics ment on the involved species between studies is poor 57. J. influenced by both heredity and intrauterine growth. and irritable environmental risk factors for irritable bowel syndrome & Moayyedi. Bengtson. Keohane. J. L. A. 4. & Enck. Hotopf.. A. et al. Aamodt. This leads to the virtually instantaneous generation of gas242. Martens. 1317–1325 (2015). D. 9.. A. Psychosocial mechanisms 5. Irritable bowel syndrome in Rome III criteria. British birth cohort. Effect of gender on pooled prevalences but also several risk factors 8. Many of the diet­ isms with either enhanced growth capacity or those that ary components implicated in IBS symptoms are actu­ adhere to the mucosa to deal with rapid flow within the ally consumed as solids and hence delivered into the colon243. Irritable bowel syndrome-type 18. 107. Zipfel. D. R. Olafsdottir.000 (2007). Gastroenterol. by genome-wide association studies microbiota of selected patients with IBS. 833–841 (2010). Aliment. M. Kruse. Stability of the irritable Am. Janssens. 1. S. study. Barsky.PRIMER Box 8 | Key questions to be addressed in future research transit and rapid delivery into the colon.. 15.. . disorder patients: a cross-sectional survey using the community: systematic review and meta-analysis. Henningsen. C. P. Ford. Natural history of functional a singular or two different clinical syndrome? for the transmission of somatic symptoms from gastrointestinal disorders: a 12‑year longitudinal World J. Ther. A challenge to the functional-organic dichotomy. & Ford. van Tilburg.241 or the tailoring of diet to the existing microbiota in a patient. (2003). P. et al.. Gastroenterol. World J. natural history of symptoms and factors that influence study. H. 13. Irritable bowel syndrome and chronic pelvic pain: 20. 27. M. et al. W. S. Future studies should also take into account the important role of transit time and its The physical form of food is another key variable variability.. Global prevalence of consultation behavior. 643–650 12. 14.e4 (2012). Forman. J. disaccharides. A. which a sensitized individual may • Evidence of bile acid excess experi­ence as cramps. Med. population-based study. Furthermore. G. M. W. & Herzog. S. 102. among Norwegian twins. 2–4 a meta‑analysis. Ther.. M. Gudjonsson. B. is bowel syndrome: an international survey of 40. Gastroenterol. markers of function that could predict responsiveness to monosaccharides and polyols (FODMAP) intervention with assessment of changes microbiota manipulation. Aliment. R. A. 20 | 2016 | VOLUME 2 www. & Rosmalen. 202–210 & Thjodleifsson.. Zijlema. A. thereby reducing the number of patients needed to evaluate new metabolize the sudden excess of substrate. A. Am. 21. 17. Psychosom. Long. (2010). The rapid entry of osmotically active poorly to which differences in microbiota are the cause or the absorbed substrates — mainly in liquid form — such as effect of rapid transit. Halder. & Malekzadeh. The challenge of rapid transit favours organ­ whose importance is yet to be defined. might encourage the provision of prebiotics that • Effect of placebo-controlled diets on faecal or serum bacterial metabolites favour butyrate-producing bacteria. J. 2. R. J. A. 991–1000 (2012).. J. 9 (2015). C. Future studies should define how • Biopsy supernatant mediators that activate enteric neurons the physical form of FODMAPs alters their tolerability. H. et al. J. such as Eubacterium rectale and Roseburia cecicola. C. 17. H. A. Assessing the new DSM‑5 diagnosis of and risk factors for irritable bowel syndrome: 1229–1239 (2008). Motil. B. Y. Characteristics of functional bowel prevalence of irritable bowel syndrome in the common to all studies. 103. Hepatol. 799–807 (2007). Comorbidity in irritable bowel & Harris. Med. 19. A. Stansfeld. G. population-based data across 90 studies in dysfunctional symptoms. or what?: self‑reported irritable bowel syndrome in the 1958 3. Vatn. N. Tack. 1789–1794 (2010). bowel syndrome and subgroups as measured by 10. Psychosom. Familial aggregation of irritable three diagnostic criteria — a 10‑year follow‑up symptoms in patients with inflammatory bowel disease: bowel syndrome: a family case–control study. Goodwin. 5532–5541 (2015). given that the microbiota are unable to fully mechanisms. W. 10. P. Neurogastroenterol. therapeutic agents? Possible factors that should be taken into account are: distension of the ascending colon generates propul­ • Transit time sive colonic motility. Clin. Irritable bowel syndrome: a 10‑yr bowel syndrome: results from the LifeLines Cohort and dyspepsia. Whitehead. 946–955 (2007). Am. BMC Gastroenterol.

predominant irritable bowel syndrome: in vitro studies Neurogastroenterol. 1737–1745 (2014). 46. 50. J. P. Scully.. Gunsalus. J. 1792–1801 (2011). S. 281. et al. et al. Gastroenterol. I. B. & Enck. et al. & Bushnell. J. L. Short-chain fatty acids and the irritable Systematic review with meta-analysis: post-infectious and ulcerative colitis patients exert opposite effect on bowel syndrome: the effect of wheat bran. 22. Methanogens in human health and by supernatants of colonic biopsy specimens from syndrome. 41. G. Engl. The degree of breath methane shows food-associated changes in the intestinal 55. 77. et al. distension of IBS patients can be transferred to rats Best Pract. P. Gut http://dx. et al. W. Suppl. M. J. K. 38. H. Gut 65. 46. 52. S. 58. Mazurak. M. A. M. 1299–1311 (2014). Pimentel. Pain 144. S. Clin. Cenac. Post-infectious irritable bowel syndrome — a review of pain in irritable bowel syndrome. 91–99 (2016). mesalazine for the treatment of IBS with diarrhoea (2013). biopsies to study the pathogenesis of irritable bowel symptoms in patients with irritable bowel syndrome: 384–404 (2008). Y. Ther. Is irritable 18 reports of IBS occurrence following an acute patients is linked to visceral sensitivity. A. O. 87. A. 1. Lower Bifidobacteria counts 34. 86. C. Dietary triggers of abdominal animal models to drug development. e272–e282 (2013). 26. syndrome. et al. D. 44. Fritscher-Ravens. Aliment. 1322–1331 (2013). 49. N. 26. Hughes. D. 997–1006 (2012). A. R. Inflammation as a basis for functional GI syndrome. et al. Ford. 3–11 (2015).1136/gutjnl-2015-309889 (2015). V.. Kastoff. 1072–1080 (2008). T.e4 (2014). 34. Mayer. H. Fasting and postprandial differences according to the disease subtype. (2009). randomised placebo-controlled trial of composition. 