#98932: Irritable Bowel Syndrome

IBS affects persons regardless of age and biological sex but is most common in women and younger individuals. The worldwide prevalence of IBS among adults is between 4.1% (Rome IV criteria) and 10.1% (Rome III criteria) [213]. A population-based survey among 5,931 adults found that prevalence values (4.4% to 4.8%) of IBS (Rome IV criteria) are similar in the United States, Canada, and United Kingdom [214]. The estimated lifetime prevalence of IBS in adult North American and European populations is 10% to 20%, but only 5% to 7% have been diagnosed. IBS shows highest prevalence in South America (21%) and lowest prevalence in Southeast Asia (7%) [5,6].

IBS is among the most common diagnosed GI disorders, accounting for 41% of patients with functional GI symptoms [5,6,7]. Among clinical populations, IBS accounts for 12% of all patients seen in primary care and 28% in gastroenterology clinics [7]. In the United States, patients with IBS are evenly distributed among three common presenting clinical patterns: IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), and mixed IBS (IBS-M); in Europe, most patients reportedly have either IBS-C or IBS-M [5,6].

Of all persons with IBS symptoms, only a minority seek primary care medical attention, estimated at 10% to 70% in European countries and around 30% in the United States. In a 2017 online survey of 1,924 participants with a history of gastrointestinal symptoms, 43% of individuals who met the criteria for IBS-D had not received a formal diagnosis of the disorder [9]. Patients with IBS-D tend to seek medical attention at higher rates than those with IBS-C or IBS-M. Those seeking medical care report greater levels of pain and anxiety and greater impact on quality of life. In contrast, GI symptom severity does not differ greatly between the two groups [4,8,10].

The global prevalence of IBS is 14% in women and 8.9% in men, meaning the rate is 67% higher among women than men. This difference in reported sex-specific prevalence may be influenced in part by stigma associated with the diagnosis or by differing attitudes and behaviors that influence the decision to seek medical care rather than merely a variation in susceptibility or severity of underlying pathology [4,11]. An alternative possibility is that regulatory mechanisms of the brain-gut axis may be more sensitive to fluctuations in female hormone physiology, promoting alterations that result in IBS pathophysiology [12].

In the United States, Canada, and Israel, IBS symptoms are 1.5 to 2 times more prevalent in women than men, while the female/male distribution is closer to even in Asia. Abdominal pain and constipation are more common symptom complaints in women, with diarrhea more common in men [5,11].

A meta-analysis of 81 epidemiologic studies found that IBS prevalence decreases with age. The prevalence rate in patients younger than 40 years of age is 11.0%, with decreased rates in each subsequent decade (9.6% for persons in their 40s, 7.8% for persons in their 50s, and 7.3% for persons in their 60s). The lowest IBS prevalence rates are among persons 50 years of age and older [13,14].

Prevalence estimates for IBS are impacted by stigma associated with seeking health care for IBS symptoms or receiving a functional GI disorder diagnosis. Lower reported prevalence is likely in areas where greater stigma is perceived or where symptoms are so common as to be viewed as variations of normal. For example, diarrhea (from all causes) is common in Mexico and may not be viewed as an illness that requires healthcare contact [15]. The reported prevalence of IBS is likely to be higher in communities with higher perceived stress, lower perceived quality of life, greater potential gain from receiving a diagnosis, or fewer barriers to health care access [4,16,17].

The absence of a criterion-standard case definition or standardized diagnostic criteria over time has created difficulty in defining IBS cases for epidemiologic studies. Widely used ancillary data in other disorders are limited in IBS. Relatively few patients are hospitalized for IBS or diagnosed during admission, and IBS is not a cause of death that would show on death certificates [4]. Prescription data are only recently relevant as more medications have received U.S. Food and Drug Administration (FDA) approval for IBS.

For most patients with IBS, the symptoms of IBS are intermittent and over time show considerable fluctuation in frequency and duration. In the first three months after diagnosis, patients experience an average of four distinct symptom episodes per month, with the longest episode averaging five days, and most patients experience symptoms more than 50% of the days. One year after initial diagnosis, 30% to 45% of patients report they now have prolonged symptom-free periods. In the second year of follow-up, some patients experience symptom resolution, while others develop new symptoms and rate of symptomatic IBS episodes remains stable. After 10 years, 50% to 70% of patients report persistent symptoms [33,34,35].

