Irritable Bowel Syndrome (IBS)

Practice Essentials

Irritable bowel syndrome (IBS) is a disorder of gut-brain interactions (DGBI). DGBIs are a group of gastrointestinal (GI) disorders that occur from alteration of the interconnected gut-brain pathways. This can result in many different symptoms, such as pain, bloating, cramping, nausea, feelings of satiety, and others.^{[1, 2]} Population-based studies estimate the prevalence of IBS at 4-11%^[3] and the incidence of IBS at 1-2% per year.^{[4, 5]} It is the seventh most common diagnosis by primary care physicians.^[3] IBS contributes to large direct and indirect costs on a personal and societal level.

Signs and symptoms

IBS is a chronic disorder. Manifestations of IBS include the following^[6] :

• Abdominal pain
• Change in stool frequency and/or form
• Abdominal pain related to defection; this could be relief or worsening of the pain

Symptoms not consistent with IBS should alert the clinician to the possibility of an organic pathology. Inconsistent symptoms include the following:

• Onset after age 45 years
• Acute symptoms (IBS is defined by chronicity)
• Progressive symptoms
• Nocturnal symptoms
• Unexplained weight loss
• Fever
• Rectal bleeding
• Painless diarrhea
• Steatorrhea

See Presentation for more detail.

Diagnosis

The Rome IV criteria for the diagnosis of IBS require that patients have had recurrent abdominal pain on average at least 1 day per week during the previous 3 months that is associated with two or more of the following^[7] :

• Defecation
• A change in stool frequency
• A change in stool form or appearance

In 2021, the Rome IV criteria suggested that IBS can be diagnosed if symptoms have lasted at least 8 weeks (therefore are chronic) and interfere with daily activities, cause worry, or interfere with quality of life.^[8]

Supporting symptoms include the following:

• Altered stool passage (straining and/or urgency)
• Nonbloody mucorrhea
• Abdominal bloating or subjective distention. This is common in IBS but is not required for diagnosis.

Four bowel patterns may be seen with IBS, and these remain in the Rome IV classification.^[7] These patterns are as follows:

• IBS-D (diarrhea predominant)
• IBS-C (constipation predominant)
• IBS-M (mixed diarrhea and constipation)
• IBS-U (unclassified; the symptoms cannot be categorized into one of the above three subtypes)

IBS subtypes are often dynamic. Notably, within 1 year, 75% of patients change subtypes, and 29% switch between constipation-predominant IBS and diarrhea-predominant IBS. The Rome IV criteria differ from the Rome III criteria in basing bowel habit on stool form solely during days with abnormal bowel movements rather than on the total number of bowel movements.^[7] Understanding a patient's IBS subtype helps in selection of therapies.^[6]

A comprehensive history, physical examination, and tailored diagnostic testing can establish a diagnosis of IBS in most patients. The American College of Gastroenterology (ACG) updated their IBS management guidance which is highlighted by a positive diagnostic strategy, in contrast to the old strategy that IBS is a diagnosis of exclusion^{[6, 9]} : The following "alarm symptoms," however, should prompt diagnostic testing including colonoscopy^[6] :

• Unintentional weight loss
• Rectal bleeding
• Older age of onset (> 45 years)
• Iron deficiency anemia
• Family history of certain organic GI illnesses (eg, inflammatory bowel disease, celiac disease, colorectal cancer)

Further testing using a positive diagnostic strategy is detailed under Workup.

Management

Management of irritable bowel syndrome has progressed with better understanding of pathophysiology, the role of food in causing and treating IBS, the role of comorbid psychiatric disorders, and development of new medications.

Dietary measures may include^[10] :

• Soluble fiber (for instance, oats, psyllium)
• Adequate hydration
• Limiting known triggers (for instance, lactose, high fruit/FODMAP (low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) intake, bran, spicy food, fatty food)
• Low FODMAP diet (often helpful to involve a dietician)

Behavioral and psychological interventions are helpful in treating IBS. These treatments are called brain-gut behavior therapies (BGBTs) and can often improve GI symptoms by targeting the gut-brain connection.^[2] Examples of effective therapies include disease self-management, cognitive behavioral therapy (CBT), gut-directed hypnotherapy, mindfulness, and psychotherapy.^[2]

Pharmacologic agents used for the management of symptoms in IBS are chosen based on patient subtype and symptoms. According to the American Gastroenterological Association (AGA) clinical practice guidelines, these include^{[4, 5]} :

• Anticholinergics/antispasmodics (eg, dicyclomine, hyoscyamine, trimebutine, peppermint oil)^[11]
• Antidiarrheals (eg, diphenoxylate, loperamide)
• Neuromodulators such as tricyclics (eg, imipramine, amitriptyline)
• Prokinetic agents (prucalopride)
• Bulk-forming laxatives
• PEG laxatives
• Serotonin receptor antagonists (eg, alosetron, tegaserod)
• Chloride channel activators (eg, lubiprostone)
• Guanylate cyclase C (GC-C) agonists (eg, linaclotide, plecanatide)
• Altering bacterial flora and gas formation (eg, rifaximin)^[12]
• Sodium-hydrogen exchange 3 (NHE3) inhibitors (eg, tenapanor)^[13]
• Peripherally acting mixed opioid receptor agonist/antagonist (eluxadoline)^[4]

See Treatment and Medication for more detail.

View Video

Irritable Bowel Syndrome (IBS). What is IBS? IBS is a condition that involves recurrent abdominal pain, as well as abnormal bowel motility, which can include diarrhea and/or constipation.

• References

Background

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction (DGBI). DGBIs are a group of gastrointestinal disorders that occur from alteration of the interconnected gut-brain pathways. This can result in many different symptoms such as pain, bloating, cramping, nausea, feelings of satiety, and others.^{[1, 2]}

Population-based studies estimate the prevalence of irritable bowel syndrome at 4-11%^[3] and the incidence of irritable bowel syndrome at 1-2% per year.^{[4, 5]} However, there is significant heterogeneity among studies of IBS prevalence.^{[14, 15]} It is the seventh most common diagnosis by primary care physicians.^[3]

Substantial direct medical costs arise from IBS, ranging from $1.5 to $10 billion per year in the United States,^[6] 8 billion Euros in Europe, and 123 billion Yuan in China.^[16] Certain groups are overrepresented, including women and younger patients,^[6] patients with hypermobility spectrum disorders,^[17] patients who report adverse reactions to food,^[6] and adverse life events including childhood abuse, anxiety, depression, posttraumatic stress disorder, and others.^{[2, 16]} A 2023 study concluded that loss of productivity is the greatest socioeconomic cost of IBS.^[18] IBS is not associated with increased mortality.^[19]

• References

Pathophysiology

Traditional theories regarding the pathophysiology of irritable bowel syndrome (IBS) visualized IBS as a three-part complex of altered gastrointestinal (GI) motility, visceral hyperalgesia, and psychopathology.^[20] More recently, it is understood that IBS is a disorder of gut-brain interaction (DGBI) and, as such, theories inch closer to a unifying mechanism, though with multiple underlying etiologies.^{[21, 22]} These may include altered GI motility, intestinal dysbiosis, visceral hypersensitivity, food triggers, mucosal inflammation and postinfectious reactivity, altered influence of gravity, and others.^{[21, 23, 24, 25, 26]} The interconnectedness of the gut and brain are the key to understanding IBS.

Altered GI motility

Altered motility is often seen in IBS. Yet, no single motility change encompasses all patients with IBS.