82–90 (2016). Shepherd. Mortensen.e4 faeces. Gastroenterology 126.. Coeffier. A. E. J. 85. M..doi. An irritable bowel syndrome irritable bowel syndrome. et al. et al. Pharmacol. Y. 18. et al. Spiller.. nov. M. P. 1002–1011.. 104–119 (2008). and prognosis of post-infectious irritable bowel for abdominal pain in constipation-predominant IBS. Keita. Arffmann. Kottachchi. L. King. Am. Am. R. 837–841 Gastroenterology 147. Am. A. composition and host-microbe cross-talk following 74. N. Valentin. P. & de Vos. P. Ivanov. G.. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 21 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . 508–510 (1982). Sensory neuro-immune 71.. bacteria in nutrient metabolism. Nasser. N. C.. et al. Sci. disease. Neurogastroenterol. Nature 504. 209–217 Scand. Confocal endomicroscopy (2010). S. This is so far the largest meta-analysis of biopsy supernatants from irritable bowel syndrome 69. Clin. C. Clin. 28–33 patients with irritable bowel syndrome.. Lancet 352. Gut 62. The expression and the exploring the microbial part of ourselves in a changing fermentation in irritable bowel syndrome. 235–245 post-infectious IBS) and its potential risk factors 47. E. 1782–1791 Methanogenic flora is associated with altered colonic technique to identify biomarkers of (2011). Am. 996–1047 BMC Gastroenterol. 22. Mast cell-dependent excitation of 65. 352–358 (2014). & Hunter. & Rao. Muir. Gastroenterol. Quantification and potential functions (1997). 38. Gastrointestinal microbiome (2012). S. Motil. Barbara. Valestin. E. Gastroenterol. et al. through microbiota transplantation. J. M. A. Proc. 26. A. S. Clin. R. J. C. Functional GI disorders: from Schemann. et al. Weissfeld. S. M. Abnormal colonic 28. and description 27. G. 88. signatures of pediatric patients with irritable bowel 75. 753–760 irritable bowel syndrome with diarrhoea.. De Palma. 559–563 Neuropharmacology 55. Gastroenterol. Schwille-Kiuntke. et al. & de Vos. M. 105. 105. disease? Gastroenterol. E. Evol. Barbara. Ahsan. Microbiol. review and meta-analysis.. Gastroenterol. Bercik. S. 32. transit but not stool characteristics in constipation micro-inflammation in IBS by using supernatants 54. G. Gastroenterol. a relevant factor for symptoms and treatment in IBS. M. D. Cremon. G. T. bowel syndrome measured using serial MRI. et al. World J. 1146–1159 of Yersinia spp. A. G. to isolated neurons of the ENS of animals. 14. Clin. nov. (2015). G. comb. Characterisation of faecal protease & Farmer. J. T. Physiol. J. et al. J. Microbiol. 81. 41. & Marshall. Invest. V.. A. S. J. Reclassification of Eubacterium abnormalities in the jejunal epithelial barrier. J. W. 1181–1188 (2010). et al. A l l r i g h t s r e s e r v e d . & Pimentel. P. et al.. C. subtypes. A. Nerve fiber outgrowth is increased in formicigenerans gen. E. E. Res. Clin. Gastroenterology 141. J. 997–1003 (2011). Neurogastroenterol. Rao. N. et al.. 106. Hamer. bowel syndrome a low-grade inflammatory bowel gastrointestinal viral or bacterial infection (called 99. Simmering. 1187–1189 (1998). J. or origin and effect of gut transit. D. co‑morbidity. Gastroenterol. (2010). S. 189 (2014). Chem. J. Gastroenterol. et al. O. (IASP Press. 30. Am. Gastroenterology 148. Aliment. The human microbiome project: 72. et al. J. Arpaia. Z. G. M. J. (2009). A.. N. Bajor. are altered in irritable bowel syndrome patients with 51. Sci. to colonic nerves correlate with abdominal pain in (2014). nov. syndrome. gastrointestinal microbiota in irritable bowel constipation. Slattery. Crouzet. analysis of microbiota signatures in fecal samples from volumes of the undisturbed colon: normal values Am. 6. Frick. Clin. Rudling. 433–444. Aziz. S. 25. Gut 65. 43. Motil. G. Zanger. Andersen. Wouters. The immune system in irritable and gut dysfunction from IBS patients to axenic mice 1722–1732 (2001). Chatterjee.. Motil. 40. Gastroenterol. R. Collins.. & Hyams. cellular distribution of the tight junction proteins world. & Sonnenwirth. Serotonin and GI clinical disorders. Aliment. Association of symptoms with production in IBS correlates with the severity of mucosa of patients with irritable bowel syndrome. G. M. Schwille-Kiuntke. et al. A. Gastroenterol. This paper reports the relevance of a novel syndrome. Function of the microbiota. 31. Cenac. A. D. & Stanghellini. Tornblom. et al. and predictors. J.. Niaz. M. D. 804–810 (2007). Kong. 66. Plasma cytokine profiles in females with without IBS. probiotic and 17246–17252 (2006). 423–428 involvement of soluble mediators. Annahazi. M. Taras. 84–92 (2015). & Bushnell. F. 42. Bischoff. J. E. Mayer. Pritchard. Gastroenterology 137. Med. 2887–2892 (2009). 1012–1020. consequences. 15. Pharmacol. M.. G. Pharmacol. 23. Tims. (IBS‑D). Gastroenterology 132. et al. 64. 17. Using human intestinal & Gibson. from feces. J. sensory nerves by mediators from colonic biopsies of 70. 39. et al. Verdu.. Intestinal microbiota in functional in both duodenal mucosa-associated and fecal functional bowel disorder with diarrhoea: a systematic bowel disorders: a Rome foundation report. P.. 1634–1643 (2013). S-845 (2014). F. 280–286 (1996). the literature. Peripheral mechanisms in irritable bowel (2014). S. et al. Pediatr. 15. E. K. Annahazi. S. Valdez-Morales. (2002). J. Activated mast cells in proximity the human gut microbiome. M. M. Review article: the role of butyrate Syndromes: Presentation and Pathophysiology channels in patients with irritable bowel syndrome. J. 531–565 (eds Mayer. 23. Dig. disorders.. M. M. Bertiaux-Vandaele. Hepatol. Rapid isolation group. 26–37 (2007).. Salmonella to use ethanolamine to compete with the 37. 49. A. and changes in diarrhea-predominant irritable 29. Attaluri. 278–287 (2014). Syst. J.. Gastroenterol. M. Parker. Natl Acad. Jackson. isolated from human the colon of patients with irritable bowel syndrome: syndrome. 16. microbiota in irritable bowel syndrome patients. 117. 1456–1465 (2013). 1425–1434 (2009). Aliment. S. 10. R. 1029–1037 (2015). T.. P. Pharmacol. 26. S. 146. Gut 63. S. 718–733 (2010). J.. syndrome. Am. 2009). 68. & Vanner. Gut 63. Biomarkers for bile acid diarrhoea in 57. 16. 67. Increased proteasome-mediated Gastroenterology 141. 42. P. Role for protease activity in visceral of carbohydrate fermentation. 15. A mechanistic multicentre. A serpin from the gut bacterium 33. et al. mesalazine in IBS. Microbiol.. 4532–4540 (2007). 