Long-term follow-up data from clinical IBS populations indicate that 2% to 18% of patients worsened, 30% to 50% remained unchanged, and 12% to 38% improved over time. Poor outcomes were associated with previous surgery, longer disease duration, higher somatic scores, and higher baseline levels of anxiety or depression [5,36].

Up to 67% of patients with IBS experience functional dyspepsia. Among patients who report IBS symptom resolution, 45% subsequently develop other functional GI disorders [25,37,38]. Even if all GI symptoms resolve, many patients with IBS develop symptoms of other functional disorders. Patients with lower quality of life and higher levels of anxiety are most susceptible to comorbid functional disorders. Converging evidence suggests IBS is one expression of an underlying predisposition for functional disease [4,25,39,40,41].

Patients may also experience migration between predominant symptoms and IBS subtypes over time. Most commonly, IBS-C or IBS-D switches to IBS-M; switching between IBS-C and IBS-D is less common. A possible confounding factor in natural history studies of IBS is the effect of treatment, which can result in difficulty discerning symptom variation due to medical intervention versus true natural history [5,42].

With the passage of time, overlapping symptoms and adjustments in the prevailing diagnostic subtype within a given patient are very common. In one study of 432 primary care patients with IBS-C or functional constipation followed over 12 months, roughly 33% had a change in dominant diagnosis from functional constipation to IBS-C or from IBS-C to functional constipation [43,44]. In a cohort of female patients with IBS initially classified as constipation, diarrhea, or mixed subtypes, roughly 25% had the same subtype at 12-month follow-up, while 75% made at least one transition into another subtype [45].

Evidence of lower IBS prevalence in older age groups suggests symptom resolution over time, which is contradicted by natural history studies showing symptom chronicity. One explanation is that the diagnosis changes, rather than resolves. As discussed, patients with IBS have a high prevalence of other functional syndromes. In addition, "symptom shifting" occurs in some patients, characterized by resolution of functional bowel symptoms followed by development of extra-intestinal functional symptoms [4].

Although patients with IBS have a significantly reduced quality of life, greater risk of depression and suicidal ideation, and higher frequency of invasive procedures and surgery, community-based studies have not associated IBS with increased mortality risk [4,46].

Childhood Social Learning

Childhood functional GI disorders aggregate in families. Research into genetic factors is ongoing, but what children learn from parents is considered a greater contributor to the risk for developing functional GI disorders. One important contributor is the learning principle of positive reinforcement or reward. Children whose mothers reinforce illness behavior experience more severe stomachaches and more school absences than other children. In children with functional abdominal pain, cognitive-behavioral therapy (CBT) designed to improve parent and child coping strategies and beliefs about (and responses to) the child's complaints is more effective for relieving pain and reducing symptoms than an educational intervention. This effect is mediated by changes in parents' cognitions about their child's pain [39,55,56].

A strong association is found between parental psychological status (e.g., anxiety, depression, somatization) and children's abdominal symptoms [57]. This association may occur through modeling, whereby children observe and learn to display the behaviors they observe—in this context, heightened attention to or catastrophizing about somatic sensations. This effect of parental traits on children's symptoms can also occur through reinforcement. Parents with certain traits or beliefs (e.g., excessive worry about pain) might pay more attention to and reward somatic complaints. Parental catastrophizing about their own pain reinforces these types of responses to abdominal pain in their children, which encourages illness behavior and predicts child functional disability [55,58,59].

Childhood and Adult Stressors

Early life trauma is associated with increased risk for IBS and other functional GI disorders, major psychiatric disorders, ischemic heart disease, diabetes, asthma, and other medical disorders in adulthood [60]. In general, patients with IBS report a high prevalence of adverse life events, including childhood physical punishment, emotional abuse, and sexual abuse. This psychosocial history is related to greater functional GI disorder severity and higher rates of psychological distress and impaired daily functioning. These effects increase health care seeking and explain the higher prevalence of abuse histories among patients with IBS seen in specialty clinics than in primary care; those with mild IBS symptoms and psychosocial histories may not seek medical care. A past history of childhood abuse is also common (approaching 50%) in patients with chronic functional somatic syndromes such as chronic pelvic pain, headaches, and fibromyalgia [61,62,63].