There may be frequent motility changes in IBS, but only 25-75% of IBS patients exhibit motility abnormalities. These suggest rapid small bowel transit in diarrhea-predominant IBS (IBS-D) and slow transit in constipation-predominant IBS (IBS-C), increased frequency and amplitude of high-amplitude propagating contractions (HAPCs) in IBS-D with abdominal pain, greater phasic contractions of the colon after meals, stress, neostigmine, and intravenous (IV) cholecystokinin (CCK), exaggerated gastrocolic reflex, and accelerated whole gut and colon transit in IBS-D but not in IBS-C.^{[22, 27]}

More recent articles using a wireless capsule that records pH and pressure determined that colonic transit is significantly slower in IBS-C patients than in IBS-D and mixed diarrhea and constipation IBS (IBS-M) patients.^[28] There was no correlation found between small bowel transit times among patients.^[28] Yet other studies using colonic scintigraphy identified rapid colon transit in those with IBS-D and 20% of subjects with IBS-C.^[29]

Colon transit studies correlate poorly with symptoms of bloating, flatulence, and abdominal pain. Interestingly, 72% of IBS-D and 86% of IBS-C patients had normal colon transit, though there was a greater proportion of IBS-D patients with accelerated transit (27% vs 1% of IBS-C) and IBS-C patients with delayed transit (12% vs 2% for IBS-C). This suggests that, at least currently, colon transit is not a reliable method to diagnose IBS.^[30]

Visceral hyperalgesia

Visceral hyperalgesia is common in IBS.^[31]  Enhanced perception of normal motility and visceral pain characterizes IBS. Rectosigmoid and small bowel balloon inflation produces pain at lower volumes in patients than in control subjects. Notably, hypersensitivity appears with rapid but not gradual distention.

Patients who are affected describe widened dermatomal distributions of referred pain. Sensitization of the intestinal afferent nociceptive pathways that synapse in the dorsal horn of the spinal cord provides a unifying mechanism.

Food has been shown to trigger DGBIs including IBS. In particular, mechano- and chemosensitivity of the gut may lead to abnormal gut peptide release and change afferent and efferent signaling. In addition, mucosal immune activation from both food and microbiota lead to visceral hypersensitivity through mast cell dependent and independent mechanisms. Mast cell activation in the small and large bowel in IBS enhances production of histamine, proteases, and prostaglandins, stimulating local nerves and affecting afferent signaling through the dorsal root ganglion, resulting in visceral hypersensitivity.^[22]

Gut-brain dysregulation, mucosal immune activation, and microbiome relationships

The gut-brain axis includes the gut's nervous system (the enteric nervous system [ENS], the central nervous system [CNS], the gut wall, and the hypothalamic-pituitary-adrenal axis [HPA] axis).^[24] As translational studies have shown, the ENS and CNS communicate bidirectionally. GI afferents to the CNS, spinal, and vagal afferents influence efferent changes in intestinal secretion, motility, visceral sensation, and the immune system.^{[24, 32]} Neuron sensitization and neuroimmune activation cause multiple up- and downstream effects, including triggering of pain receptors that lead to visceral hypersensitivity.^[22] Hyperactivation of CNS areas, such as the anterior cingulate cortex, amygdala, and midbrain, increased mucosal permeability, heightened intestinal response to corticotropin-releasing hormone (CRH) release, and decreased volume of the dorsolateral prefrontal cortex, which correlates with decreased coping mechanisms.^[33]

For example, tryptophan metabolism is increased in IBS and associated with microbial changes such as increased Firmicutes/Bacteroides ratio, increased Streptococcus and Ruminococcus concentrations, and decreased Lactobacillus and Bifidobacterium.^[34] As 5-hydroxytryptamine (5-HT; serotonin) is synthesized from tryptophan, 5-HT production and receptor magnitude are stimulated by changes in the gut microbiota.^[26] Secondary bile acids have also been noted to stimulate 5-HT production. 5-HT1 and 5-HT4 receptor stimulation on gut afferent nerve endings changes intestinal motility and secretion, and 5-HT3 stimulation increases visceral hypersensitivity.^[26]

However, there is no single clearly defined microbiome profile in IBS. Using rRNA sequencing, Swedish IBS patients were found to have similar microbiome profiles to control subjects, though with greater heterogeneity.^[35] In a study of 56 IBS patients in the UK, many had microbiome profiles indistinct from healthy controls. Others showed lower amounts of Bacteroides and higher Firmicutes. This changed profile may allow greater intestinal fermentation and thus may lead to symptoms.^[35] A 2023 study found lower alpha-diversity (microbial diversity within a single sample) in IBS, though whether this was causative of the IBS or a result of food intake changes (specifically a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols [FODMAP] diet) was unclear.^[36]

In IBS, changes may occur in the metabolism of other neurotransmitters and local intestinal mediators, such as dopamine, gamma-aminobutyric acid (GABA), and histamine.^[26] Increased intestinal permeability may be greater in all individuals with IBS subtypes versus control subjects.^[36]

Postinfection (PI) intestinal changes

Laparoscopic full-thickness jejunal biopsy samples revealed infiltration of lymphocytes into the myenteric plexus and intraepithelial lymphocytes in a subset of patients in one study.^[37] Neuronal degeneration of the myenteric plexus was also present in some patients. Research into Campylobacter jejuni–associated PI-IBS suggests certain bacterial genes confer increased susceptibility to PI-IBS. These genes caused greater virulence, enhancing adhesion, invasion, interleukin (IL)-8 and tumor necrosis factor alpha (TNFα) secretion on colonocytes, and conferred increased susceptibility to PI-IBS than other strains of C jejuni lacking these genes.^[38] Microbiota changes seen in PI-IBS include lower Firmicutes counts, higher Bacteroides and Clostridioides counts, and lower Firmicutes/Bacteroides ratios.^{[38, 39]}

Putative pathophysiologic changes seen in PI-IBS include epithelial changes of increased density of lamina propria enterochromaffin cells, leading to an increase in serotonin secretion with resultant changes in chemo- and mechano-sensation, increased CCK-reactive immune cells, dysbiosis, enhanced proinflammatory cytokine production, epithelial mast cell infiltration, disruption of the epithelial barrier leading to increased mucosal permeability, increased bile acid production, loss of enteric neurons, and others.^{[38, 39]}

Small intestinal bacterial overgrowth (SIBO)

Historically, SIBO was defined as more than 10⁵ of bacteria per mL of jejunal fluid aspirate. As this is cumbersome and has other limitations, the readily available lactulose- and glucose-hydrogen breath tests are used in the vast majority of IBS-related studies.^[40] More recently, breath testing for methane has been available, particularly for IBS-C patients. Limitations of these breath tests are beyond the scope of this article. A 2024 translational technique, high-throughput 16S ribosomal RNA sequencing of duodenal aspirates in symptomatic patients undergoing esophagogastroduodenoscopy (EGD), suggests that SIBO may be defined by duodenal aspirate growth on MacConkey agar.^[41] This study identified that SIBO may be defined by 10³ or more colony-forming units (CFU) per mL of jejunal fluid. At this cutoff, microbial metabolic pathways for carbohydrate fermentation and production of hydrogen and hydrogen sulfide correlated with symptoms and were enhanced.^[41]

A 2020 American College of Gastroenterology (ACG) guideline defined SIBO clinically as "the presence of excessive numbers of bacteria in the small bowel causing GI symptoms."^[42] Typical symptoms in the majority of patients include bloating, gas, abdominal distention, flatulence, abdominal pain, and diarrhea.^[42] Myriad other symptoms including nausea, constipation, fatigue, and poor concentration have been described.^[42]  Moreover, nutritional consequences are seen in cases of more severe SIBO, including low vitamin B12, elevated folate, steatorrhea, fat-soluble vitamin malabsorption, and weight loss. These malabsorptive findings are most typical in situations of intestinal stasis, anatomic abnormalities, immune deficiency (inherited or acquired), and hypochlorhydria.^[40]