1626–1635 (2012). C. Buhner. Kerckhoffs. Nature 505. et al. PRIMER 22. M. et al. C. Turnbaugh. W. 89. M. H. Jørgensen. Camilleri.. Q. Rajilic´-Stojanovic´. N. Motil. syndrome. C. Int. degradation of occludin in irritable bowel syndrome. Nature 449. P. Systematic review with meta-analysis: 56. E. bowel syndrome: an organic disorder with structural interactions differ between irritable bowel syndrome & Blaut.. 45. Barbara. P. & Macfarlane. 451–455 (2013). et al. et al. Malinen. N. Gut 64. Nutr. Neurogastroenterol. Motil. Rajilic´-Stojanovic´. Long-term 17480–17485 (2011). Elia. 79. in Functional Pain of endogenous agonists of transient receptor potential 63. H. Gut 62. Randomised controlled trial of 60. M. J. S. epiphenomena? Am. Simrén. R. Buhner. Gastroenterol. Rajilic´-Stojanovic´. & Mortensen. Lam. 59. Environ. 1407–1411 from biopsies of patients with IBS applied in vitro irritable bowel syndrome and extra-intestinal (2010). and its influence through dietary. 636–647 (2007). B. Ther. & Enck. 102. C.. and its regulation by neuroimmune factors. A. K. J. Rev. Nutr. M. G. Dis. J. E. Neuronal activation by mucosal 641–661 (2004). Cummings. Barbara. Res. 61. G. Exp. M. patients with irritable bowel syndrome. Gastroenterol. Tooth. J. 52. 105.) Gastroenterology 149. Treem. et al. et al. A. et al. Gut 62. 185–192 (1987). H. D.. N. 110. 27. The first 25.org/ 159–176 (2013). The intestinal barrier visceral-nociceptive sensory neurons in irritable bowel Fecal short-chain fatty acids in patients with diarrhea. 78. microbiota. Dothel. Gut 57. Lawson. Faecal microbiota Neurogastroenterol. 30. Gastroenterology 82. et al. 3–11 in faecal microbiota. 5–16 Inflammatory bowel disease and irritable bowel through their fecal microbiota. bowel syndrome. Impaired intestinal barrier integrity in the intestinal mucosa of patients with irritable bowel of Dorea longicatena sp. Best Pract. David.e7 (2015). Intestinal inflammation allows 349–359 (2011). Increased colonic bile acid exposure: knowledge on the role of the gut microbiota like serine proteases. patients: a role for PAR2. Intestinal microbiota activity in irritable bowel syndrome with diarrhoea: the prevalence of bile acid malabsorption in the and diet in IBS: causes. 535–544 Am. USA 108. Heilig. & Soderholm. et al. et al. Sensitization of peripheral (2005).. Rajilic´-Stojanovic´. P. Gut 61.. microbiota. 53. S. Park. C. S. 455–469 randomized placebo-controlled evidence. 27. Hydrogen sulfide Gastroenterol. Thabane. J. pharmacological manipulation. The hypersensitivity to colonic 80. et al.. (2013). 108. Ther. North Am. J. S. Activation of human enteric neurons gastroenteritis and in postinfectious irritable bowel & Zhang. Gastroenterol. Global and deep molecular 73. M. Jeffery. Diet rapidly and reproducibly alters 84. M. This narrative review summarizes state‑of‑the-art Bifidobacterium longum inhibits eukaryotic elastase- & Simren. A. World J. J. J. Saulnier. on colonic function. 62. Curr. Low. Zoetendal. 35. 765–771 (2008). et al... irritable bowel syndrome after travellers’ diarrhoea. 367. visceral sensitivity in mice. 2165–2173 (2011). (2007). Spiller. Opin. Diarrhoea-predominant irritable 48. & Collins. R. Biol. Jalanka-Tuovinen. FEMS Microbiol. Martinez. E. C. Ung. syndrome: similarities and differences. et al. Barbara. 36. Gastroenterol. Boeckxstaens. Gastroenterol. 124–130 (2014). 2235–2243 76. D. Ther. . parallel monitoring of the human intestinal microbiota 83. M. Role of intestinal subtype defined by species-specific alterations 693–702 (2004). et al. P. C. Gut 58. 196–201 (2015). 108. Gastroenterol. The adoptive transfer of anxiety and colonic epithelial metabolism. P. M. Rajilic´-Stojanovic´. Thiennimitr. Intestinal permeability — a new diarrhea-predominant irritable bowel syndrome 1000 cultured species of the human gastrointestinal target for disease prevention and therapy. (2014). Fecal proteases from diarrheic-IBS & Krag. Piche.. A. Metabolites produced by commensal 24. formicigenerans Holdeman and Moore 1974 as Dorea 1160–1168 (2013). Luminal cysteine-proteases degrade bacteria promote peripheral regulatory T‑cell Systematic review and meta-analysis: the incidence colonic tight junction structure and are responsible generation.

an important factor for severity of GI symptoms 156. Pain 110. R. 13. Chenodeoxycholate in females with 1195–1203 (2004). and their suspected functional bowel disorders. et al. B. among patients with nonconstipated irritable bowel microbiota-related parameters and develops a novel 115. Med. B. D. Dis. in patients with irritable bowel syndrome. Genetic variation in GPBAR1 130. 1480–1491 (2006). intolerance: pathogenesis. Zhou. et al. Rev. J. 1).. brain changes in irritable bowel syndrome. K. biomarkers and psychomarkers. et al. 152. Fukudo. J. Gastrointestinal-specific anxiety: hydrogen breath tests. & Verne.. The HTR3A polymorphism symptoms in IBS are common and associated with of postprandial diarrhea syndrome. diarrhoea adequate? Evaluation of two different are associated with GI symptoms and morphological 683–691 (2014). B. 848–858 (2010). Dechelotte. 297–303 (2006).. 11. Gastroenterol. 114. Am.. Dig. profiles in peripheral blood mononuclear cells and gastroenterologists. G. A. Predictive value of the Rome criteria (2015). A. Hepatol. e0135910 (2015). A. syndrome with diarrhea. MicroRNA 29 targets nuclear e1 (2013). J. Breath tests and irritable and bile acid excretion. C. A. 109. Grupe. J. Sood. Gut 59. American College of Gastroenterology Task Force on 92. W. 399 (2014). Gupta. M. Money. M. Dickinson. PLoS ONE 10. A. Comorbidity of irritable bowel syndrome 154. Deciphering microRNA code in pain and inflammation: (2015). controlled US trial. C. Genome-wide association study 814–820 (2010). bowel syndrome with diarrhea. functional variant in the microRNA‑510 target site of calprotectin. Am. M. K. fecal 488–501 (2013). symptom-based 144. leads. 7. 117. B. N. et al. 104. et al. A diagnostic score for the irritable bowel and meta-analysis. J. 775–784 (2010). S. predisposes to quantitative changes in colonic transit & Farup.. 2912–2917 (1999). 109. Am. O. Symptomatic fructose malabsorption 107. Gastroenterol. Correlation between gene expression of exclusion?: A survey of primary care providers. Efficient diagnosis of 100. manometry in patients with chronic constipation and syndrome. 