Functional GI disorder onset frequently coincides with experiencing a highly threatening event, such as the breakup of an intimate relationship. Stressful life events are associated with symptom exacerbation and frequent health care-seeking in adults with IBS. Chronic life stress is the greatest predictor of IBS symptom severity one to two years after diagnosis and negatively affects functional GI disorder treatment outcomes. Presence of a single stressor within 6 months of initiating IBS treatment predicts poor outcomes and higher symptom intensity at 16-month follow-up [55,64].

Social Support

Quality of social support is related to many aspects of IBS. Patients have reported that finding social support helps them overcome IBS. Perceived social support adequacy is linked to IBS symptom severity, possibly through reducing stress levels. Negative social relationships with frequent conflict and adverse interactions consistently show a greater impact on poor outcomes than the absence of social support. A supportive patient-practitioner relationship improves symptoms and quality of life in patients with IBS, showing the clinically valuable role of social support [55,65,66].

Psychological distress is an important risk factor for developing functional GI disorders. The presence of psychological comorbidity may perpetuate or exacerbate symptoms and negatively affects the clinician-patient relationship and treatment outcomes. Comorbid anxiety or depression strongly predicts postinfectious IBS and functional dyspepsia and is also associated with severity of symptoms and quality of life impairment. The absence of co-occurring psychiatric comorbidity does not exclude contribution to functional GI disorder from dysfunctional cognitive and affective processes.

Mood Disorders

The overlap between major depressive disorder and functional GI disorder is about 30% in primary care and slightly higher in specialist care. Depression can influence the number of functional GI symptoms and diagnoses. Suicidal ideation is present in 15% to 38% of patients with IBS and is linked to hopelessness surrounding symptom severity, interference with life, and an unsatisfactory response to treatment. Comorbid major depressive disorder is linked to poor outcomes, including high health care utilization and cost, functional impairment, poor quality of life, and poor treatment engagement and outcomes [67,68,69].

Anxiety Disorders

Anxiety disorders are the most common psychiatric comorbidity in patients with functional GI disorders, with an estimated prevalence of 30% to 50%. Anxiety can initiate or perpetuate functional GI disorder symptoms by amplifying autonomic arousal (in response to stress) or interfering with GI sensitivity and motor function. Common pathways might exist between vulnerability to anxiety disorders and functional GI disorders, especially through anxiety sensitivity, bodily vigilance, and discomfort intolerance [67,70].

Somatization, Somatic Symptom Disorder, and Functional Somatic Syndromes

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), somatic symptom disorder replaced the abandoned term "somatization," which described patients who responded to psychosocial stress by experiencing, communicating, and seeking medical help for physical symptoms unconfirmed by pathologic findings. The number of symptom complaints was emphasized [55,71].

In the DSM-5, somatic symptoms may or may not have a specified medical diagnosis but are distressing, disabling, and associated with excessive and disproportionate thoughts, feelings, or behaviors persisting longer than six months. This designation shifts the experience of medically unexplained symptoms from subconscious manifestations of psychological distress to the abnormal cognitive-affective processes surrounding the symptoms [55,72,73].

Gastrointestinal somatization is associated with processes such as gastric sensitivity and emptying, symptom severity, and impaired quality of life. It is linked to higher health care use and predicts poor treatment response and discontinuing medication from side effects. Somatization is used extensively in the medical literature to account for syndromes, often with pain the prominent symptom, that lack apparent physiologic cause following standard diagnostic workups. In assessing possibility of somatization, it is clinically useful to consider the severity of the multiple somatic symptoms [73,74,75].

Somatization may explain the extra-intestinal symptoms experienced by patients with IBS and the common occurrence of other functional somatic syndromes among patients with IBS. The overlap is extensive; 67% of patients with functional GI disorders also have a positive history for conditions such as interstitial cystitis, chronic pelvic pain, headaches, fibromyalgia, or other functional somatic syndromes, independent of psychiatric comorbidity [55,76,77].

Cognitive-Affective Processes

The psychological constructs of health anxiety, GI symptom-specific anxiety, attentional bias/symptom hypervigilance, and catastrophizing are linked to functional GI disorders independent of psychiatric comorbidity (Table 2). These are important treatment targets for CBT [55].