Intestinal dysbiosis, such as that in SIBO, may cause IBS by multiple mechanisms as detailed above. In addition, using breath testing and translational techniques, distinct microbe profiles have been described relatively recently as identifying IBS subtypes, particularly IBS-C and IBS-D.^[43] Elevated methane breath test results correlate with elevated levels of stool methanogens such as Methanobrevibacter and identified IBS-C subjects. These patients had higher stool microbial diversity. Elevated H2 breath test findings correlated with IBS-D and lower microbial diversity. IBS-D subjects also had higher levels of hydrogen sulfide on breath testing, associated with greater Fusobacterium and Desulfovibrio levels.^[43]

Bile acid malabsorption (BAM)

BAM is common in the general population and in IBS, particularly IBS-D.^{[6, 44]} Bile acid is reabsorbed in the terminal ileum; BAM is well-defined in conditions where reabsorption is limited (eg, ileal resection) or delivery is increased (eg, cholecystectomy). BAM has been determined to be frequent in IBS and alternative mechanisms have been proposed.^{[6, 44]}

Central neurohormonal mechanisms

Current neuroimaging studies in IBS often reveal brain structural and functional changes, though with varied findings and no single brain signature of IBS.

For instance, a 2022 systematic review of 22 functional magnetic resonance imaging (fMRI) studies in IBS patients versus control subjects found increased or decreased brain activity in areas associated with the processing of pain (caudate, insula, hypothalamus, cingulate cortex, prefrontal cortex, and others).^[45] This suggests sensitization of visceral pain pathways, and it persists in IBS in remission. Functional connectivity studies often find hippocampal dysfunction in IBS; however, enhanced, unchanged, and suppressed connectivity to higher brain regions have been found.^[45]

Aberrant activation and functional connectivity involving the amygdala and insula features prominently in fMRI studies in IBS. The amygdala is activated in anticipatory pain. The insula (location of self-awareness and emotional arousal and regulation) is activated in IBS, and its connection with limbic and cortical regions is activated both at rest and during painful stimuli in IBS.^[46] Taken together, studies suggest dysfunction in the areas of pain anticipation and processing, self-regulation and self-awareness, emotion, and others in IBS.

The hypothalamic-pituitary axis appears involved in the pathogenesis of IBS. Motility disturbances such as colonic hypermotility and delayed gastric emptying correspond to a production increase in the hypothalamic corticotropin-releasing factor (CRF) in response to stress. CRF antagonists eliminate these changes.^[32] IBS-D patients manifest elevated morning (AM) cortisol levels but lower adrenocorticotropic hormone (ACTH) levels, suggesting HPA axis dysfunction.^[47]

The majority of the body's serotonin is produced in the gut. It is stored in enterochromaffin cells and undergoes reuptake by the serotonin transporter (SERT) in gut epithelial cells and platelets.^[32] Serotonin stimulates gut motility, secretion, vasodilation, activates vagal and spinal afferents that mediate sensation, and may promote local gut inflammation. Circulating postprandial 5-HT is elevated in IBS-D and PI-IBS but reduced in IBS-C.^[32] Mucosal SERT expression is decreased in IBS-D and IBS-C, which enhances local mast cell and intraepithelial lymphocyte production, leading to local inflammation.^[48]

Other proteins may be altered in IBS, including mucosal chromogranins and secretogranins, glucagon-like peptide 1, melatonin,^[32] and neurotransmitters such as glutamate, GABA, norepinephrine, and acetylcholine.^[48]

IBS often coexists with depression, anxiety, or other psychiatric disorders. Many of the changes described above are also present in patients with comorbid anxiety, depression, posttraumatic stress disorder, and a history of abuse, among other conditions.

Gravity

A novel hypothesis published in 2022 suggested that "ineffective anatomical, physiological, and neuropsychological gravity management systems" may cause IBS.^[25] This hypothesis puts forth that gravity resistance mechanisms evolved to support our intestinal function in the upright posture. Aberrant gravitational force resistance, detection, and vigilance mechanisms within an individual may then contribute to the development of IBS.^[25] This hypothesis potentially explains the increase in comorbid IBS in patients with hypermobility spectrum disorders such as hypermobile Ehlers-Danlos syndrome.^{[17, 25]}

• References

Etiology

Multiple possible etiologies of irritable bowel syndrome (IBS) have been proposed. Please refer to the Pathophysiology section for detailed discussions.

Postinfection IBS (PI-IBS)

The multiple putative mechanisms by which infectious gastroenterocolitis may result in PI-IBS is described under Pathophysiology. While viral infections are more common, bacterial and protozoal infections are more likely to result in long-term PI-IBS.^[39] Infectious gastroenterocolitis is a strong predictor of IBS development. Its risk increases 4.2 times within 1 year after an acute infectious episode versus individuals without an acute infectious episode. Of those with acute infectious gastroenterocolitis, about 10% will develop PI-IBS. The pattern is typically mixed- or diarrhea-predominant.^[38]

Risk factors include severe symptoms, being women, being younger patients, absence of vomiting during illness, higher premorbid or coexistent anxiety or depression,^[38] and smoking.^[23] When assessed within 1 year of acute bacterial, viral, and protozoal infection, 13%, 19%, and 7% of patients, respectively, developed IBS. Prevalence rates change with time, however. When assessed more than 1 year after acute infection, rates were 13%, 4%, and 53%, respectively, after bacterial, viral, and protozoal infection.^[38]

Infections that have been associated with PI-IBS include but are not limited to Clostridioides difficile, Vibrio cholerae, Campylobacter, Shigella, Salmonella, Escherichia coli, Giardia, coronavirus disease 2019 (COVID-19), norovirus, and rotavirus.^{[38, 49]}

For instance, infection with Giardia lamblia leads to an increased prevalence of IBS, as well as chronic fatigue syndrome. In a historic cohort study of patients with G lamblia infection as detected by stool cysts, the prevalence of IBS was 46.1% for as long as 3 years after exposure, compared with 14% in control subjects.^[50] Approximately 25% of patients with Clostridioides difficile infection develop PI-IBS.^[49]

Small intestine bacterial overgrowth (SIBO)

Up to 78% of patients with IBS have SIBO. The vast majority of SIBO studies in IBS have used the glucose- or lactulose-hydrogen breath test to identify SIBO^[42] and, more recently, added the methane breath test for subjects with IBS-C.^[43] Multiple conditions elevate the risk of SIBO, including the following^[40] :

• Small bowel dysmotility, as seen in diabetic autonomic neuropathy, scleroderma, amyloidosis, hypothyroidism, intestinal pseudo-obstruction, gastroparesis, Parkinson disease, and chronic opioid use
• Anatomic alteration, including postsurgical (Billroth II, bariatric surgery, end-to-side anastomosis, surgically created blind loops), stricture-related narrowing (radiation damage, Crohn disease), small bowel diverticula, gastrocolic or jejunocolic fistula, and resection of the ileocecal valve
• Innate or acquired immunosuppression, such as common variable immunodeficiency and acquired immunodeficiency syndrome (AIDS)
• Hypochlorhydria (disease- or medication-related)

Dietary factors

Up to 50% of IBS patients report that specific foods induce or worsen IBS symptoms.^[6] However, immunoglobulin (Ig) E–related food allergies are not more common in IBS. Thus, IBS-related food-induced symptoms likely occur from food intolerance or sensitivity.^[6]

