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Pathophysiology of irritable bowel syndrome

Pathophysiology of irritable bowel syndrome
Author:
Arnold Wald, MD
Section Editor:
Nicholas J Talley, MD, PhD
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Literature review current through: Dec 2022. | This topic last updated: Sep 01, 2022.

INTRODUCTION — Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause. It is the most commonly diagnosed gastrointestinal condition and accounts for approximately 30 percent of all referrals to gastroenterologists [1]. The pathophysiology of IBS remains uncertain [2]. It is viewed as a disorder resulting from an interaction among a number of factors. Despite multiple investigations, data have been conflicting and no abnormality has been found to be specific for this disorder.

The traditional focus has been on alterations in gastrointestinal motility and on visceral hypersensitivity. More contemporary studies have considered the role of inflammation, alterations in fecal flora, and bacterial overgrowth. Also being considered is the role of food sensitivity. Whether a genetic predisposition exists is also being investigated.

This topic will review the multiple factors that have been considered to play a role in the pathophysiology of IBS. The clinical manifestations, diagnosis, and therapy of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults" and "Treatment of irritable bowel syndrome in adults".)

GASTROINTESTINAL MOTILITY — Although the symptoms of irritable bowel syndrome (IBS) have focused attention on both small intestinal and colonic motility, no predominant pattern of motor activity has emerged as a marker for IBS. However, motor abnormalities of the gastrointestinal tract (GI) are detectable in some patients with IBS. Abnormalities observed include increased frequency and irregularity of luminal contractions [3-5], prolonged transit time in constipation-predominant IBS [6], and an exaggerated motor response to cholecystokinin and meal ingestion in diarrhea-predominant IBS [7]. The relevance of these motor function alterations to symptoms has yet to be established. However, pharmacologic stimulation of gut motility in IBS patients has been reported to reduce gas retention and improve symptoms, suggesting that a motility disturbance underlies this complaint in some patients [8].

VISCERAL HYPERSENSITIVITY — Visceral hypersensitivity (increased sensation in response to stimuli) is a frequent finding in irritable bowel syndrome (IBS) patients. Perception in the gastrointestinal (GI) tract results from stimulation of various receptors in the gut wall. These receptors transmit signals via afferent neural pathways to the dorsal horn of the spinal cord and ultimately to the brain.

Several studies have focused on selective hypersensitization of visceral afferent nerves in the gut, triggered by bowel distention or bloating, as a possible explanation for IBS symptoms (see "Overview of intestinal gas and bloating", section on 'Abdominal bloating and distension'):

Distention – Various studies have shown that in patients with IBS, awareness and pain caused by balloon distention in the intestine are experienced at lower balloon volumes compared with controls, suggesting receptor hypersensitivity [9-12]. This possible increase in sensitivity may be specific for visceral afferents, since it is reported that patients with IBS have normal or even increased thresholds to somatic pain [13,14], although there are data to the contrary [15]. Rectal distension in patients with IBS also increased cerebral cortical activity more than in controls [16]. However, in one study involving balloon distension of the descending colon, increased colonic sensitivity was influenced by a psychological tendency to report pain and urgency, rather than increased neurosensory sensitivity [17].

Bloating – About half of patients with IBS (mainly those with constipation) have a measurable increase in abdominal girth associated with bloating (sensation of abdominal fullness), although this may not be related to the volume of intestinal gas [18]. Patients who complain of bloating and excess gas actually had volumes of gas in the GI tract similar to asymptomatic controls, but exhibit impaired transit of intestinal gas loads [19,20]. Another study, comparing the effect of a given lipid load on gas motility in patients with IBS and controls, found that IBS patients exhibited a heightened inhibitory response of motility to the introduction of a low lipid load [21].