GI symptom-specific anxiety is an important perpetuating factor that describes threatening interpretation and out-of-proportion behavioral response to GI sensations. This anxiety is characterized by worry and hypervigilance around GI sensations common to normal bodily functions (e.g., hunger, satiety, gas) as well as to symptoms of an existing GI condition (e.g., abdominal pain, diarrhea, urgency). Worry and hypervigilance generalize into fear about when sensations/symptoms will occur and about the social contexts where this could happen. Avoidance or behaviors disproportional to symptoms follows [55,78].

As an example, a person with IBS who has not eaten all day becomes aware her stomach is rumbling. This is interpreted to mean that the need to defecate may be imminent, triggering anxiety about whether and how this can be managed, as she is in public with friends. The anxiety increases when no restroom is visible, and the person leaves her friends for fear they would not understand [55].

Genetic Predisposition

Variations in the gene that encodes serotonin reuptake transport system have been found in patients with IBS. It is believed that polymorphism of the 5-HT2A receptor gene may be associated with the development of IBS [79].

Acute Infectious Gastroenteritis

The prevalence of IBS is increased six- to seven-fold in persons who have experienced a prior infectious gastroenteritis or enterocolitis, and postinfectious IBS accounts for 5% to 25% of all cases of IBS [80]. IBS develops in 3% to 30% of patients following acute gastroenteritis, illustrating an acute pathogen and host interaction that predisposes to development of chronic IBS [5,81]. Factors with the greatest risk for postinfectious IBS are elongating toxin and longer duration of the initial illness [82,83]. Other predisposing factors include:

Psychopathology increases the risk of developing postinfectious IBS by enhancing susceptibility to infectious gastroenteritis [5,84]. Mucosal inflammation and abnormal gut-host microbial interactions also promote postinfectious IBS. Mucosal immune activation and immune cell proliferation may amplify peripheral sensory signaling to result in visceral hypersensitivity, a primary IBS pain mechanism [5,84].

Patients with postinfectious IBS are important to identify because roughly 50% will experience spontaneous remission within six to eight years of the initial infection. This disease course differs from the chronic relapsing nature of typical IBS [5,85].

Acute gastroenteritis is now known to cause marked disruptions in the gut microbiota by pathogen overgrowth and substantial reduction in the diversity of normal flora. In the past, gut equilibrium was assumed to normalize after the infection cleared. However, research indicates individuals recovering from Campylobacter jejuni enteritis (a common cause of food poisoning) are as likely to show continued alteration in microflora (with potential progression to IBS-D) as they are full recovery of gut equilibrium [86,87].

Alterations in the Intestinal Microbiome

Gut dysbiosis is defined as an imbalanced or maladapted, but stable, gut ecosystem that has potential for reducing homeostasis and increasing the risk of disease pathogenesis [88]. Gut dysbiosis may influence the natural history of psychiatric disorders, cognitive disorders, and chronic visceral pain (due to brain-gut mediation). The intestinal flora of patients with IBS differs from healthy persons, and intestinal flora profiles also differ among IBS subtypes [89]. Deficiency in Bifidobacterium has been associated with greater abdominal pain and bloating. As such, treatment with probiotics has shown some promise in alleviating symptoms in IBS. In one study, probiotic administration was found to alter central processing of emotional stimuli and resting brain connectivity in sensory and affective brain circuits. The hypothesis of a microbiome gut-brain axis is emerging, and there is a possibility that gut microbiota will represent a therapeutic target in the treatment of IBS [55,90,91].

Bile Acids and Bowel Dysfunction

Secretory diarrhea arises from colonic perfusion of bile acids caused by inadequate ileal reabsorption (less than 95%). Excess bile acids entering the colon increase gut permeability, activate adenylate cyclase, stimulate colonic secretion, and increase stool water and colonic motility. Decreased circulating fibroblast growth factor 19 (FGF19) leads to excessive bile acid production and can be primary or secondary to ileal resection or ileitis. Around 10% of patients with IBS-D have severe bile acids malabsorption—defined as less than 5% retention at seven days. In the United Kingdom, bile acid diarrhea accounts for nearly 25% of patients with IBS referred to specialist care for diarrhea [87,92].