Much attention has been paid to FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols). These highly fermentable and poorly absorbable sugars cause symptoms in the majority of IBS patients, and following a low FODMAP diet has been shown to improve symptoms. The mechanisms are protean and more complex than the gas and abdominal distention created by increased fermentation. Food products can induce intestinal dysbiosis, with downstream effects resulting in IBS symptoms. Gut microbiota interactions with food products may change afferent and local neurotransmission, secretion of proteins (eg, 5-HT, histamine, tryptamine, proteases), proinflammatory cytokine release, and enhance gut mechanosensitivity, among other possibilities. Specific biomarkers are being investigated to measure some of these changes.^[22]

Nonceliac gluten sensitivity (NCGS) receives a lot of attention. There is overlap with FODMAPs here as sensitivity to fructans may yield gluten sensitivity. Other components of wheat may also induce local gut inflammation independent of gluten.^[22]

Disaccharidase deficiency (lactase, fructase, sucrase, isomaltase) is common in the general population and more common in IBS patients.^[51] Relatively recent evidence shows an association between functional variants in the sucrase-isomaltase (SI) gene and an increased risk of IBS. In one study, investigators sequenced SI exons in seven familial cases, as well as screened for four congenital sucrase-isomaltase deficiency (CSID) mutations and a common SI coding polymorphism in a multicenter cohort comprising 1887 patients and control subjects.^[52] The investigators found that individuals affected by the SI mutations that code for defective or enzymatic activity in disaccharides had a predisposition to IBS.^[52] Similarly, another multinational genotype study of 2207 patients indicates that there is an increased prevalence of rare sucrase-isomaltase pathogenic variants in those affected by IBS.^[53]

Environmental factors

A systematic review found a potential association between environmental risk factors and the development of IBS, particularly air pollution.^[54] In addition, there was a link between microbial exposure, following a natural disaster or a result of poor sanitation, and IBS development and gut dysbiosis. An IBS risk also existed in those who had early pet ownership or other exposures.^[54]

• References

Epidemiology

Population-based studies often estimate the prevalence of irritable bowel syndrome (IBS) at 4.1% (Rome IV criteria) to 10.1% (Rome III criteria)^[5] or up to 11%,^[3] and the incidence of IBS at 1-2% per year.^{[4, 5]} It is the seventh most common diagnosis by primary care physicians.^[3] IBS contributes to large direct and indirect costs on a personal and societal level.

Of people with IBS, approximately 30% seek medical care.^[14] An estimated 10% of gastroenterology referrals relate to this symptom complex.^[55] The prevalence is markedly different among countries, with the lowest reported in South Asia (7%) and the highest in South America (21%).^[14] A 2018 study by Quigley suggested that in Asia, the lowest prevalence was in China (6%), with a higher prevalence in Japan (15%) and South Korea (16%).^[21] However, the Rome Foundation found in 2017 that there was significant heterogeneity among studies of IBS prevalence. In the same year, an expert literature review among community-based studies worldwide suggested that the lowest prevalence is in France (1.1%) and the highest is in Mexico (35.5%); a 7.1% prevalence was found in the US/Europe/Australia/New Zealand.^[15]

Adolescent and young adult women are most commonly affected with IBS.^[21] In Western countries, women are 2-3 times more likely to develop IBS than men, although in the Indian subcontinent males represent 70-80% of patients with IBS.

Patients often retrospectively note the onset of abdominal pain and altered bowel habit in childhood. Approximately 50% of people with IBS report symptoms beginning before age 35 years. The development of symptoms later in life does not exclude IBS but should prompt a closer search for an underlying organic etiology.

• References

Prognosis

Irritable bowel syndrome (IBS) is a chronic disorder. At 7-year follow-up, 55% of IBS patients remained with IBS, a more stable prevalence than those with other gastrointestinal conditions such as gastroesophageal reflux disease (GERD) and dyspepsia.^[56]

Psychologic comorbidity is seen in 70% of IBS patients, with IBS symptom severity correlating with an increased number of comorbid psychologic disorders. When followed for 1 year, increased psychologic comorbidity also correlated with increased healthcare seeking, treatments used, severity and continuity of symptoms, and impact on daily activities.^[16]

Patients with IBS also experience greater work absenteeism, presenteeism, and negative impact of disease on work productivity.^[18]

Individuals with IBS may carry an increased risk of ectopic pregnancy and miscarriage—but not stillbirth. The reasons for this are unknown. Whether the risk increases because of IBS itself, or due to another factor such as medications used for IBS, is unknown.^[57]

IBS patients do not have an increased risk of all-cause or cause-specific mortality.^[19]

• References

Patient Education

Good communication between patient and provider is key. Patient education remains a cornerstone of irritable bowel syndrome (IBS) care. Understanding that IBS is chronic is imperative to set reasonable expectations. Many patients may not be familiar with the concept of the gut-brain axis, yet understanding the basic interplay of the gut and brain will assist the patient in understanding that IBS is complicated but treatable. It will also help the patient grasp the importance of intervention for comorbid psychologic disorders, such as different therapy and mindfulness approaches.

Clinicians may also wish to refer patients to the following short video, which provides a simplified but clear and concise overview about what IBS is and its epidemiology, risk factors, and management options, as well as a brief explanation of the difference between IBS and inflammatory bowel disease (IBD).

View Video

Irritable Bowel Syndrome (IBS). What is IBS? IBS is a condition that involves recurrent abdominal pain, as well as abnormal bowel motility, which can include diarrhea and/or constipation.

• References

History and Physical Examination

History

Spending time on and meticulously taking the patient history is key establishing the diagnosis of irritable bowel syndrome (IBS), which comprises a range of manifestations and aggravation factors. Physical as well as psychologic symptoms should be discussed given the complex interplay of both in disorder of gut-brain interactions (DGBIs). Currently, the 2021 interpretation of the Rome IV criteria may be the most helpful in clinical practice; IBS is diagnosed if Rome IV symptoms have lasted at least 8 weeks (therefore are chronic) and interfere with daily activities, cause worry, or interfere with quality of life.^[8]

Supporting symptoms include the following:

• Altered stool passage (straining and/or urgency)
• Nonbloody mucorrhea
• Abdominal bloating or subjective distention (This is common in IBS but not required for diagnosis.)

Showing a patient the Bristol Stool Scale is helpful to identify stool form.^[6]  The scale includes seven stool types ranging from hard and lumpy to watery liquid stool.

Elucidating a patient's known triggers is also helpful, including life activities and/or foods.

Symptoms inconsistent with IBS

Inconsistent symptoms should be discussed, as these may signify an underlying organic pathology and the need for prompt diagnostic workup. Inconsistent symptoms include the following:

• Onset after age 45 years
• Acute symptoms (IBS is defined by chronicity.)
• Progressive symptoms
• Nocturnal symptoms
• Anorexia or unexplained weight loss
• Fever
• Rectal bleeding
• Painless diarrhea
• Steatorrhea

Postinfection IBS (PI-IBS)

Diagnosis of PI-IBS is made based on the Rome IV criteria for IBS with additional supportive criteria to delineate PI-IBS, including the following^[39] :

• Likely infectious gastroenteritis, as defined by either a positive stool culture in a symptomatic patient, or at least two symptoms including fever, vomiting, or diarrhea
• Acute onset of IBS symptoms without preceding IBS symptoms
• Symptom development either immediately after resolution of acute infectious gastroenteritis or within 30 days of resolution of acute symptoms

Physical examination

Patients with IBS often have an overall healthy appearance. There are no pathognomonic findings.

• References

Approach Considerations

Guidelines in recent years dictate that irritable bowel syndrome (IBS) is a positive diagnosis (ie, no longer a diagnosis of exclusion).

