31: Irritable bowel syndrome


CHAPTER 31
Irritable bowel syndrome


Elizabeth J. Videlock and Lin Chang


David Geffen School of Medicine at UCLA, Los Angeles, CA, USA


Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) that is characterized by abdominal pain associated with alterations in stool form and/or frequency. IBS is frequently diagnosed in both primary care and specialty practice. IBS occurs in the context of a grossly and histologically normal gastrointestinal (GI) tract. For this reason, it has been referred to as a “functional” GI disorder. Over the past decade, the traditional dichotomy between “functional” and “organic” has been called into question by the growing body of evidence for changes at the molecular level associated with IBS and other functional disorders. Furthermore, there is a biochemical basis for all symptoms at the peripheral (gut‐based) or central (brain, spinal cord) level. One could view IBS as multiple “organic” diseases. Despite the increasing identification of distinct pathophysiology, there is not a unifying putative mechanism and patients are grouped clinically by symptoms, so that IBS is appropriately designated as a syndrome rather than a disease. The images that follow illustrate the prevalence, putative pathophysiological mechanisms, diagnosis, and treatment of IBS.

Schematic illustration of global prevalence of IBS.

Figure 31.1 Global Prevalence of IBS (Rome III criteria). IBS has a very high prevalence, though it varies based on geographical region, diagnostic criteria, and population studied (e.g., healthcare seeking versus community). IBS is more prevalent in women (about twofold), and the increased prevalence is stable across geographic regions. IBS is also more commonly diagnosed in patients under the age of 50, and is more prevalent among those with lower income.


Source: Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta‐analysis. Clin Gastroenterol Hepatol 2012;10(7):712. Reproduced with permission of Elsevier.

Schematic illustration of interrelatedness of IBS pathophysiology concepts.

Figure 31.2 Interrelatedness of IBS pathophysiology concepts. Our understanding of the pathogenesis of IBS has evolved over recent years but is still far from complete. A unifying theme is that the symptoms of IBS result from dysregulation of the “brain–gut axis,” which manifests as enhanced visceral perception and altered bowel habits. There is no consensus on the underlying etiology of this dysregulation, and the disorder may represent a combination of factors involving different mechanisms. This figure shows putative pathophysiological mechanisms leading to enhanced visceral perception and alterations in stool form and frequency that characterize IBS. Solid lines are used to depict connections from mechanisms to symptoms (either directly, such as direct effects of Stress/CRF [corticotrophin releasing factor] on motility, or via mediators). Dashed lines indicate evidence (discussed in text) for possible connections between pathophysiological mechanisms. For example, alterations in both serotonin signaling and the microbiome have been observed in IBS and there is evidence that the microbiome can regulate serotonin.


Source: Videlock EJ. Molecular mechanisms in irritable bowel syndrome [doctoral thesis]. escholarship: UCLA, 2019.

Schematic illustration of enhanced visceral perception.

Figure 31.3 Enhanced visceral perception. Peripheral sensitization, central sensitization, and descending pain modulation can result in altered visceral perception. Enhanced perception of visceral stimuli can occur in IBS patients either as a result of greater sensitivity of visceral afferent pathways or as central amplification of visceral afferent input. This phenomenon may represent dysfunction in any of, or even a combination of, the components involved in gut sensation, including signal transmission from the gut, signal transmission to the CNS, and modulation and processing of sensation by the CNS. Enhanced visceral perception is a reproducible finding in a significant subset of patients with IBS. Central sensitization is hypothesized to occur at both the spinal cord and brain level. The important brain regions can be grouped into those associated with visceral sensation (in healthy controls as well), those involved in endogenous pain modulation, and those involved in emotional circuits. Studies have shown that patients without enhanced visceral perception, despite having similar symptoms to patients with enhanced perception, have brain activation patterns that are more similar to healthy controls. Areas associated with endogenous pain modulation have consistently shown altered activation in response to rectal distension in IBS. DRG, dorsal root ganglion.

Schematic illustration of the brain–gut axis.

Figure 31.4 The brain‐gut axis. The hypothalamic‐pituitary‐adrenal (HPA) axis, immune system, and nervous system all participate in the complex and bidirectional communication between the gut and the CNS. There is both preclinical and clinical evidence to support the link between chronic stress and IBS. Chronic stressful life events affect clinical outcome in IBS. Postinfection IBS (PI‐IBS) is predicted by psychological symptoms and stress. Furthermore, experimental stress increases visceral sensitivity and gut permeability. In addition, patients with IBS have an exaggerated increase in motility in response to stress. The effect of stress on gut function and sensation likely results from alterations in the brain‐gut axis, which describes the bidirectional communication between the enteric, autonomic, and central nervous systems. The nature of this communication is complex and multidimensional. In addition to communication via neurons, communication occurs via humoral mediators of the HPA axis, ANS, and immune system.


Source: Modified from Kennedy PJ, Clarke G, Quigley EM, et al. Gut memories: towards a cognitive neurobiology of irritable bowel syndrome. Neurosci Biobehav Rev 2012;36(1):310.

Schematic illustration of brain networks involved in processing and modulation of visceral pain.