The presence of bile salt overproduction is identified by measuring the seven-day retention of a synthetic radiolabeled bile acid, selenium-75 homocholic acid taurine (SeHCAT). However, access to SeHCAT is limited; another approach measures fasting FGF19 using an enzyme-linked immunosorbent assay (ELISA). FGF19 <145 pg/mL predicts reduced SeHCAT retention [87].

The cause of low FGF19 levels is not fully known, but bile acid malabsorption can begin acutely after an ileitis episode, common with Salmonella spp. or C. jejuni gastroenteritis. Sudden onset and high-volume nocturnal diarrhea are characteristic features [87].

The prevalence and role of ileal malabsorption of bile acids in diarrhea-like symptoms has historically been underestimated in IBS-D. Identification can lead to specific treatment with bile acid sequestrants [15,93].

Diet

Many patients report that certain foods trigger IBS symptoms. The contribution of true food allergies is small, but food intolerances are common in patients with IBS. Gluten (present in wheat products) is increasingly recognized as an important symptom trigger in patients with IBS and inducer of IBS-like symptoms in persons without IBS diagnosis. Non-celiac gluten sensitivity is an emerging syndrome provoked by gluten ingestion in patients in whom celiac disease and wheat allergy are ruled out. Other triggers of non-celiac gluten sensitivity pathogenesis include wheat proteins (i.e., amylase and trypsin inhibitors) and FODMAPs (fermentable oligo-, di-, monosaccharides, and polyols) [94,95]. Emerging evidence supports gluten-free and low-FODMAPs diets for patients with IBS. FODMAPs are poorly absorbed carbohydrates that can induce osmotic effects, result in increased fermentation in the small bowel or colon, and trigger symptom exacerbation in patients with IBS with abnormal gut function or sensitivity [5,94].

Dietary constituents also influence the impact of intraluminal factors on gut function. Among these are microflora alterations in short-chain fatty acids; the effects of enteroendocrine cell products (i.e., granins) on nervous, endocrine, and immune cells; and the ratio of secondary to primary bile acids that impact gut transit rates [15,96].

A six-week placebo-controlled, double-blind trial in patients with IBS with gluten sensitivity histories found poorly controlled IBS symptoms in 68% randomized to diets with gluten, compared with 40% receiving a gluten-free diet. In patients receiving a gluten-free diet, double-blinded gluten re-challenge worsened pain, bloating, stool consistency, and fatigue [97]. A study of patients with IBS-D reported that gluten administration led to altered gut permeability and increased stool frequency and immune activation [98].

While these data suggest that symptom exacerbation after ingesting wheat is primarily caused by gluten, wheat also contains fructans and other proteins that may trigger symptoms in patients with IBS [5]. A clinical trial of 920 patients with IBS found that 33% of subjects experienced worsened symptoms of increased abdominal pain and distension after receiving wheat (not limited to gluten), but not after placebo [99].

In IBS, colorectal distension activates brain stress response areas but deactivates brain areas that modulate stress response [80,107,108]. This pattern reflects up-regulated connectivity in emotional arousal circuitry and helps explain the increased sympathetic arousal, anxiety, and vigilance often observed in patients with IBS, and the association between IBS symptoms and functional alteration in multiple brain networks [55].

When anticipating experimentally induced visceral pain, anticipatory response in the locus coeruleus predicts subjective perception and brain response to the actual painful stimulus. Sensory filtering is degraded by anxiety-related dysfunction of the descending pain modulation system [107,109].

Alterations in brain structure have been demonstrated in patients with IBS. The role of structural brain changes in IBS and other functional pain disorders is not clear, because these changes may represent pre-existing vulnerability factors or consequences of long-term exposure to the pain [106].

Female patients with IBS have shown increased cortical thickness in the somatosensory cortex and decreased cortical thickness in pain processing regions, including the insula and anterior cingulate cortex. IBS symptom severity is negatively correlated with cingulate thickness, suggesting a role for loss of neural density in symptom generation [106,110,111].

Patients with IBS have also shown decreased gray matter volumes in widespread regions, with early life trauma contributing to these decreases [106]. Decreased gray matter density in prefrontal and posterior parietal cortex areas is consistent with the close relationship between IBS and mood disorders. Pain catastrophizing negatively correlates with the degree of cortical thickness in the prefrontal cortex [112,113,114].

Structural abnormalities of brain white matter tracts have been found in multiple areas of the brain in patients with IBS. These white matter changes are associated with symptom severity, trait anxiety, and catastrophizing [115,116,117].