It is unclear whether heightened sensitivity of the intestines to normal sensations is mediated by the local GI nervous system, by central modulation from the brain, or by some combination of the two [22-28]. In addition, other factors may contribute to visceral hyperalgesia, such as specific gastrointestinal mediators (serotonin, kinins) [29,30] or increases in spinal cord excitability due to activation of an N-methyl-D-aspartate (NMDA) receptor [31]. The recognition of these interactions has led to the concept that IBS is a disorder of brain-gut axis, and this term is now used instead of the previous designation of a "functional bowel disorder" [32].

INTESTINAL INFLAMMATION — Immunohistologic investigation has revealed mucosal immune system activation characterized by alterations in particular immune cells and markers in some patients with irritable bowel syndrome (IBS) (those with diarrhea-predominant IBS and patients with presumed postinfectious IBS) [33-38]. (See 'Postinfectious' below.)

Lymphocytes — Increased numbers of lymphocytes have been reported in the colon and small intestine in patients with IBS [33,35]. One study in which full-thickness jejunal biopsies were obtained in 10 patients with severe IBS found an increase in lymphocyte infiltration in the myenteric plexus in nine patients and neuron degeneration in six patients [35].

These cells release mediators (nitric oxide, histamine and proteases) capable of stimulating the enteric nervous system, leading to abnormal motor and visceral responses within the intestine. Stool examinations from diarrhea-predominant IBS patients have revealed a high level of serine-protease activity [39,40]. A fecal extract from these patients, when infused intra-colonically into mice, increased colonic cellular permeability and visceral pain in the mice; these effects were prevented by serine protease inhibitors [40]. The role of intestinal serine-proteases in the pathophysiology of IBS remains under investigation.

Mast cells — Mast cells are effector cells of the immune system. An increased number of mast cells has been demonstrated in the terminal ileum, jejunum, and colon of IBS patients [36,37]. Studies have demonstrated a correlation between abdominal pain in IBS and the presence of activated mast cells in proximity to colonic nerves [37]. (See "Mast cells: Development, identification, and physiologic roles", section on 'Physiologic roles'.)

Proinflammatory cytokines — Cytokines are proteins that are mediators of immune responses. Elevated levels of plasma proinflammatory interleukins have been observed in patients with IBS [34,38]. In addition, peripheral blood mononuclear cells of IBS patients produce higher amounts of tumor necrosis factor than healthy controls [34]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokines' and "An overview of the innate immune system", section on 'Cell-associated pattern recognition receptors'.)

POSTINFECTIOUS — The development of irritable bowel syndrome (IBS) following infectious enteritis has been suspected clinically based upon a history of an acute diarrheal illness preceding the onset of irritable bowel symptoms in some patients. The increased risk of postinfectious IBS is associated with bacterial, protozoan, helminth infections, and viral infections [41-45].

Two meta-analyses demonstrated an increased risk of IBS in patients who experienced an episode of acute gastroenteritis [46,47]. The larger review of 18 studies (10 controlled studies) reported that the pooled incidence of IBS was ten percent, and the odds of developing IBS are increased sixfold after an acute gastrointestinal (GI) infection. Risk factors for postinfectious IBS included young age, female gender, prolonged fever, anxiety, and depression [47]. A longer duration of the initial infection has also been associated with increased risk for IBS [41].

One of the largest prospective studies included a total of 2069 individuals who had been exposed to contaminated drinking water after heavy rainfall [42]. Pathogens included Escherichia coli O157:H7 and Campylobacter jejuni. There were 904 cases of self-reported gastroenteritis and several documented positive stool cultures. The outbreak spawned development of a prospective cohort study to evaluate long-term outcomes in affected individuals. During follow-up, significantly more individuals with self-reported gastroenteritis fulfilled the Rome I criteria for IBS compared with controls (28 versus 10 percent). The predominant symptom was diarrhea.

The cause of bowel symptoms following acute infection is uncertain, although several theories have been proposed:

Malabsorption – The development of idiopathic bile acid malabsorption has been observed following enteric infections, which may be result in diarrhea-predominant IBS [48,49]. (See "Overview of nutrient absorption and etiopathogenesis of malabsorption", section on 'Fat'.)