955–960 (2010). stability and associates with colon transit in irritable of irritable bowel syndrome in individuals with United European Gastroenterol. physiology and syndrome: a GWA study in the general population and 1197–1204 (2015). M. L. B. L. 2. C. S50–S63 (2015). I.. et al. 122.. anticipation in anxiety: an integrated neurobiological (2013). D. S. 1943–1951 (2011). et al. J. Marwaha.doi.. Dig. Kilpatrick. A. Rex. results from a prospective. P. e0126438 96. A. Shin.. Regional brain morphology is 119. S. M. Gastroenterol. & Drossman. Holliday. B. E. M. L.. Cairns. Rao.. PLoS ONE This narrative review describes how — based on United European Gastroenterol. M. New clinical method for Am. Pract. Impaired miRNA regulation may syndrome is similar to controls. 1187–1193 (2011). 946–951 (2009). Zhou. Gourcerol. J. E. P. 1–7 (1984). Towards a systems view of IBS. 96. Q. Am. 123. M. et al. 1 (Suppl. P. Gastroenterol. Lackner. Gastroenterol. Rep. Gastroenterol. Pain catastrophizing miR‑342‑3p in patients with irritable bowel syndrome. E.. B. M. Begtrup. et al. Gastroenterol. E. S. W. Gastroenterology 87.. J. K. Manning. G. Am.. C. Clin. c. et al. Gastroenterol. Am. Rana.. et al.e1 (2010). Gunnarsson. K. Vijayvargiya. lead to altered 5‑HT4 receptor levels in IBS‑D patients. Gastroenterology 140. G. Spiegel. et al. Dis. 57. S. & Malik. W. Clin. 3 (Suppl.. M. D. Pharmacol. P. et al. P. U. Jerndal. Gazouli. et al. 1232–1239 (2013). Camilleri. A. 11. Self-reported food-related gastrointestinal 151. 95.. 597–604 (2004). 12. 7587–7601 (2014). Lim. 2. Pimentel. 137–146 (2006). associated with reassurance or improved health-related in IBS and critically discusses the methodological 159–172 (1990). definitions in patients with chronic diarrhoea. J. Fourie. Br. The yield of colonoscopy in 158–169. Sci. 538–544 (2012). et al. P. 110.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . J.. 3. 20. and IBS experts. Gastroenterology 139. J. Cortical criteria. 105. in general practice: a striking feature with clinical bowel syndrome. Bengtsson. Kurlander. Gut 56.. Camilleri. polymorphism on brain activation by colorectal 128. Clin. A. 125. Guidelines for colorectal cancer 102. Heaton. 129. & Gurtman... A. Chey. position statement on the management of irritable Gastroenterol. & Saenger. A.1262–1270. Gastroenterol. [corrected]. Soh. et al. W. P. (2010). 16. P. S. Neurosci. R. patients with non-constipated irritable bowel syndrome: 104. Stotzer.. A meta-analysis of the utility of C‑reactive and psychological perspective. 139. J. 145. Gastroenterol. Talley. 22. E. 151–159 (2013). responses to visceral stimuli. Ek. J. R. symptom-based criteria.. & Simren. 24. J. Diagnosis of IBS: Aliment. C. et al. epithelial barrier dysfunction through modulation of 135. Ther. Wohlfarth. 77–87 (2015). J. E. Tillisch.. combinations may enable the diagnosis of IBS. Gastroenterology 148. 381–386 (2015). A. 956–962. et al. Patients with irritable bowel the serotonin receptor-type 3E gene with diarrhea inflammatory bowel disease in adults with IBS. C. 3773–3789 (2013). A. S. 105. Pharmacogenetics of the effects 646–e179 (2010). Am. Aliment. Brain–gut 113. 157.e8 (2015). & Chrousos. dyspepsia. Ther.e1 (2013). biomarkers or 143. Gastroenterology 139. United European Gastroenterol. 110. Jones. Wong. Neuropsychopharmacology 39. Int.. Pain lessons from bladder pain syndrome. The diagnostic value of a digital rectal Abrahamsson. et al. J. C. and quality of life in IBS. et al.. Erpelding. First evidence for an association of a protein. Wong. United European Irritable Bowel Syndrome et al. 802–808 (2007). Misselwitz. & Ford.. Croce. 22 | 2016 | VOLUME 2 www.. 64. intestinal permeability. The prevalence of celiac disease genomic-. Cash. & Nitschke. secondary care. F. et al. in irritable bowel syndrome: systematic review of colesevelam on colonic transit in irritable bowel 132. Law. W. Pharmacol. E. 634–641 (2013). P. et al. Thompson. exclusions in the diagnosis of irritable bowel syndrome. 145–149 (2010). G. J. 422–425 (2014). Gastroenterol. Are the definitions for chronic 99. 138. et al. J. Rev. Gastroenterol.. J. & Camilleri. S1–S35 This narrative review summarizes the current pain in patients with IBS through translational (2009). 426–437 (2014). E. Mayer. J. Hepatol. syndrome in human subjects.org/10. Towards positive diagnosis of the noninferior to a strategy of exclusion for patients with of genetic factors in irritable bowel syndrome. M. 10. C. O. A. R. Whitehead.. Neurogastroenterol. 8. 11. W. Drossman. Decreased miR‑199 augments visceral bowel syndrome. & Rao. M. et al. B. morbidity differentiates the irritable bowel syndrome 97. Catecholaminergic gene polymorphisms ‘psychomarkers’? Nat. 444–454 (2015). B. J. et al. M. J. Gastroenterology 148. Mol. Gastroenterol. 155. immune. Talley. Vanner. Functional bowel disorders and Gastrointest. 5. C. A l l r i g h t s r e s e r v e d . microbiome interactions and functional bowel the jejunal mucosa of IBS-D is involved in intestinal 8. Rev. H. Gastroenterology 145. et al. 62. J. C. W. S. Ther. G. Am. M. J. N. Stress 112. C. Clin. B. A. clinical practice. S. Melchior. Am. Gastroenterol. G. J. S. J. Labus. M. 1500–1512 (2014). B.. S-142 120.. clinical relevance of the findings. Elevated circulating miR‑150 and an overview. Thompson. A. erythrocyte sedimentation rate. bowel syndrome (IBS).nature. W. 1549–1558. Gastroenterol. Nat. Ford. 116. et al. Gastrointest. Physiol. C. Aliment. Gastroenterol. 17. immunoregulation. Longstreth. Mayer. Q. and fecal lactoferrin to exclude 94. Rev. irritable bowel syndrome.1136/ 136. D. J. Labus. P. Storsrud. Endosc. S. Gastroenterol. from health and provides novel pathophysiological associated with gut microbial metabolites in irritable Gastroenterology 130. 140. Moayedi. A. Orand. Kilpatrick. K. Nat. Kruis. Hepatol. 121. Hepatol. specific tight junction proteins. T. This narrative review summarizes the current Identification of sub-groups of functional 146. irritable bowel. J. Leroi. 105. D. W. Small intestinal bacterial overgrowth 110. G. Hepatol. S. Liver Physiol. G. Curr. L. P. et al. P. & Davis. (2012). W. 108. syndrome. M. syndrome have altered emotional modulation of neural predominant irritable bowel syndrome. J. II43–II47 147. A. Clin. replication in multinational case–control cohorts. et al. Uncertainty and United European Gastroenterol. Gut 45 (Suppl. Esrailian. S. Stotzer. Exploring the genetics of irritable bowel fecal incontinence. S. et al. & Simren. Gastroenterology 146. W. Hepatol. H. 70. M. Small intestinal or fecal excretion in irritable bowel syndrome-diarrhea.. 