Figure 31.5 Brain networks involved in processing and modulation of visceral pain. This figure summarizes the functional, structural, and anatomical networks (default mode, emotional arousal, central autonomic control, central executive control, sensorimotor processing, and salience detection) that have been altered in the resting state and task‐related functions in FGIDs. Alterations in these networks found in IBS patients provide plausible explanations for a biased threat appraisal (e.g., catastrophizing behavior), expectancy of outcomes, autonomic hyperarousal, and hyperattentiveness towards symptoms. These alterations include: (1) greater volume and cortical thickness of sensorimotor cortex that correlates with symptom severity, particularly in women, (2) alterations in functional connectivity of anterior insula and amygdala, (3) greater engagement of salience network regions, e.g., anterior and anterior midcingulate cortex, in response to actual and expected rectal distension, (4) increased responsiveness of emotional arousal network to actual or expected rectal distension, (5) decreased inhibitory feedback loop, and (6) increased activation of central autonomic network that controls and modulates the autonomic nervous system. Amyg, amygdala; aINS, anterior insula; aMCC, anterior midcingulate cortex; BG, basal ganglia; dlPFC, dorsolateral prefrontal cortex; Hipp, hippocampus; Hypo, hypothalamus; IPL, inferior parietal lobule, LCC, locus coeruleus complex; M1, primary motor cortex; M2, supplementary motor cortex; mPFC, medial prefrontal cortex; NTS, solitary nucleus; OFC, orbitofrontal cortex; PAG, periaqueductal gray; PCC, posterior cingulate cortex, pgACC, pregenual anterior cingulate cortex; pINS, posterior insula; PPC, posterior parietal cortex; S1, primary somatosensory cortex; S2 secondary somatosensory cortex; sgACC, subgenual anterior cingulate cortex; Thal, thalamus; vlPFC, ventrolateral prefrontal cortex.


Source: Reproduced from Mayer EA, Labus J, Aziz Q, et al. Role of brain imaging in disorders of brain‐gut interaction: a Rome Working Team Report. Gut 2019;68(9):1701, which was modified from Mayer EA, Labus JS, Tillisch K, et al. Towards a systems view of IBS. Nat Rev Gastroenterol Hepatol 2015;12(10):592.

Schematic illustration of overview of peripheral pathophysiological mechanisms in IBS.

Figure 31.6 Overview of peripheral pathophysiological mechanisms in IBS. This figure summarizes peripheral factors implicated in IBS pathophysiology. These factors include the gut microbiota, intestinal permeability, immune cell reactivity, neuronal sensitivity, serotonin signaling, and bile acid processing. Plus symbols indicate activating effect on target cell. Parentheses indicate data from animal models only. 5‐HT, 5‐hydroxytryptamine (serotonin); CGRP, calcitonin gene‐related peptide; GDNF, glial cell‐derived neurotrophic factor; IL, interleukin; PAR2, proteinase‐activated receptor 2; TNF, tumor necrosis factor.


Source: Enck P, Aziz Q, Barbara G, et al. Irritable bowel syndrome. Nat Rev Dis Primers 2016;2:16014. Reproduced with permission of Springer Nature.

Schematic illustration of postinfection IBS (PI-IBS).

Figure 31.7 Postinfection IBS (PI‐IBS). PI‐IBS is the onset of IBS symptoms following resolution of acute infectious gastroenteritis, characterized by two or more of the following: fever, vomiting, diarrhea, or a positive bacterial stool culture, in an individual without a history of IBS. Gastrointestinal (GI) infection is the strongest risk factor for IBS and is associated with an approximately fourfold increase in risk of IBS symptoms at 12 months in comparison to uninfected individuals. The risk is even greater in those with preexisting GI conditions such as gastroesophageal reflux disease (GERD) or dyspepsia, a history of more severe diarrheal illness, younger age, female gender, chronic stressful life events, or psychological comorbidities. PI‐IBS is most often characterized by diarrhea or mixed bowel habit. It is associated with increased intestinal permeability, increased numbers of T lymphocytes in the lamina propria compared to controls, and increased expression of the proinflammatory cytokine interleukin‐1β (IL‐1β).


Source: Barbara G, Grover M, Bercik P, et al. Rome Foundation Working Team Report on Post‐Infection Irritable Bowel Syndrome. Gastroenterology 2019;156(1):46. Reproduced with permission of Elsevier.

Photo depicts increased intestinal permeability in IBS.

Figure 31.8 Increased intestinal permeability in IBS. Permeability has been linked to abdominal pain and enhanced visceral perception. Several studies have found small intestinal and colonic permeability in IBS patients, and increased paracellular permeability in colonic biopsies. This has been corroborated by studies showing decreased expression and altered cellular distribution of tight junction proteins in the colon and jejunum of patients with IBS‐D. The association between increased permeability and IBS is strongest in PI‐IBS and IBS‐D. This figure shows decreased expression of the tight junction protein zonula occludens (ZO) in the jejunum of IBD‐D. Filled symbols represent female subjects and open symbols represent male subjects. IBS‐D, irritable bowel syndrome with diarrhea.