Increase in enteroendocrine cells/lymphocytes – An increase in serotonin-containing enteroendocrine cells and T lymphocytes, has been demonstrated following acute Campylobacter enteritis [50].The increased serotonin levels lead to increased GI motility and visceral hypersensitivity. Neither a reduction in enteroendocrine cells nor improvement in symptoms was observed in a controlled trial of glucocorticoids given to patients with post-infectious IBS [51]. One study suggested that increased numbers of enteroendocrine cells and depression were independent predictors of developing post-infectious IBS [52].

Antibiotic use – The use of antibiotics for GI or other infections was observed to be a risk factor for developing functional bowel symptoms [53,54].

ALTERATION IN FECAL MICROFLORA — The complex ecology of the fecal microflora has led to speculation that changes in its composition could be associated with diseases or disorders including irritable bowel syndrome (IBS). Emerging data suggest that the fecal microbiota in individuals with IBS differ from healthy controls and vary with the predominant symptom [55-59]. This concept was supported by a study that demonstrated that colonic hypersensitivity in IBS patients can be transferred to germ-free animals by inoculating the animals with fecal microbiota from IBS patients but not from healthy controls [60]. Additional studies are needed to validate these observations.

In view of potential microflora alterations in IBS, it is possible that patients with diarrhea-predominant IBS would benefit from probiotics, which influence the composition and metabolism of the microflora [61]. One placebo-controlled randomized trial found that administration of Lactobacillus plantarum did not significantly affect the intestinal flora of patients with IBS, although patients who received the probiotic had a decrease in symptoms of flatulence [62]. Similar findings were described in a study in which a probiotic yogurt consisting of a mixture of B. animalis subsp lactis Bb12 and K. marxianus B0399 improved symptoms but did not alter intestinal microbiota in IBS patients [63]. More data on the mechanisms of action of probiotics in IBS are needed. (See "Probiotics for gastrointestinal diseases", section on 'Irritable bowel syndrome'.)

BACTERIAL OVERGROWTH — Small intestinal bacterial overgrowth (SIBO) is associated with an increased number and/or type of bacteria in the upper gastrointestinal (GI) tract. However, data reporting an association between irritable bowel syndrome (IBS) and SIBO have been conflicting.

In support of an association between SIBO and IBS are studies demonstrating abnormal breath hydrogen levels in IBS patients after receiving a test dose of a carbohydrate, as well as improvement in symptoms after eradication of the overgrowth [64-66]. In addition, increased methane production, a gas byproduct of intestinal bacteria, has been associated by some with constipation-predominant IBS [67,68].

However, other studies have failed to support an association between SIBO and IBS [69,70]. The abnormal breath tests in patients with IBS may have been due to more rapid orocecal transit in patients with IBS, rather than SIBO [71,72]. In addition, an improvement of symptoms with antibiotics in patients with IBS may be due to an improvement in intestinal motility or a change in colonic flora rather than SIBO [73]. One study using cultures of jejunal aspirates from 162 patients with IBS and 26 controls found SIBO (>105 organisms/mL) in 4 percent of both patients and controls. Although a mild increase in bacterial counts was more common in IBS patients (42 versus 12 percent), this was unrelated to small intestinal motility and was not associated with symptoms [70]. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis", section on 'Jejunal aspirate culture'.)

FOOD SENSITIVITY — The role of food in the pathophysiology of irritable bowel syndrome (IBS) is not clear. Some patients with IBS report worsening of symptoms after eating and perceive food intolerance to certain foods [74,75].

Multiple factors have been considered to contribute to food sensitivity in patients with IBS. Investigations have centered on food specific antibodies, carbohydrate malabsorption, and gluten sensitivity.