739–750 factor-κB-repressing factor and claudin 1 to increase 126. (2014). Gastroenterol. A. Camilleri. & Chey. P. M. 666–689 (2010). Hepatol. Martinez. Gastroenterology 141. Gut http://dx. Attaluri. J. Cell. Its value in the exclusion of organic disease. Mayer. & Stotzer. Whitehead. Savidge. 401–409 153. S. et al. N. 5). W. Hum.. 131–137 (2014). Is irritable bowel syndrome a diagnosis for diagnosing the irritable bowel syndrome. Tantiphlachiva. & Shulman. D. A. et al. screening and surveillance in moderate and high risk MicroRNA‑29a regulates intestinal membrane 125. D. O. & Monastyrskaya.–42C>T is associated with amygdala responsiveness more severe symptoms and reduced quality of life. M. Gut 134. Goel. 39. 592–605 (2015). A. Gastroenterol. 2). Imaging brain mechanisms in chronic visceral pain. W. for the diagnosis of irritable bowel syndrome in 148. Gheinani. A Klothoβ variant mediates protein Systematic review and meta-analysis of the prevalence in irritable bowel syndrome: a prospective study. Spiegel. Hepatol. 94. guidelines for colorectal cancer screening 2009 103. P. Spiegel. 3. Y. I. J. Farid. Thompson. Development and validation of a and interpersonal problems: a circumplex analysis of the Exp. (1999). Menees. thickness correlates of pain and temperature sensitivity. A biomarker panel and psychological 156.PRIMER 90. 142. 20. H. J. 498–507 (2008). J. Sci. & Moayyedi. 653–654 (1978). et al. current knowledge — symptoms. model to understand their importance in IBS. Pharmacol. Ford. 14. 141. A.and gut gutjnl-2013-306464 (2015). Genet. G. G. Validation of (2009). 1. N. H. Clin. a pharmacodynamic and pharmacogenetic analysis. Nat. Souba. Validation of the Rome III criteria groups. quality of life in irritable bowel syndrome? limitations that have to be overcome to underline 124. Mol. Hepatol. 307. & Chang. L. Gastroenterol. Kapeller. M. Neuroimmunomodulation 13. syndrome: a critical review... J. 1279–1286 (2009). F. Review: management 106.. Pathol. Lactose malabsorption and 1934–1942 (2011). 892–899 (2005). Med. & Ducrotte. A88 (2015). symptom-based diagnostic criteria for irritable bowel 149. A. Cole. system — organization. A. American College of Gastroenterology Gut 59. 55. 770–772 distinguishing D‑IBS from other gastrointestinal 150. gastrointestinal-. Ford. 2967–2977 (2008). & Simren. Powell. Posserud. I. An evidence-based & Baldi. Q. M. Gastroenterol. Gut 55. visceral pain. examination compared with high-resolution anorectal bacterial overgrowth in patients with irritable bowel Am. A. Gastroenterology 140. diagnosis and treatment. S. Burkhard. . G508–G516 (2014). et al. et al.. Elsenbruch. 1621–1630 (2014). Gastroenterol. W. 104. Motil. disorders. 118. 93. V. M. Bohn. & Talley. Is a negative colonoscopy knowledge about genetic and epigenetic findings gastrointestinal disorders. 108. Ihlebaek. S641–S642 (2014). E. 1602–1609 (2012). P. Digital rectal examination is a useful tool for identifying 91. N. et al. 109. C. NeuroImage 47. implications. F. biomarker for diarrhea-predominant irritable bowel communal coping model. A positive diagnostic strategy is 101. A. & Moayyedi. Zhou. Mol. & Surawicz. M. Elenkov. Pain 153. Am. Effect of increased bile acid synthesis 133. Infectious diarrhea: 1310–1319 (2010). 1222–1226 syndrome. O. Wilhelmsen. Mayer. 111. permeability in patients with irritable bowel syndrome.. A27 137. E. symptoms. Impact of serotonin transporter gene strategy. Utility of red flag symptom structural and functional brain networks in chronic Am. Gastroenterol. S. functional abdominal pain. et al. Lessons learned: resolving the enigma & Morris. M. E. et al. Rao. K. 859–865 (2010). Functional bowel disorders. knowledge on brain networks in relation to upregulation of TRPV1. distention. Differential expression of miRNAs in patients with dyssynergia. Simren. P. et al. 257–267 (2006). identifies two novel genomic regions in irritable bowel 127. Bjornsson. 98. Nat. Use and abuse of irritable bowel syndrome-constipation: 131. World J. conditions causing diarrhea: the LA/IBS diagnostic Methods for diagnosis of bile acid malabsorption in 105. D. 1774–1782 (2014). Life Sci. & Hong. Tornblom. Pimentel. Vandvik.

506–514 (2014). Rifaximin therapy for patients bowel syndrome: relations with functional. 54. Phytomedicine 13 (Suppl. Pharmacol. A. Halder. Fukudo. K. S. Hill. Antidepressants in the 214. and post-marketing surveillance data. A. C. constipation. framework and item selection. 171. P. in irritable bowel syndrome: systematic review and Gibson. Gut 58. E. J. J. A. Gastroenterology 146. 21. Condition-specific deactivation of syndrome in a British urban community: consulters enteritis: a case–control study. Psychopharmacology delivery system of peppermint oil is an effective and the physician-patient interaction. e530–e539 in irritable bowel syndrome (IBS): a systematic review a subgroup of patients with irritable bowel syndrome. nested case–control study diarrhea: effects on bowel frequency and intestinal 199. 25. et al.. J. syndrome. S. et al. placebo. D. Beyens. therapy for irritable bowel syndrome symptoms. 188. O. 1051–1055 (2011). Care 30. Neurosci. Evidence-based clinical practice (2014). A. M. chronic idiopathic constipation: systematic review N. Pharmacol. Why do subjects with irritable bowel sensitivity after dietary reduction of fermentable. & Schuler.. Neuropsychiatr. 101. 264. 212. et al. free diet in patients with irritable bowel syndrome. 1. 1357–1371 (2015). treatment of fibromyalgia. Symptoms of irritable bowel fibromyalgia in patients with associated lymphocytic 200. antagonists versus spasmolytic agents: similar dyspepsia and patients with both diagnoses to 179. and somatoform disorders. W.e2 (2015). Motil. Y. 169. Med. 16. 165. Diet low in FODMAPs reduces 3ʹ. et al. 19. 198. Bulking agents. Wermelinger. severity of irritable bowel syndrome in women: results symptoms of irritable bowel syndrome as well as 1334–1346. et al. 7. Fraher. Gastroenterol. S. H. Shepherd. & Briley. 219. 43–52 (2013). S. Evaluation of a new quality of life in patients with irritable bowel syndrome. 374. antispasmodics. & Vandeplassche. 547–552 Scand. irritable bowel syndrome with constipation. G. 167. primary care. C. 107–112 (1995). 537–548 (2006). Cash. Kilbourne. 1532–1541 (2009). C. J. habits and irritable bowel syndrome: a case–control 191. et al. et al. Incidence of ischemic colitis and 159. The placebo-controlled. Berg. 233–242 (2004). Gaylord. Irritable 183. M. D. 969–977 (2002). 