Irritable bowel syndrome

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.

Figure 1. IBS subtypes according to the Rome III criteria

A two-dimensional graph of the four possible irritable bowel syndrome (IBS) subtypes according to bowel form at a particular point in time, and the percentage of time this bowel form has to be present to meet the criteria for IBS with constipation (IBS-C), IBS with diarrhoea (IBS-D), mixed-type IBS (IBS-M) and unsubtyped IBS (IBS-U). Adapted with permission from REF. 119, American Gastroenterology Association.

Figure 2. IBS prevalence in population studies around the world

Pooled prevalence data per country are colour-coded. Data from REF. 1 are supplemented by studies from another nine countries (see Supplementary information S1 (table)). IBS, irritable bowel syndrome; N/A, not applicable.

Figure 3. IBS-associated comorbidities

A model of irritable bowel syndrome (IBS) and its associations with other clinical, intestinal, extra-intestinal and psychiatric conditions. For each of the listed disorders, overlap with IBS symptoms has been reported in the literature. The different components should be viewed as layers of complexity: the IBS subtypes are part of the group of functional bowel disorders, these are part of all kinds of functional disorders and these again are part of a `layer' of psychiatric disorders. GERD, gastroesophageal reflux disease; IBS-C, IBS with constipation; IBS-D, IBS with diarrhoea; IBS-M, mixed-type IBS; IBS-U, unsubtyped IBS; PMS, premenstrual syndrome.

Figure 4. Overview of the pathophysiology of IBS

Although the aetiology of irritable bowel syndrome (IBS) has not yet been completely elucidated, various factors have a role, including composition of the gut microbiota, intestinal permeability, immune cell reactivity and sensitivity of the enteric nervous system, the brain–gut axis (spinal, vagal or pelvic pathways) or the brain. The figure highlights those mediators that are probably involved in IBS pathology. The plus symbols indicate whether a mediator activates or inhibits its target cell; those in parentheses denote actions established in animal models and those without parentheses are effects demonstrated in humans (human tissue). 5-HT, 5-hydroxytryptamine (also known as serotonin); CGRP, calcitonin gene-related peptide; GDNF, glial cell-derived neurotrophic factor; IL, interleukin; PAR2, proteinase-activated receptor 2; TNF, tumour necrosis factor.

Figure 5. Neuroimmune interactions in the gut

An intimate anatomical and functional association between enteric neurons, terminals from extrinsic nerves and cells of the enteric immune system is the basis for neuroimmune interactions in the gut wall. Functional signalling between nerves and immune cells mostly happens in the epithelial and submucosal layers where there is a high density of immune cells — in particular, T lymphocytes, mast cells and macrophages. The neuroimmune interactions are bidirectional. Enteric neurons, extrinsic nerves and glial cells respond to cytokines and mast cell mediators. Some patients with irritable bowel syndrome (IBS) have circulating autoantibodies against neuronal structures and antibodies that are generated as a response to antigen exposure from the lumen. Neurons can respond directly to antibodies through direct activation of channels or receptors. They also respond to antigens through pathways involving neuronal Toll-like receptor 3 (TLR3), TLR4 and TLR7. Direct signalling between microbiota and the host involves activation of neurons through polysaccharide A. These direct effects of luminal factors are very likely to be outnumbered by signalling between epithelial (in particular, enteroendocrine cells), immune and nerve cells. Neurons also express receptors for adenosine and ATP; both molecules are released in the gut wall under inflammatory or stress conditions. Reciprocally, nerves release factors that affect epithelial or immune cells. The best-documented effect is the activation of mast cells through the release of calcitonin gene-related peptide (CGRP) from extrinsic visceral afferents or enteric neurons. Conversely, acetylcholine (ACh) inhibits the activation of macrophages. Neurogenic inflammation, which is sometimes observed in animal models, is probably caused by the release of CGRP and substance P from extrinsic fibres followed by permeabilization of blood vessels. In addition, adipocytes in the lamina propria nestle against nerve fibres, and release of their pro-inflammatory mediators modulates nerve activity. The plus and minus symbols indicate whether a mediator activates or inhibits its target cell; those in parentheses denote actions established in animal models and those without parentheses are effects demonstrated in humans (human tissue). 5-HT, 5-hydroxytryptamine (also known as serotonin); CCK, cholecystokinin; CRF, corticotropin-releasing factor; IL-10, interleukin 10; NGF, nerve growth factor; PUFA, polyunsaturated fatty acid; TRP, transient receptor potential cation channel.