Criteria for diagnosis of IBS

A consensus panel created and continually updates the Rome diagnostic criteria to provide a standardized diagnosis for research and clinical practice. The Rome IV criteria for the diagnosis of IBS were released in 2016; they require that patients have had recurrent abdominal pain on average at least 1 day per week during the previous 3 months that is associated with two or more of the following^[7] :

• Defecation
• A change in stool frequency
• A change in stool form or appearance

In 2021, the Rome IV criteria suggested that IBS can be diagnosed if symptoms have lasted at least 8 weeks (therefore are chronic) and interfere with daily activities, cause worry, or interfere with quality of life.^[8]

As noted earlier, supporting symptoms include the following:

• Altered stool passage (straining and/or urgency)
• Nonbloody mucorrhea
• Abdominal bloating or subjective distention (common in IBS but not required for the diagnosis)

Four bowel patterns may be seen with IBS, and these remain in the Rome IV classification, as follows^[7] :

• IBS-D (diarrhea predominant)
• IBS-C (constipation predominant)
• IBS-M (mixed diarrhea and constipation)
• IBS-U (unclassified; the symptoms cannot be categorized into one of the above three subtypes)

IBS subtypes are often dynamic. Notably, within 1 year, 75% of patients change subtypes, and 29% switch between constipation-predominant IBS and diarrhea-predominant IBS. The Rome IV criteria differ from the Rome III criteria in basing bowel habit on stool forms solely during days with abnormal bowel movements rather than on the total number of bowel movements.^[7] Understanding a patient's subtype helps in selecting therapies.^[6]

• References

History-Specific Examinations

The history usually guides the necessary testing in irritable bowel syndrome (IBS). Defining a patient's IBS subtype, particularly whether diarrhea- or constipation-predominant, helps to determine the next steps.

In IBS-D, serologic testing for celiac disease is recommended, typically with levels of serum tissue transglutaminase immunoglobulin (Ig) A and quantitative IgA.^[6] Celiac disease prevalence is common, approximately 1.4% in pooled North American studies.^[6] In addition, patients with celiac disease often meet criteria for IBS-D. Thus, patients with IBS-D, or mixed/alternating IBS, should be serologically screened for celiac disease.^[6]

Individuals with inflammatory bowel disease (IBD) have a higher incidence of comorbid IBS than control subjects. Alarm symptoms may not be present in patients meeting criteria for IBS who are discovered to have IBD. Therefore, in IBS patients with diarrhea, check fecal calprotectin or lactoferrin levels. These are markers of intestinal inflammation and, if elevated, are supportive of the possibility of IBD.^[6] A low C-reactive protein (CRP) level (≤0.5) or calprotectin level of 40 mcg/g or less has been suggested to confidently exclude IBD in IBS.^[58]

A complete blood cell (CBC) count has been included in the framework of a positive diagnostic strategy for IBS.^[6] Thus, it is reasonable to obtain.

Colonoscopy may also be helpful in patients at higher risk of microscopic colitis. The 2021 American College of Gastroenterology (ACG) guidelines suggest risk factors include age 60 years or older, female sex, and "more intense diarrhea."^[6]

While routine stool testing for pathogens is not recommended in IBS, certain risk factors support specific testing. If risk factors for Giardia infection exist, the pretest probability of Giardia is higher, and stool testing is recommended. Common settings of higher Giardia exposure include travel to developing countries, poor water quality, camping, and daycare exposure.^[6]

Routine colonoscopy is not recommended in patients younger than 45 years without alarm symptoms or signs (ie, hematochezia, melena, unintentional weight loss, older age of symptomatic onset, family history of IBD, colon cancer, or other significant gastrointestinal disease). However, note that US colon cancer screening guidelines recommend testing starting at age 45 years. Thus, confirming that the patient is up to date on screening is imperative.^[6]

Routine testing for food allergies is not recommended unless reproducible consistent symptoms occur.^[6] Consistent symptoms include nausea, vomiting, diarrhea, and abdominal pain. Food allergies are not more likely in IBS patients relative to the general population.^[6] Clinicians should be aware of the limitations of food allergy testing if ordering such tests.

Food intolerance is common in IBS. An estimated 84% of IBS patients report food-related symptoms compared to 20% of the general population.^{[6, 59]} IBS symptom severity correlates with an increasing number of self-reported IBS-causing food items,^[59]  and carbohydrate intolerance is reported in 70% of these patients.^[59] Typical symptoms of carbohydrate malabsorption (lactose, fructose, sucrose, isomaltose) mimic those common to IBS, such as diarrhea, bloating, abdominal distention, flatulence, nausea, constipation, and abdominal pain.^{[22, 51, 60, 61]}  European guidelines published in 2022 suggested carbohydrate breath testing is useful in patients with typical symptoms.^[60] US expert opinion also suggests early carbohydrate breath testing may be time efficient and cost effective in patients with typical symptoms.^[59] It may also be useful in IBS patients who do not respond to a low FODMAP (low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet.^[51] The collection of methane in addition to hydrogen (H2) is under investigation. If breath testing is considered, attention to factors that may alter results (eg, recent antibiotic use, laxative use) should be considered before testing.^{[18, 60]}

Small intestine bacterial overgrowth (SIBO) appears more prevalent in IBS patients than in control subjects.^[62] A 2020 meta-analysis and systematic review found an odds ratio (OR) of 4.9 for SIBO in IBS patients relative to healthy controls.^[62] SIBO diagnosed by hydrogen breath test yielded an OR 1.86 for IBS-D versus IBS-C, whereas methane breath testing yielded an OR of 2.3 for IBS-C compared to IBS-D. More IBS patients were diagnosed with SIBO using breath testing than small bowel aspirate, with an OR of 4.4.^[62] Lactulose H2 breath testing yielded more sensitivity than specificity, and glucose H2 breath testing yielded more specificity than sensitivity based on performance characteristics of the test (glucose is absorbed more proximally than lactulose), and this has caused differences in prevalence studies depending on the chosen test. Because a positive glucose- or lactulose-H2 or methane breath test often correlates with response to treatment, breath testing has both diagnostic and prognostic value in IBS.^{[40, 63]}

Note that in relatively recent years, a positive methane breath test is considered an indication of intestinal methanogen overgrowth (IMO) rather than classic SIBO.^[40] Methanogens are Archaea (single-cell microorganisms similar to but evolutionarily distinct from bacteria; they lack cell nuclei), not bacteria.

Patients with severe SIBO, typically those with comorbid conditions causing dysmotility or anatomic alterations, may have laboratory findings consistent with malabsorption including low levels of vitamin B12 and vitamin D, as well as iron deficiency. Elevated folate levels may result from bacterial production.^[40]

Further testing is recommended in patients whose condition is unresponsive to initial therapy and who have signs and symptoms suggestive of an underlying disorder.^{[6, 64]} These include anorectal physiology testing (eg, anorectal manometry and balloon expulsion) to detect a pelvic floor disorder or dyssynergic defecation.^[6] Bile acid malabsorption may be detectable by the nuclear medicine SeHCAT (⁷⁵selenium homotaurocholic acid seven-day retention test) test (not available in the United States), fecal bile acids, low serum fibroblast growth factor 19 level, and a high C4 level (7a-OH-4-cholesten-3-one, C4, a bile acid precursor),^{[6, 44]} although serum-based testing is relatively new and under investigation.

Motility testing, such as radiopaque marker testing in refractory constipation, may be useful in some cases.^[6] Other methods of motility testing, which incorporate pH and other measurements, are being investigated.

• References

History-Specific Procedures

Patients who are age 45 years and older who have not had colorectal cancer (CRC) screening should be offered this. Colonoscopy is often performed but is not the only recommended test for CRC screening. Endoscopy and/or colonoscopy may be useful in situations where celiac disease, inflammatory bowel disease, colorectal neoplasia, and other conditions are considered.