400–411 (1998). F. Hahn. randomized. syndrome with diarrhea. Cochrane Database Syst. Bobes. O. I.. Vazquez-Roque.. G. Owens. D. 93–100 (2015). J. & Vatn. Power. A focus group assessment of Am. Nat. S. A randomised trial of ondansetron & de Wit.. J. T. R. Fond. 199–208 (1990). Hepatol. Tack. Transl Gastroenterol. randomized. 22–32 (2011).. L. Acute tryptophan depletion syndrome. Patrick. (2015). L.. B. L. A. the data compare a diet low in double-blind. & Chang. 20. Symptom pattern following a meal 1547–1561 (2014). of irritable bowel syndrome and chronic idiopathic CG61. 48. L. M. W. 253. Irritable bowel syndrome: an Zinsmeister. P. D. irritable bowel syndrome. Sci. sensitivity of the gallbladder to cholecystokinin BMJ 337. 175. Fullerton. Blanco. 160. 11–30 (2015). 15. Efficacy of prebiotics. A. 164. M. J. & Quigley.. 1069–1079 (2006). 182. et al. and its 329–341 (2009). 122. Smout. M.. Y. K. 903–911. A. http://www. 649–656 (2014).. M. G650–G655 (1987). Nat. Nutrient intake in be done about it? J. octapeptide in irritable bowel syndrome. Rodrigo. 187. N. Drossman. R. Frederick. Hays. Berman. L. 6. Lee. Gralnek. et al. evidence for clinical efficacy still poor and what can 206. Gastroenterol.. P. K. H. T. K. Med. syndrome — results of two randomized. 107. Anxiety and depression comorbidities & Schulzke. . care in the Netherlands. E. short-chain carbohydrates.e21 (2013). Rev. K. trial. B.. 421 (2014).. Gastroenterology 149. Garsed. Ther. in functional gastrointestinal disorders. Simmen. Quality of life in persons with 174. reduces kynurenine levels: implications for treatment CD003460 (2011).. A l l r i g h t s r e s e r v e d . P. Altered syndrome: systematic review and meta-analysis.. 1194–1203 (2007). Mazurak. 11.. Rev. E. M.. L. including hypnotherapy. J. Gastroenterol. Effect of fructose-reduced diet controlled studies. Gut 64. E. Gastroenterol. S. preparations: results of a double-blind. 19. Halmos. et al. J. et al. A. D. J. 242–253 (2016). & Hotz. Epstein. Nelson. Gastroenterol. and extracellular cyclic guanosine 215. et al. syndrome with diarrhea. mental. Hepatol. J. the general population. Expert consensus document. 320–328. Bernklev. Clin. J. PRIMER 158. & Simren. Ther. S. Celiac disease-like abnormalities in intestine. J. P. S. 29. NICE [online]. Krueger. M. M. (2010). 20.. R. 651–660 (2014). et al. & Mayer. Naliboff. questionnaire for patients with irritable bowel correlation to a standard fructose breath test. antispasmodics and 210. et al. Ullrich. illness severity. F. D.. J. Mindfulness training reduces the 172.) 232. patients with functional function. 67–75. Dis. Gastroenterol. EuroQol — a new facility for the in patients with IBS. Med. 364. Ware. B. Gastroenterology 145. Miller. Gastroenterology 145. Am. Hayes. patients with self-reported non-celiac gluten serious complications of constipation among patients & Simren. et al. et al. C. 1617–1625 (2014). 5). J. 21. B. Nakashima. Ringstrom. Pharmacol. R. Ida. The effect of dietary intervention to evaluate the efficacy and safety of linaclotide in Health Policy 16. Eur. 1714–1724 (2012). & Abdollahi. 43. M.. U. D. World J. J. Phillips. Clave. Bohn. et al. Treatment of IBS‑D with 5‑HT3 receptor compares patients with IBS. its components to intestinal 5‑HT. J. American College of Dig. M. S. M. M. multi-centre trial. S. E. Ford. (Buscopan®) on cholinergic pathways in the human 208. Intestinal microbiota in 202. P. Gastroenterol. Dig. R. Ann. S. 1962–1967 (1992). Gastroenterol. A. D. 271–279 (2004). Ruepert. 176. W. on irritable bowel syndrome: a systematic review. Heaton. Gastroenterol. 565–581 and controversies. This population-based. Ther. 178. patients with constipation-associated irritable bowel of a new measure.... L. 6024–6030 (2014). A 12‑week. 750–763 (2015). 1554–1563 (2014). randomized. 109. J. A.. United European therapy in the irritable bowel syndrome — why is the World J. 168 (2014). et al. N. Dig. A double. C. therapeutical effects from heterogeneous healthy control individuals for health-related QOL Effect of one year of a gluten-free diet on the clinical pharmacological targets. and meta-analysis. & Shah. Diagnosis and management of microbiota for treatment of IBS and IBD-challenges consistency in male patients with irritable bowel IBS. Scand. et al. Fructose and lactose intolerance and dissatisfied with laxatives. et al. L. M.. et al. Y. A. et al. Arch.. G. 61. P. Pimentel.) 10. Weusten. (2013).e11 (2013). 2. using alosetron: systematic review of clinical trials syndrome seek health care for their symptoms? poorly absorbed. Gastroenterology 123. & de Serres. Am. M. Gastroenterol. 12. J. brain regions by 5‑HT3 receptor antagonist alosetron. Bohn. Hungin. Gastroenterol. 25. 8.. of impaired visuospatial memory performance in 189. controlled 217. Efskind.. Didari. J. Gastroenterol. et al. blind placebo-controlled trial with loperamide in 654–660 (2000). E. thus counteracts the 1702–1712 (2012). Irritable Prebiotics consensus statement on the scope 207. I. Effect of fibre. placebo-controlled trial to evaluate Short-Form Health Survey (SF‑36). and peppermint oil in the treatment of irritable bowel 209. 3072–3084 (2015). syndrome and healthy controls. Dis. 196. 203. & Muir. Treat. Riecken. Gastroenterology 144. P. et al. E. Gut 62. 166. & Lee. M. Kennedy. Effect of ramosetron on stool 161. and report equal efficacy. J. J. Neurogastroenterol. J. U. Jr & Sherbourne. Motil. Storsrud. Rev. Moayyedi. Irritable bowel syndrome in adults: diagnosis Gut 56. and opioid receptors. 205. and management. Broelz. D. Materna. V. Linaclotide for irritable bowel 106. Motil.. Aliment. A. P. Impact of functional gastrointestinal 177.uk/ guidelines for irritable bowel syndrome. 170.. Hepatol. D. Lembo. 23–30. Fukudo. J. 473–483 (1992).. Sci. 37.. Arthritis Res. treatment of severe chronic constipation in patients 220. Gastroenterol. Chang. Treatment of irritable bowel syndrome with herbal patients with irritable bowel syndrome compared with 471–485 (2015). Aliment. Effectiveness of probiotics in irritable bowel syndrome: challenge test in patients with irritable bowel 184. L. Engl. J. Holtmann. L. Dis. Ther. & Charboneau. 42. 173. A. 11. et al. The MOS 36‑item In this paper. Nikfar. Association between diet and lifestyle guidance/cg61/documents (2008). on health-related quality of life. EuroQoL-Group. D. S. Binding of STW 5 (Iberogast®) and bowel syndrome: the role of food in pathogenesis and appropriate use of the term probiotic. 