Source: Martinez C, Vicario M, Ramos L, et al. The jejunum of diarrhea‐predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations. Am J Gastroenterol 2012;107(5):731. Reproduced with permission of Wolters Kluwer Health.

Schematic illustration of luminal and tissue mediators increase neuronal sensitivity.

Figure 31.9 Luminal and tissue mediators increase neuronal sensitivity. There is strong evidence for the presence of sensitizing mediators in the tissue or intestinal lumen of IBS patients. Biopsy supernatants from IBS (Rome II) patients increase firing of afferent neurons in animal models (a) and submucosal enteric neurons in human biopsies (b). Protease activity is increased in IBS supernatants and may mediate their effect on neuronal sensitivity. IBS, irritable bowel syndrome; DRG, dorsal root ganglion; D, IBS with diarrhea; C, IBS with constipation; D/C, IBS with alternating bowel habits (this classification has been replaced by “mixed”, see Figure 31.12); HC, healthy control.


Source: (a) Cenac N, Andrews C, Holzhauzen M, et al. Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest 2007;117:636–47; (b) Buhner S, Li Q, Berger T, et al. Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients. Neurogastroenterol Motil 2012;24(12):1134. Reproduced with permission of John Wiley & Sons.

Schematic illustration of IBS patients have an augmented colonic motor response to meals.

Figure 31.10 IBS patients have an augmented colonic motor response to meals. Alteration in colonic motility has long been recognized as a factor in IBS and in early studies it has been associated with psychological and physical stress. Changes have included increased number of rapid contractions in response to balloon distension and increased transit in IBS‐D. Patients with IBS have increased motor activity in fasting states, in response to meals, and in response to cholecystokinin octapeptide (CCK‐8).


Source: Chey WY, Jin HO, Lee MH, et al. Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea. Am J Gastroenterol 2001;96(5):1499. Reproduced with permission of Wolters Kluwer Health.

A bar chart depicts the colonic transit time differs by bowel habit subtype.

Figure 31.11 Colonic transit time differs by bowel habit subtype. This figure shows the comparison of colonic geometric center (0 = ileum, 5 = stool) at 8 (GC8), 24 (GC24), and 48 h (GC48) in healthy controls and lower FGID patients with different types of bowel dysfunction (total n = 287). There was a significant association of colonic transit at 8, 24, and 48 h with bowel habit subtype status (ancova p<0.01 for GC8, p<0.001 for GC24 and GC48). After adjusting for gender and BMI, there was a lower geometric center in the IBS‐C and functional constipation group vs healthy controls at 24 and 48 h (p<0.05), which means that mean colon transit was slower in the constipation group. In contrast, there was a higher genometric center in the IBS‐D and functional diarrhea group compared to healthy controls at 8, 24, and 48 h (p<0.01). This difference demonstrates a faster mean colon transit time in the diarrhea group. There is a numerical difference in IBS‐M compared to controls, suggesting that IBS‐M patients have a faster transit at 48 h than controls, but this was not significant.


Source: Manabe N, Wong BS, Camilleri M, et al. Lower functional gastrointestinal disorders: evidence of abnormal colonic transit in a 287 patient cohort. Neurogastroenterol Motil 2010;22(3):293. Reproduced with permission of John Wiley & Sons.

Schematic illustration of bile acid diarrhea (BAD).

Figure 31.12 Bile acid diarrhea (BAD). Bile acids (BAs) are synthesized in the liver and are responsible for digestion and absorption of lipids in the small intestine. The primary BAs, chenodeoxycholic acid (CDCA) and cholic acid (CA) are synthesized from cholesterol and conjugated with taurine or glycine in the liver. BAs are recycled through active reuptake in the terminal ileum (enterohepatic circulation (a)). Dysregulation of the enterohepatic circulation resulting in increased biosynthesis or secretion of BAs or decreased reabsorption can cause BAD. BAs in the colon can stimulate fluid, mucus, or sodium secretion, increase gastrointestinal motility, damage the mucosa, and stimulate defecation. BAD may be present in 25–33% of patients with chronic diarrhea and it is estimated to affect 1% of the population. Fasting serum levels of 7α‐hydroxy‐4‐cholesten‐3‐one (C4) and total stool bile acids are increased in IBS‐D (b). BA, bile acid; C4, 7a‐hydroxy‐4‐cholesten‐3‐one; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; FGF19, fibroblast growth factor 19; IBS, irritable bowel syndrome; IBS‐C, IBS with constipation; IBS‐D, IBS with diarrhea.


Source: (a) Vijayvargiya P, Camilleri M. Current practice in the diagnosis of bile acid diarrhea. Gastroenterology 2019;156(5):1233; Reproduced with permission of Elsevier. (b) Vijayvargiya P, Camilleri M, Shin A, Saenger A. Methods for diagnosis of bile acid malabsorption in clinical practice. Clin Gastroenterol Hepatol 2013;11(10):1232. Reproduced with permission of Elsevier.

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Nov 27, 2022 | Posted by in GASTROENTEROLOGY | Comments Off on 31: Irritable bowel syndrome

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