• References

Approach Considerations

No single therapeutic approach is effective for all cases of irritable bowel syndrome (IBS). Management of IBS incorporates pharmacologic, dietary, brain-gut behavioral, and other interventions, and should be tailored to the patient.^[65]  See the discussions in the sections that follow.

• References

Dietary Measures

Soluble fiber is viscous, increases stool water content, and is poorly fermented. Examples include psyllium, oats, and beans. A 2022 Rome Working Group article on the role of food as treatment in functional bowel disorders suggests increasing soluble fiber, limiting fruit intake to three portions daily, and avoiding supplementation with insoluble fiber such as wheat bran, which is highly fermented in the colon and may worsen some IBS symptoms.^{[6, 10]}

Judicious water intake and limitation of caffeinated beverages and alcohol is recommended.^[10]

Avoid sugar alcohols and artificial sweeteners as they may worsen diarrhea.^[10]  Avoid trigger foods, if present; commonly reported triggers include spicy and fatty foods.^[10]

Lactose predigested products or lactase enzyme supplements are useful in patients with lactose maldigestion. Sucrose and starch avoidance may be recommended to patients with sucrase/isomaltase deficiency. Sacrosidase oral supplements may also help.^[51]

Kiwifruit, figs, dried plums, and apricots are examples of functional foods that provide natural laxation and are helpful in constipation.^[10]

A diet low in FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) (LFD) may help overall and specific IBS symptoms.^{[66, 67]}  The LFD is implemented in three phases. First, substitution of low FODMAP foods for those that are high FODMAP over 2-6 weeks. Second, rechallenge by gradually reintroducing FODMAPs, identifying dose tolerance, and monitoring symptoms. Third, long-term maintenance through a personalized diet to eliminate identified triggers but avoiding unnecessarily restricted intake. Working with a dietician is highly recommended when embarking on a LFD.^{[6, 10]}  A less restrictive LFD proposes to reduce the most common FODMAP groups, lactose, fructans (eg, onion, garlic, cereal grains), mannitol, and galacto-oligosaccharides (eg, legumes), with further restriction only if necessary.^[10]  Note that a gluten-free diet is different but overlaps with a low FODMAP diet.

Research into the mechanisms by which the LFD may help patients is ongoing. For instance, Valeur et al found 10 of 54 bacterial markers differed significantly between 32 patients who responded to FODMAPs and 29 who did not; using their findings, the investigators developed a response index that assesses gut microbial composition and has the potential to identify patients who are more likely to respond to a dietary FODMAP restriction.^[68]  A 2024 systematic umbrella review and meta-analysis of the effects of an LFD on IBS symptoms evaluated data from 1646 particpants in 11 meta-analyses and 24 randomized controlled trials.^[69]  The investigators found that an LFD significantly improved total symptoms based on the IBS-SSS (symptom severity scale) questionaire across all IBS subtypes, as well as favorably impacted stool consistency and frequency. Although quality of life also significantly improved, anxiety and depression did not. More clinical trials are needed.^[69]

Probiotics are commonly used, discussed, and researched. However, it is unclear for which patients probiotics are helpful, and in what form, dose, combination, or strain.^{[70, 71, 72]}  A meta-analysis concluded that Bifidobacterium infantis may help alleviate some IBS symptoms.^[73]  A systematic review and meta-analysis evaluated 43 articles on probiotics and showed that probiotics may help relieve pain, bloating, and gas.^[74]  A 2023 review article on probiotic use in IBS found that "most meta-analyses of probiotics in IBS report a beneficial impact on global symptoms and specific symptoms."^[35]  Unfortunately, probiotic studies are fraught with concerns such as heterogeneity, small sample size, poor reproducibility, and bias.^{[35, 75]}  Thus, current guidelines recommend against the use of probiotics in the treatment of global IBS symptoms^[6]  except in the context of a clinical trial.^[75]

Peppermint oil is recommended for overall IBS symptom relief and abdominal pain. It's considered a smooth muscle relaxant with other possible mechanisms. Enteric-coated peppermint oil may limit the side effect of heartburn in susceptible patients.^[6]  

Other dietary strategies have been described but are of limited evidence.^[10]

• References

Psychologic Therapy

Given the bidirectional interplay between the gastrointestinal system and the brain, management of irritable bowel syndrome (IBS) would be incomplete without a focus on psychologic comorbidity. Comorbid psychologic disorders are common in IBS and were discussed earlier. (See Pathophysiology and Prognosis.)

In IBS, illness perception appears to lead to maladaptive coping and greater visceral sensitivity.^[76] Hypervigilance, somatization, stress sensitivity, and fear of symptoms are common.^{[6, 77]} Suicidal ideation has been reported in IBS.^[78]

A Rome Working Team Report identified strong evidence for brain-gut behavioral therapies in IBS and other disorders of gut-brain interactions (DGBIs).^[2] These include patient education to facilitate disease self-management, cognitive behavioral therapy, gut-directed hypnotherapy, mindfulness, and psychotherapy.^[2] Behavioral interventions combined with effective medical and dietary therapies are considered low risk with a low number needed to treat of 4.^[6] Collaboration with a mental health expert is recommended.^[2]

• References

Medical Care

Published guidelines have reviewed the data on medication management of  irritable bowel syndrome (IBS).^{[4, 5, 6]} Minor differences exist and are briefly discussed below.

The American Gastroenterological Association (AGA) 2022 guideline recommends the following for constipation-predominant IBS (IBS-C)^[5] : strong recommendation for linaclotide and conditional recommendations for tenapanor, plecanatide, tegaserod, lubiprostone, polyethylene glycol, tricyclic antidepressants (TCAs), and antispasmodics. The AGA recommends against the use of selective serotonin reuptake inhibitors SSRIs). No recommendation was made regarding use of serotonin-norepinephrine reuptake inhibitors (SNRIs) due to lack of data.^[5] With regard to diarrhea-predominant IBS (IBS-D)^[4] : conditional recommendations for eluxadoline, rifaximin, alosetron, loperamide, tricyclic antidepressants, and antispasmodics. The AGA conditionally recommends against SSRIs.^[4]

The American College of Gastroenterology (ACG) 2020 guideline recommends the following for IBS-C^[6] : strong recommendation for chloride channel activators, guanylate cyclase activators, and, in limited situations, tegaserod. Polyethylene glycol laxative products are not recommended. The following are recommended for IBS-D^[6] : rifaximin, alosetron (in specific situations), and mixed opioid agonists/antagonists. The ACG recommends against bile acid sequestrants for IBS-D. For global symptom relief, TCAs are recommended but antispasmodics are not.^[6]

Note that eluxadoline is contraindicated in patients with a history of pancreatitis or alcohol abuse, those who drink more than three alcoholic beverages daily, and those without a gallbladder, in whom the risk of pancreatitis and sphincter of Oddi spasm are greater.^{[4, 6]}

Alosetron may be used in women with severe IBS-D whose condition has not responded to other management.^[4] Until very recently, it was available under an FDA REMS (Risk Evaluation and Mitigation Strategy) program; However, it was determined that this program is no longer necessary for prescribing alosetron, with the caveat that patients are selected appropriately.

Tegaserod is recommended in women with IBS-C younger than 65 years and without history of cerebrovascular disease.^[5]

The British Society of Gastroenterology (BSG) 2021 guidelines for the management of IBS are similar to the US guidelines above, with minor changes.^[79]

Emerging pharmacologic treatment for IBS focuses on a modern understanding of IBS pathophysiology, such as modulating concentrations of gamma-aminobutyric acid (GABA), acetylcholine, and glutamate^[48] ; fecal microbiota transplant^[6] ; new bile acid treatments like farnesoid X receptor (FXR) agonists^[44] ; and others.