50. Ther. et al. A. Comparison of medical costs pathophysiology and management of irritable bowel for the treatment of irritable bowel syndrome with generated by IBS patients in primary and secondary syndrome. The Oslo definitions for coeliac 463–468 (1996). Motil. Shanahan. traditional dietary advice: a randomized controlled 193. reduces symptoms of irritable bowel syndrome. Guidelines on the irritable bowel Gastroenterology monograph on the management 190. Gastroenterology 119. C. 162. Am. Hausteiner-Wiehle. S. 164–174 (2014). 218. K. & Quigley. No effects of gluten in 201. Halmos. Linaclotide inhibits colonic nociceptors meta‑analysis. Prucalopride (Resolor) in the (1997). S. A novel The irritable bowel syndrome: long-term prognosis irritable bowel syndrome. Gastroenterol. Gastroenterol. C. Gastroenterol.. & Puder. G. 180.. current enthusiasm with low FODMAP diets 194. F. Diets that differ in their FODMAP 195. N. Am. P. Am. H. R.. Physiol. H. Am. The impact of irritable bowel syndrome malabsorption testing: the relationship with symptoms 197.e3 (2013). World J. 1074–1083 (2013).5ʹ‑monophosphate. 1678–1688 (2011). DiCesare. Y. H. Gastroenterology 146. 1329–1338 (2001). E. Spiller. et al.. J. 27. A diet low in FODMAPs 192. Strid. L. A controlled trial of gluten. and nonconsulters. Ludvigsson. J. 31. Sci. probiotics. Intern. C. et al. BMC Gastroenterol. L. J. integrated explanatory model for clinical practice. W. 358–367 (2013). Pharmacol. E. 216. antidepressants for the treatment of irritable bowel patient perspectives on irritable bowel syndrome and 168. Motil. Neurogastroenterol. O. (Berl. N. Med. Gastroenterol. D. J. et al. Khan. Pharmacol. Scand. 936–943 (2013). Effect of hyoscine butylbromide 51–55 (2006). Kellow. G. B. Gastroenterol. of QOL are psychological in nature. L.e3 (2013). J. Manipulation of the & Matsueda. and meta‑analysis. Ther. psychological therapies. Gut Liver 9. 109. J. K. et al. Gastroenterol. e107 (2015). Drossman. van Outryve. 181. Ford. J. J. et al. Madisch. L.nice.. Kerstens. E. E. 204. et al. a2313 (2008). A. 8886–8897 diarrhoea. 163. Hepatol (N. 185. Guo. Effect of antidepressants and study. Biesiekierski. Gut 63. Plein. and relieves abdominal pain via guanylate cyclase‑C 1350–1365 (2014). K.e5 (2014). 107.. J. Probiotic updated systematic review with meta-analysis. of a randomized controlled trial. Neurogastroenterol. Rao. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 23 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . J. C. Ford. Mozaffari. H. Flik. Akiho. C. Eluxadoline for irritable bowel based case–control study. S2–S26 and management of irritable bowel syndrome in 213. Chey. 211. Neurogastroenterol. C. Clinical trial: lubiprostone in irritable bowel syndrome: development and validation content alter the colonic luminal microenvironment. 186. A. A. 357–365 (2009). Castro. P. Wahnschaffe. 221. A. J. J. M. F. Moret. syndrome: mechanisms and practical management. A. et al. R. Aliment. Aliment. et al. S. & Henningsen. I. I. syndrome with constipation: a 26‑week. Drossman. S. (SF‑36) and reports that most of the determinants evolution of irritable bowel syndrome plus 23. and synbiotics in irritable bowel syndrome and with irritable bowel syndrome without constipation.. disorders on health-related quality of life: a population- disease and related terms.. Wilder-Smith. trial with a 4‑week randomized withdrawal period measurement of health-related quality of life. Engl. Kirchdoerfer. International Scientific Association for Probiotics and Aliment.org. I. Dis. Conceptual FODMAPs with conventional dietary advice in IBS efficacy and safety. M. Abrahamsson. et al. Neurogastroeterol. Gastroenterology 102. 1399–1407. Posserud. Clin. Storr. & Talley. 953–959. 109. National Institute of Health and Care Excellence. I. muscarinic M3.. & Enck. Psychiatry Clin. Ford. Laan.. N. Gastroenterology 121. 560–571 (2016). & Mayer. 1770–1798 (2007). Am.e4 (2014).

et al. The cost-effectiveness of psychotherapy and P.B. Gastroenterology 60. 608–613 (1985). 5–11 (2005). Postprandial changes in small bowel The authors have received unrestricted research grants from 227.E.Simren).S.‑K. and M. EURope. (E. et al.B.. H.). Boehringer-Ingelheim (P.M. 14. El‑Serag.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d .M. Rodrigues. 226. 1773–1780 & Mauderli. 21. S. M. 544–e205 on the colonic metabolism of lactulose in man (R. and Q.Q.).E.).Q. Lotenzatto (G. (M. and J. M. placebo-controlled and dose-finding 242. Competing interests Hepatol.).S. et al.M.). F. B.Q.). Stool consistency is strongly (Q. G.. J. Hyphantis.Simren). 78. 303–317 (2003). bowel syndrome. Pharmaceuticals (Q. Efficacy of 5‑HT3 antagonists 243. Bionorika 230. Lesaffre (R. et al. Serotonin-transporter 250. disorders by objective physiological criteria based on Gastroenterology 124. Camilleri.).. Rao. Parmalat (G. which tested psychological interventions in patients (M. 294–301. F.).). Hepatol. Diagnosis. Motil.Schemann). P.). Pain 115. 425–432 (2002).).).). 41.B.B. Melasci (G.B. M. 537–544 (2009). Olden. R. IM Sciences (E. T. 39. Boehringer-Ingelheim (M.E. Pretexin (Q.). Marciani. C. S.). and R. Res. Efficacy and safety of alosetron in syndrome: a meta-analysis. Guided self-help interventions for irritable See online article: S1 (table) predominant irritable bowel syndrome. & Bjorkman. 205–222 (2015).M.Schemann). Kissei (S. Kao (S. J.M. Influence of chronic lactulose ingestion Ferring (M. E.). involving of some of the authors. and S. Quality of life (S. J. S. Introduction (P. Hepatol. Pharmacol. et al. J. et al. Schwabe and 5‑HT4 agonists in irritable bowel syndrome: associated with gut microbiota richness and (M. transit with wireless motility capsule and radiopaque (2015). Yakult (G.B. Lancet 355. Allergan (G. 164.S. 223. Dtsch.B. Leitner.).). Ono (2011).).. Chr Hansen women with irritable bowel syndrome: a randomised. 236. R. Kaneko.). efficacy of alosetron in the treatment of irritable bowel 751–760 (2011).B.M. J. Intern. Ther.. Singh.).Q.Q. B.M. Afa Wassermann (G.Simren. M. Review article: Abbott (S. Gastroenterol. Aliment. L. (M.e5 (2015). C. & Gibson.B. Camilleri. neurosensory sensitivity. Epidemiology (P. (GENes in Irritable Bowel Syndrome Research Network related quality of life in patients with irritable bowel 238.C. irritable bowel syndrome and inflammatory bowel AstraZeneca (E.