Food allergy — Data reporting intolerance to specific foods by skin prick testing have been conflicting. The number of positive food skin-prick tests was greater in IBS patients compared with controls [76]. However, in another study, challenge with those foods that caused positive skin prick tests did not exacerbate symptoms [77]. (See "Diagnostic evaluation of IgE-mediated food allergy", section on 'Skin testing'.)

Other evidence of immune responses to food — IgG is thought to represent the normal immune response to food, and is not evidence of a recognized form of food allergy. However, studies focusing on IgG antibodies have shown that eliminating specific foods in patients with IBS who have elevated IgG titers associated with those foods may reduce gastrointestinal symptoms [78,79]. The use of IgG testing in the diagnosis of food allergy is unvalidated, although its role in the management of patients with IBS may warrant further research. (See "Diagnostic evaluation of IgE-mediated food allergy", section on 'Unvalidated methods'.)

Carbohydrate malabsorption — One theoretical etiology of IBS suggests that symptoms may be related to impaired absorption of carbohydrates. This theory originated in studies of patients with inflammatory bowel disease (IBD), but has been suggested as well for patients with IBS. The theory holds that fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) in patients with IBS or IBD enter the distal small bowel and colon where they are fermented, leading to symptoms and increased intestinal permeability and possibly inflammation [80].

Fructose intolerance has been suggested as a possible form of carbohydrate malabsorption contributing to gastrointestinal (GI) symptoms such as flatus, pain, bloating, belching and altered bowel habits [81]. One small controlled trial found that dietary restriction of fructose and/or fructans improved symptoms in patients with IBS who had been selected because of prior response to dietary change [82]. Another small crossover trial of patients with diarrhea-predominant IBS found a clinical benefit with a very low carbohydrate diet (20 g of carbohydrates per day) [83].

Although data suggest a similar absorption capacity of fructose, sorbitol, and lactose in IBS patients and controls [84-86], symptoms after a carbohydrate challenge are more easily produced in IBS [85]. The role of carbohydrate malabsorption remains a topic of investigation. (See "Overview of nutrient absorption and etiopathogenesis of malabsorption", section on 'Carbohydrate'.)

Gluten sensitivity — Several studies suggest some overlap between celiac disease and IBS [87,88]. There are few studies that have explored the pathologic basis for this relationship. One study suggested that in patients without villous atrophy, the presence of serum IgG antigliadin antibodies and expression of HLA-DQ2 (associated with celiac disease) may predict response to a gluten free diet in patients with diarrhea-predominant IBS [89]. A study in patients with irritable bowel syndrome with diarrhea without celiac disease found that dietary gluten altered small intestinal permeability and had a greater effect on bowel movement frequency in patients who were HLA-DQ2/8 positive compared with those who were HLA-DQ2/8 negative [90]. However, steps should be taken to confirm the absence of celiac disease prior to making a diagnosis of IBS in a patient with serologic tests suggestive of celiac disease. (See "Diagnosis of celiac disease in adults", section on 'Positive serology and diagnostic small bowel biopsy'.)

GENETICS — Familial studies and studies on select gene polymorphisms suggest a genetic susceptibility in some patients with irritable bowel syndrome (IBS).

Familial studies suggest a modest contribution of genetics to the development of IBS [91]. Data from studies of twins are contradictory; some studies show a higher concordance rate for IBS in monozygotic twins compared with dizygotic twins [92-95], with concordance rates for IBS in monozygotic twins ranging from 2 to 22 percent and rates in dizygotic twins ranging from 1 to 9 percent. However, in a study of 5032 twins (888 monozygotic pairs and 982 dizygotic pairs) the concordance rate did not significantly differ between monozygotic and dizygotic twins (17 versus 16 percent) [96]. In addition, one study found that having a parent with IBS was a greater independent predictor of IBS than having an affected twin, suggesting that the familial nature of IBS could be due to social learning, as well as genetics [92].