Figure 6. Summary of the genetic findings associated with different pathophysiological mechanisms underlying IBS

Irritable bowel syndrome (IBS)-related pathways that are potential pharmacogenetic targets are marked in red when based on genetic findings and in blue when based on epigenetic findings; those in black are currently not seen as potential pharmacogenetic targets. Various pathways might be affected in specific subgroups of patients with IBS: epithelial barrier (permeability), immune function, impaired bile acid metabolism and function, neuronal processing and signal transduction via spinal afferents from the periphery to the central nervous system in addition to the bidirectional crosstalk via the brain–gut axis, presumably contributing to psychological conditions such as anxiety, depression and somatization. Brain networks that have been associated with structural and functional alteration in IBS are depicted. ADRA, adrenoceptor-α; aINS, anterior insula; aMCC, anterior midcingulate cortex; CDC42, cell division cycle 42; CDH1, cadherin 1; CGN, cingulin; CLDN, claudin; COMT, catechol-O-methyltransferase; CRHR1, corticotropin-releasing hormone receptor 1; FGFR4, fibroblast growth factor receptor 4; GLUL, glutamate-ammonia ligase (also known as glutamine synthetase); GPBAR1, G protein-coupled bile acid receptor 1; GRID2IP, GRID2-interacting protein; HPA, hypothalamus–pituitary–adrenal; HTR, 5-hydroxytryptamine receptor; hypo, hypothalamus; IL, interleukin; KLB, Klotho-β; LCC, locus coeruleus complex; mir, microRNA; mPFC, medial prefrontal cortex; NKRF, nuclear factor-κB-repressing factor; NR3C1, nuclear receptor subfamily 3 group C member 1; NTS, solitary nucleus; OFC, orbitofrontal cortex; PAG, periaqueductal grey; PGR, progesterone receptor; SCN5A, sodium voltage-gated channel α-subunit 5; sgACC, subgenual anterior cingulate cortex; SLC6A4, solute carrier family 6 member 4; TNF, tumour necrosis factor; TNFSF15, TNF superfamily member 15; TRPV1, transient receptor potential cation channel subfamily V member 1.

Figure 7. A diagnostic algorithm for patients with IBS

This diagram gives a schematic overview of the sequential approach to irritable bowel syndrome (IBS) diagnosis. CBC, complete blood count; CRP, C-reactive protein. Figure from REF. 144, Nature Publishing Group.

Figure 8. Mechanisms of action of different drugs used for the treatment of IBS

Drugs currently used for the treatment of irritable bowel syndrome (IBS) (orange boxes) target nerve activity, epithelial functions or the contractile state of the smooth muscle layers. Several drugs act by enhancing the activity of chloride channels to increase fluid secretion into the intestinal lumen as a consequence. Other mechanisms of action include modulation of visceral sensitivity at a central or peripheral level. Finally, drugs act to modulate signal transduction at the neuromuscular junction or alter motility by direct myogenic actions. The plus and minus symbols indicate whether a mediator activates or inhibits its target cell; those in parentheses denote actions established in animal models and those without parentheses are effects demonstrated in humans (human tissue). 5-HT, 5-hydroxytryptamine (also known as serotonin); ACh, acetylcholine; CFTR, cystic fibrosis transmembrane conductance regulator; CIC2, chloride channel protein 2; GC-C, guanylyl cyclase C; VIP, vasoactive intestinal peptide.

Figure 9. Concept of multifactorial quality-of-life effects in IBS

The genome and epigenome partially determine (`filter') the response of an individual to external stressors (psychosocial factors) and internal stressors (ingested food or microbiota). These, together with social support, appraisal, emotion and coping behaviours against stressors, determine the stress response affecting the brain–gut interactions. This response might involve regional brain activation, changes in autonomic and neuroendocrine function, which might lead to many of the clinical manifestations observed in irritable bowel syndrome (IBS), including visceral hypersensitivity, alteration in gastrointestinal motility, increased mucosal permeability and low-grade inflammation. These gastrointestinal symptoms and other extra-intestinal manifestations (such as multiple somatic symptoms and psychiatric comorbidities) impair the quality of life (QOL) of patients with IBS.