-K. et al.Simren) predicting effectiveness of ramosetron in diarrhea.M.). and P. 75. Gruenenthal (P. M. J. (2000). A double-blind. F.).F. 196–203 (2009). & Pieh. N. M. Physiol. have 229.Schemann). Pfizer 228.C.).. Arztebl.B.). and S.)... Yang. 23–34 245. Psychosomat.Schemann). 23. Gastroenterology 138. Invest.E. J. Pain 145. et al. Gastroenterol.B.). Most care costs in severe. L. Liver Physiol. irritable bowel syndrome: a systematic review. Ironwood study. C.E.M. et al. J. et al. C.)..M. Andresen.Simren). Gut 56.). Management (E.Q. Shiotani.GENIEUR.M. Parmalat (G. Aliment. 231. A.)..M. Group (G. Shire (A.B. with improvement in psychological distress.) and Zespri (G. Steigerwald (M.F..M.‑S.E. 104. Role of the small Primer (P.E. Gastroenterol.M. Eur.. K.B.M. Takeda (M.). SymbioPharm (P. 1104–1115 (B.B. Schmidt. Health‑related quality of life among persons with 239.A. Intern. M. ALL LINKS ARE ACTIVE IN THE ONLINE PDF Gastroenterology 123.A.M. of S100A10 and polymorphisms of TPH1.N.M.Simren). Yuhan Corp (R.Simren).B. Irritable bowel syndrome — the served as a consultant/advisory board members for Actavis placebo-controlled dose-ranging study to evaluate the main recommendations.F. Takeda (M. L.M. 26. G. in interpersonal difficulties in people with severe Neurogastroenterol. Stimulation of colonic motility by with IBS. E. Classification of functional bowel and paroxetine for severe irritable bowel syndrome. D.Simren).). Vandeputte.E. tendency to report pain rather than increased prevention (M. Nicholas Verne..B.E. 16. Cadi with or without irritable bowel syndrome: 469–477. G. A l l r i g h t s r e s e r v e d .).M. G413–G419 gut-directed hypnotherapy in the management of E. M. Gut 65. randomized. Lubiprostone increases spontaneous bowel 240. Commonwealth (E.). M. 1831–1843 (2009). Outlook (R. G. Sofar (G. Falk (G.S. Ironwood (G.). Gastroenterol. and G.).D.F. and as a speaker for endoluminal image analysis. C. Genet.M. 860–868 (2001). 235. J..). Kaneko.B.).M.Q. Gastroenterol.Q.Simren 7. Alimentary Health (E. Astellas (S. Genome-wide association defines Acknowledgements diarrhea have lower disease-specific quality of life than more than 30 distinct susceptibility loci for Crohn’s The research leading to these results has received funding irritable bowel syndrome-constipation.S. P. 244. Guthrie.).). Muir.D.B.). and markers in constipation.).C. P. and R. Ther. & Creed. Alfa Wassermann (G..). 1171–1185 (2002). Arch. Peters.M. 607652 (NeuroGUT). (E. and G. Ironwood (E. A.E. F. E. (E.Simren Neurogastroenterol. Nestlé MRI: comparison of split versus single dose. within psychological treatments for irritable bowel Astellas (S.). Y. irritable bowel syndrome. Pharmacol..e1 (2010).F. S.eu). P. SymbioPharm (P. A.).A. 134. Eur. Hepatol.B. Clin. Clin.S. S. 1035–1040 This meta-analysis summarizes data from 48 RCTs.M. (an in vivo study).M.Simren). 40.Q.PRIMER 222.N.S. overall.). G. D. Ther. Med.A. B. Danone (G. irritable bowel syndrome is the result of an increased M. Bardhan. Gastrointest. 1202–1209 (2007)..Simren and R. & Ueno..). 246.).S. a randomized. 1426–1436 (2014). J.).M. thermal nociceptive stimuli in irritable bowel Author contributions 225. Tomenson. M.C.B. disease. Melasci (G.). composition. et al. Cognitive behaviour therapy for irritable R. 17. improvement in Italchimici (G. V. et al. M.A. Danone placebo-controlled trial. Increased colonic pain sensitivity in Mechanisms/pathophysiology (G.. Hongo. and Q. Am.).M.. Patients with irritable bowel syndrome. M.M.Q.Q.. refractory irritable bowel activation of the innate mucosal immune system and of the authors are also engaged in and have received support syndrome.B.).A. 13. J. Yakult (G. K. of the international network COST Action BM1106 GENIEUR 224. (M.M.F. Spiegel.. et al. Pilot study of biomarkers for 11–14 (2005). Christopher.). Clin. Dorn.). Florent. 27. Marciani.). et al.E. Falk 233. Ipsen (R.-S.B. 309. Shire (E. & Bayless.. Creed. J.).F.M. visceral sensitivity. from the People Programme of the European Union’s Seventh World J.M. 82–91 (2015). SUPPLEMENTARY INFORMATION polymorphism pharmacogenetics in diarrhea. 27. Rhythme (E.). Nat. Alimentary Health (E. Clinical determinants of health.B.).). Creed. Almirall (B. Efficacy water content in healthy subjects and patients with Alfa Wassermann (G.). 57–62 (2015). IMA (G. Danone Research (M. syndrome.B. L. et al. Vivrant (E.). AstraZeneca (M. (M. et al. G. 234.). Pharmacol.C.Z.Schemann). Takano.Q. M. Ther. Tillotts (M. et al. syndrome. B. Italchimici (G. Synergy 232. Liegl.. www.Q. Boeckle. Neurogastroenterol..Z. Noos (G. chronic idiopathic constipation.Simren and P.E.. S.S. Hutton. C.B. and safety of oral lubiprostone in constipated patients irritable bowel syndrome. 8103–8109 (2015). S. et al.B. Identifying effective techniques Almirall (A.F.. H.. 237.Q.E. C. M. 845–852 (1971).M.). D. 248. Steigerwald systematic review and meta-analysis.C. 1209–1221 (2015).). Pharmacol.M. and S..E.Simren).S. movement frequency and quality of life in patients with bowel and colon in lactose-induced diarrhea. A. Sofar (G. 249. P.E..F. Fukudo.) and Zenspri (G.A. Plessen.E. and Yakult (G. declare no predominant irritable bowel syndrome: expression Psychodynamic interpersonal therapy and improvement potential conflict of interests. syndrome. SymbioPharm (P. et al. 108. 247.B.B. Q. Ford.).D.).Simren. Motil.M.E. Hypersensitivity to cutaneous (2004). Ferring (P.F.B.).E..R. R. Therevance (E.M. 241.Schemann). Med.B. 24 | 2016 | VOLUME 2 www. Investigation of colonic and whole-gut disease.).R.C. et al. 955–962 (2008).B. 302–311 (2014). (2015). Sofar (G.Q.Q. .). Int. D. Heel (P. Henrich. bowel syndrome: a systematic review and meta-analysis. H. oral PEG electrolyte bowel preparation assessed by gastrointestinal symptoms was strongly associated Menarini (G. Overview of & Ueno.A.F. A.N. Noos (G. Malagelada. Menarini (G. Astellas (S. Motil. Hongo. Lactose intolerance in irritable bowel Framework Programme under REA grant agreement no.M. enterotypes and bacterial growth rates.B. Ann. Aliment. T. and reports that.S. screening and Aliment.B.). and P.). Barrett.B. Am. Health-related quality of life and health syndrome patients with diarrhoea: the roles of anxiety. Gastroenterol. M.B.Schemann and E.nature.C.M. Shire (P.). G.). A. Fukudo. Chiesi (P.Q. Albireo (M. Salix (E.Simren). Glycom (2000)..C.