In patients with IBS, central neuromodulators are used to treat psychiatric comorbidities, modify gut motility, improve central downregulation of visceral signals, and enhance neurogenesis.^[77]  TCAs are effective in IBS pain management, as are serotonin and noradrenaline reputake inhibitors. Tapering of central modulators should comprise a slow reduction over 4 weeks, longer in the setting of discontinuation effects.^[77]

• References

Guidelines for the Management of Irritable Bowel (BSG, 2021)

Guidelines for the management of patients with irritable bowel syndrome (IBS) were published in July 2021 by the British Society of Gastroenterology (BSG) in Gut.^[79]

Fiber and Dietary Therapies

Food elimination diets based on immunoglobulin G (IgG) antibodies are not recommended, nor are gluten-free diets.

Soluble fiber is effective for global symptoms and abdominal pain, but insoluble fiber should be avoided.

A diet low in fermentable oligosaccharides, disaccharides, and monosaccharides and polyols is effective second-line therapy for global symptoms and abdominal pain.

Probiotics

Probiotics may be effective for global symptoms and abdominal pain, but no specific species or strain can be recommended.

First-Line Drugs for IBS

Loperamide may be effective for diarrhea. Peppermint oil and certain antispasmodics may be effective for global symptoms and abdominal pain. Polyethylene glycol may be effective for constipation.

Gut-Brain Neuromodulators

Tricyclic antidepressants (TCAs) used as gut-brain neuromodulators are effective second-line treatment for global symptoms and abdominal pain. Selective serotonin reuptake inhibitors (SSRIs) used as gut-brain neuromodulators may be effective second-line treatment for global symptoms.

Second-Line Drugs in Secondary Care

Eluxadoline, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, and rifaximin are efficacious second-line drugs for IBS with diarrhea (IBS-D) in secondary care. Linaclotide, lubiprostone, plecanatide, tenapanor, and tegaserod are efficacious second-line agents for IBS with constipation (IBS-C) in secondary care.

Psychologic Therapies

IBS-specific cognitive behavioral therapy (CBT) and gut-directed hypnotherapy may be efficacious for global symptoms.

Severe or Refractory Symptoms

Severe or refractory IBS should be managed with an integrated multidisciplinary approach, with care taken to avoid iatrogenic harms.

Combination gut-brain neuromodulators (augmentation) may be considered for more severe symptoms.

• References

Medication Summary

The selection of pharmacologic treatment for irritable bowel syndrome (IBS) remains symptom directed. Agents used for the management of IBS symptoms include anticholinergics, antidiarrheals, tricyclic neuromodulators (tricyclic antidepressants [TCAs]), prokinetic agents, soluble fiber, antibiotics, chloride channel activators, guanylate cyclase C (GC-C) agonists, 5-hydroxytryptamine type 4 (5-HT4) agonists, 5-HT3 antagonists, sodium-hydrogen exchange 3 (NHE3) inhibitors, and mixed opioid agonist/antagonists.

The American Gastroenterological Association (AGA) and American College of Gastroenterology (ACG) have published guidelines on the pharmacologic management of IBS. Their recommendations are similar, with minor differences. From the pharmacology perspective, the guidelines consider prescription and over-the-counter medication, and complementary treatments such as fiber, peppermint oil, and probiotics.^{[4, 5, 6]}

In their 2020 monograph on the management of IBS, the ACG recommends the following to relieve global symptoms of IBS^[6] : soluble fiber, peppermint, and tricyclic neuromodulators. Antispasmodics and probiotics are not recommended. Recommended to relieve diarrhea-predominant IBS (IBS-D) symptoms are rifaximin, alosetron, and mixed opioid agonist/antagonists. Bile acid sequestrants are not recommended. To relieve constipation-predominant (IBS-C) symptoms chloride channel activators, guanylate cyclase activators, and the 5-HT4 agonist are recommended. Polyethylene glycol (PEG) products are not recommended for global symptom relief, but they do provide relief of constipation.

In their 2022 guideline on the management of IBS-D, the AGA recommends eluxadoline, rifaximin, rifaximin retreatment, alosetron, and loperamide.^[4] In their 2022 guideline on the management of IBS-C, the AGA recommends tenapanor, plecanatide, linaclotide, tegaserod in appropriate patients, lubiprostone, and PEG laxatives.^[5] For global IBS symptoms, the AGA recommends tricyclic neuromodulators and antispasmodics and notes that while SSRIs are not recommended for relief of global or pain symptoms in IBS, these agents may be useful for comorbid mood symptoms. The AGA also notes that there is a lack of data on serotonin-norepinephrine reuptake inhibitor (SNRI) use in IBS.

In a 2020 AGA clinical practice guideline on the use of probiotics in the management of gastrointestinal disorders, probiotic use in adults and children with IBS is recommended only in the context of a clinical trial.^[75] While the authors acknowledge there is public interest in use of probiotics, significant knowledge gaps exist.

• References

Lubiprostone (Amitiza)

• Dosing, Interactions, etc.

Clinical Context:  Lubiprostone activates chloride channels on the apical part of the small bowel epithelium. As a result, chloride ions are secreted and sodium and water passively diffuse into the lumen to maintain isotonicity. This medication is FDA approved for use in idiopathic constipation and in irritable bowel syndrome with constipation.

• References

Linaclotide (Linzess)

• Dosing, Interactions, etc.

Clinical Context:  Guanylate cyclase agonist; activation of guanylate cyclase receptors in the intestinal neurons leads to increased cyclic guanosine monophosphate (cGMP), anion secretion, fluid secretion, and intestinal transit; it appears to work topically rather than systemically; when administered PO, linaclotide activates chloride channels in intestinal epithelial cells to increase intestinal fluid secretion; indicated to treat chronic idiopathic constipation and for IBS-C in adults.

• References

Plecanatide (Trulance)

• Dosing, Interactions, etc.

Clinical Context:  Plecanatide is a guanylate cyclase C (GC-C) agonist. Plecanatide and its active metabolite bind to GC-C and act locally on the luminal surface of intestinal epithelial cells. GC-C activation leads to increased cyclic guanosine monophosphate (cGMP), which, in turn, stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly by activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. It is indicated for chronic idiopathic constipation and IBS-C in adults.

• References

Alosetron (Lotronex)

• Dosing, Interactions, etc.

Clinical Context:  Alosetron is a 5-HT3 receptor antagonist. This agent controls irritable bowel syndrome symptoms through its potent and selective antagonism of serotonin 5-HT3 receptor type. These receptors are extensively located on the enteric neurons of the GI tract, and stimulation causes hypersensitivity and hyperactivity of the intestine. It is indicated only for women with severe diarrhea-predominant IBS who have: chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the GI tract excluded, and have not responded adequately to conventional therapy.

Limiting its use to this severely affected population is intended to maximize the benefit-to-risk ratio. The drug was previously removed from the US market but was reintroduced with new restrictions and a REMS program approved by the FDA on June 7, 2002. Restrictions were because of reports of infrequent but serious GI adverse reactions (eg, ischemic colitis, serious complications of constipation). In September 2023, the FDA removed the REMS program mandate for prescribers. Prescribers should note the narrow therapeutic window and select patients appropriately, as well as provide counseling regarding possible side effects.

• References

Tegaserod (Zelnorm)

• Dosing, Interactions, etc.

Clinical Context:  Tegaserod is a serotonin type-4 (5-hydroxytryptamine-4 [5-HT4]) receptor partial agonist. It stimulates the peristaltic reflex and intestinal secretions, inhibits visceral sensitivity, enhances basal motor activity, and normalizes impaired motility throughout the gastrointestinal tract. It is indicated for adult women younger than 65 years who have irritable bowel syndrome with constipation (IBS-C). Its use is further restricted to women without a history of cardiovascular risk.