Associations between specific genes and IBS are under investigation. Some genotyping studies have shown an association between IBS and polymorphisms in the serotonin transporter gene, resulting in altered serotonin reuptake efficacy that affects intestinal peristalsis [97,98]. However, other studies have not confirmed an association of serotonin transporter gene polymorphisms and IBS [99,100]. Another study suggested that some patients with IBS may be genetically predisposed to an altered pattern of anti-inflammatory cytokine interleukin production [101].

PSYCHOSOCIAL DYSFUNCTION — Psychosocial factors may influence the expression of irritable bowel syndrome (IBS) [102]. In a study of patients with symptoms of IBS or nonulcer dyspepsia, patients with gastrointestinal (GI) symptoms reported more lifetime and daily stressful events than control groups [103]. Another study found that, compared with controls, patients with IBS exhibit increased anxiety, depression, phobias, and somatization [104]. In a prospective study, psychosocial factors (anxiety, sleep problems, somatic symptoms) were shown to be independent risk factors for the development of IBS in a population not previously diagnosed with the condition [105].

Some studies report a positive association between IBS and abuse [106-109], although one paper did not confirm this relationship [110]. Abuse may not be an independent risk factor for IBS after controlling for psychosocial factors such as depression or coping strategies [108].

One unifying hypothesis concerning the role of stress and psycho neuroticism in IBS is based upon corticotropin releasing factor (CRF), a peptide released from the paraventricular nucleus and considered to be a major mediator of the stress response. Data suggest that overactivity in the brain CRF and CRF-receptor signaling system contributes to anxiety disorders and depression [111]. Intravenous administration of CRF increases abdominal pain and colonic motility in IBS patients to a higher degree than normal controls [112]. Furthermore, this response can be blunted by the administration of a CRF receptor antagonist with no effect on the hypothalamus-pituitary-adrenal axis [113].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Irritable bowel syndrome (The Basics)")

Beyond the Basics topics (see "Patient education: Irritable bowel syndrome (Beyond the Basics)")

SUMMARY

Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits in the absence of an identified cause. The pathophysiology of IBS remains uncertain. (See 'Introduction' above.)

Although motor abnormalities of the gastrointestinal tract (increased frequency and irregularity of luminal contractions, abnormal transit time) are detectable in some patients with IBS, no predominant pattern of motor activity has emerged as a marker for IBS. (See 'Gastrointestinal motility' above.)

Selective hypersensitization of visceral afferent nerves in the gut has been observed in patients with IBS and is one explanation for IBS symptoms. (See 'Visceral hypersensitivity' above.)

Immunohistologic investigation has revealed mucosal immune system activation characterized by alterations in particular immune cells and markers in some patients with IBS. (See 'Intestinal inflammation' above.)

The development of IBS following infectious gastroenteritis has been suspected clinically based upon a history of an acute diarrheal illness preceding the onset of irritable bowel symptoms in some patients. The cause of bowel symptoms following acute infection is uncertain although several theories (malabsorption, increased enteroendocrine cells/lymphocytes, and antibiotic use) have been proposed. (See 'Postinfectious' above.)

The complex ecology of the fecal microflora has led to speculation whether changes in its composition could be associated with IBS. (See 'Alteration in fecal microflora' above.)

An association between IBS and small intestinal bacterial overgrowth has been conflicting. (See 'Bacterial overgrowth' above.)

The role of food in the pathophysiology of IBS is not clear. Investigations have centered on the development of food specific antibodies, carbohydrate malabsorption, and gluten sensitivity. (See 'Food sensitivity' above.)

A genetic susceptibility to IBS is suggested by several twin studies, although familial patterns may also reflect underlying social factors. Associations between specific genes and IBS are under investigation. (See 'Genetics' above.)

Psychosocial factors may influence the expression of IBS symptoms. (See 'Psychosocial dysfunction' above.)

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Topic 2629 Version 27.0

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