• References

Eluxadoline (Viberzi)

• Dosing, Interactions, etc.

Clinical Context:  Eluxadoline is a mu opioid receptor agonist. It also is a delta opioid receptor antagonist and a kappa opioid receptor agonist. The multiple opioid activity is designed to treat the symptoms of IBS-D while reducing the incidence of constipation that can occur with unopposed mu opioid receptor agonists. It is indicated for IBS-D in adult men and women. Because of the risk of pancreatitis, eluxadoline is not indicated in patients without a gallbladder, with a history of pancreatitis, or who drink more than 2-3 drinks daily.

• References

Tenapanor (Ibsrela)

• Dosing, Interactions, etc.

Clinical Context:  Tenapanor is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for absorption of dietary sodium. NHE3 inhibition reduces sodium absorption from the small intestine and colon, resulting in an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and results in a softer stool consistency. It is indicated for adults with IBS-C.

• References

Class Summary

Linaclotide and lubiprostone enhance chloride-rich intestinal fluid secretions without altering the sodium and potassium concentrations in the serum. Linaclotide was approved by the FDA in August 2012 to treat chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.^[80]

The safety and efficacy of linaclotide in the treatment of IBS-C were evaluated in two double-blind, placebo-controlled phase III clinical trials in which linaclotide met all four primary endpoints for changes in abdominal pain and constipation in each trial. The trials involved 1605 patients aged 18-87 years, of which 807 were treated with linaclotide 290 mcg. Both trials showed a significantly higher proportion of responders in the linaclotide group compared with the placebo group.^{[80, 81, 82]}

Tenapanor, an inhibitor of sodium-hydrogen exchange (NHE3) transporter, was approved in September 2019 for IBS-C. Approval was based on two phase III trials (N = 1226) that showed a statistically significant improvement in stool frequency and abdominal pain relative to those who received placebo.^[13]

Rifaximin was approved by the FDA in 2015 for IBS-D.^[83]  A total of 1260 patients with IBS without constipation were enrolled in the TARGET 1 and TARGET 2 phase III trials at 179 investigative sites in the United States and Canada. Results showed that treatment with rifaximin (550 mg PO tid for 14 days) provided better symptom relief (eg, bloating, abdominal pain, loose/watery stools) compared with placebo, although the placebo effect was tremendous. Similarly, a 2012 meta-analysis of five studies, incorporating 1803 patients, determined that rifaximin is more effective than placebo for global symptom relief and bloating. Adverse event rates were similar to placebo.^{[84, 85]}  Rifaximin is a nonabsorbed antibiotic. Retreatment is sometimes needed and considered effective.^[6]

Tegaserod was reintroduced in the United States in 2019 after it had been suspended from the market in 2007 because of cardiovascular (CV) safety concerns.^{[86, 87, 88]}  The reapproved tegaserod indication is for women younger than 65 years with IBS-C who are without a history of CV ischemic disease and who have a low risk of developing CV disease. FDA approval was based on three multicenter, double-blind, placebo-controlled trials that stratified data from women with IBS-C (N = 2470).^{[86, 87]}  Tegaserod has been "shown to improve symptoms, enhance gastric accommodation and significantly attenuate visceral pain arising from the colon in functional dyspepsia patients."^[88]  Evidence also exists in animal models that tegaserod may have a protective effect in inflamed colons.^[88]

• References

Dicyclomine hydrochloride (Bentyl)

• Dosing, Interactions, etc.

Clinical Context:  Dicyclomine blocks the action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and CNS. This drug decreases fecal urgency and pain. It is useful in patients with diarrhea-predominant symptoms. Adverse effects are dose dependent.

• References

Hyoscyamine (Anaspaz, Levbid)

• Dosing, Interactions, etc.

Clinical Context:  Like dicyclomine, hyoscyamine is useful in patients with diarrhea-predominant symptoms and blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, which, in turn, has antispasmodic effects. The drug decreases fecal urgency and pain.

• References

Class Summary

Anticholinergic agents are antispasmodics that inhibit intestinal smooth-muscle depolarization at the muscarinic receptor. These agents help relieve symptoms of intestinal spasms in irritable bowel syndrome.

• References

Diphenoxylate hydrochloride 2.5 mg with atropine sulfate 0.025 mg (Lomotil)

• Dosing, Interactions, etc.

Clinical Context:  This drug combination consists of 2.5 mg of diphenoxylate, which is a constipating meperidine congener, and 0.025 mg of atropine to discourage abuse. The preparation inhibits excessive GI propulsion and motility, but it may exacerbate constipation.

• References

Loperamide (Imodium)

• Dosing, Interactions, etc.

Clinical Context:  Loperamide, which is available over the counter, acts on intestinal muscles to inhibit peristalsis and to slow intestinal motility. It prolongs the movement of electrolytes and fluid through the bowel and increases the viscosity and loss of fluids and electrolytes. Loperamide improves stool frequency and consistency, reduces abdominal pain and fecal urgency, and may exacerbate constipation.

• References

Class Summary

These agents are nonabsorbable synthetic opioids. They prolong the GI transit time and decrease secretion via peripheral µ-opioid receptors. They reduce visceral nociception via afferent pathway inhibition.

• References

Imipramine (Tofranil)

• Dosing, Interactions, etc.

Clinical Context:  Imipramine increases pain threshold in the gut, thereby providing a visceral analgesic effect. It prolongs oral-cecal transit time; reduces abdominal pain, mucorrhea, and stool frequency; and increases global well-being variably. It is effective in irritable bowel syndrome in doses that are subtherapeutic for antidepressive actions, suggesting an independent mechanism of action in this disorder.

• References

Amitriptyline (Elavil)

• Dosing, Interactions, etc.

Clinical Context:  Like imipramine, amitriptyline provides a visceral analgesic effect at doses subtherapeutic for antidepressive actions. It also prolongs oral-cecal transit time, reduces abdominal pain, mucorrhea, and stool frequency, and increases global well-being variably.

• References

Class Summary

Tricyclic antidepressants have both antidepressive and analgesic properties. Agents such as imipramine and amitriptyline are efficacious in treating symptoms of irritable bowel syndrome. The use of tricyclic antidepressants in irritable bowel syndrome is off label.

• References

Rifaximin (Xifaxan)

• Dosing, Interactions, etc.

Clinical Context:  Rifaximin is a semi-synthetic derivative of rifampin and acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase, blocking one of the steps in transcription. This results in inhibition of bacterial protein synthesis and consequently inhibits the growth of bacteria. The exact mechanism of action for IBS-D is not known, but it is thought to be related to changes in the microbiome of the gastrointestinal tract. Those with a positive lactulose breath test have particularly good response rates. It is indicated for IBS-D in adult men and women.

• References

Class Summary

Antibiotics may play a role in the treatment of irritable bowel syndrome by modulating the gut's microbiome; the exact mechanism by which they work is under study.

• References

Methylcellulose (Citrucel)

• Dosing, Interactions, etc.

Clinical Context:  Methylcellulose promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.

• References

Psyllium (Metamucil, Fiberall, Reguloid, Konsyl)

• Dosing, Interactions, etc.

Clinical Context:  Like methylcellulose, psyllium promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.

• References

Class Summary

Bulk-forming laxative products are made of natural and semi-synthetic hydrophilic polysaccharides and cellulose derivatives that dissolve or swell in the intestinal fluid, forming emollient gels that facilitate the passage of intestinal contents and stimulate peristalsis. As fiber supplements, these products may improve symptoms of constipation and diarrhea.

• References