Descriptions of pain associated with IBS often change, but the pain is typically described as cramping discomfort that is diffuse or variable in location, without radiation. The most common site of pain is the lower abdomen, specifically the left lower quadrant. Many patients experience periodic exacerbations that vary in intensity from mild to severe; others describe acute episodes of sharp pain, often superimposed on a more constant dull ache. Meals may precipitate or aggravate the pain. Some patients report that pain is worsened by defecation, others that the pain is relieved by defecation. On occasion, the combination of enhanced colonic peristalsis and trapped gas in the splenic flexure may produce severe left upper quadrant abdominal pain or referred pain to the chest that mimics that of cardiac ischemia. Termed splenic flexure syndrome, balloon inflation in the splenic flexure will provoke this pain and should be considered in selected patients in order to differentiate it from more serious causes of chest or left upper quadrant abdominal pain [118].

Altered bowel habits may be described as diarrhea, constipation, or alternating diarrhea and constipation. Some patients have periods of relatively normal bowel habits alternating with episodic periods of either diarrhea or constipation. Patients with predominant constipation often report painful and infrequent defecation, non-response to laxatives, often associated with passage of hard, pellet-like or narrow stools. Diarrhea is usually described as small volumes of loose stool preceded by urgency or frequent defecation. Postprandial urgency is common. [118]. Stools may also be white or clear (mucosa).

Patients with IBS frequently report increased amounts of bloating and intestinal gas, but confirmation by quantitative measurements is elusive. People with IBS can experience expanding, and measurable, abdominal circumference throughout the day. Intolerance of otherwise normal amounts of abdominal distention is common [118].

Dyspepsia, heartburn, nausea, vomiting, sexual dysfunction (including dyspareunia and poor libido), and urinary frequency and urgency frequently occur in patients presenting with IBS complaints. Fibromyalgia commonly co-occurs. Careful questioning can reveal stressor-related symptoms; if disclosed, ask further about avoidance of stressors [118].

Perimenstrual Symptom Exacerbation

Many women of reproductive age experience cyclical changes in GI symptoms (including alteration in bowel habits) during their menstrual cycle. Female patients with IBS often experience worsened GI symptoms of abdominal pain, bloating, or diarrhea during menses, possibly due to elevated prostaglandin levels during menses that enhance perception of viscera-somatic stimuli and increases nausea, abdominal distension, and pain [119].

Fatigue

Despite receiving little attention in the medical literature, fatigue is a frequent symptom in patients with IBS and is associated with poor quality of life. A study of 160 patients with IBS found a multidimensional and negative impact from fatigue on daily life [120]. Fatigue may interfere with patients' ability to perform physical activities, work, domestic work, and interact socially. Poor stamina is the most prominent feature, and strategies to limit the bodily consequences of tiredness are common. Severe fatigue is associated with more severe IBS symptoms, anxiety, and depression. Fatigue is a distressing symptom in a sizeable proportion of patients with IBS and should be assessed and, if confirmed, targeted for intervention [120].

There are data to suggest that among persons with IBS-D symptoms, a formal diagnosis may have important implications for quality of care [9]. Patients with a formal diagnosis of IBS are more likely to have a sustained clinician-patient relationship that facilitates dialog, promotes patient education, and provides access to evidence-based therapies. As a group, these patients are better informed regarding IBS pathophysiology and more attuned to the role of aggravating factors, such as diet, stress, and the state of the intestinal microbiota.

The Bristol Stool Form Scale (BSFS) illustrates and describes the appearance of seven different stool types that correspond to intestinal transit time ranging from severe constipation (Types 1 and 2) to diarrhea (Type 7). Patients can use the BSFS to record frequency and subtype of their stools [124]:

IBS is subtyped by predominant bowel habit change, but only after all medications to treat bowel habit abnormalities are discontinued. The BSFS can be used to categorize IBS into subtypes based on stool characteristics (Table 3). Predominant bowel habits are based on stool form on days with at least one abnormal bowel movement [3,44].

Functional bowel disorders are diagnosed when criteria are fulfilled for the last three months, with symptom onset more than six months before diagnosis [3].

Functional Constipation

In order for a diagnosis of functional constipation to be made, two or more of the following must be present [3]:

In patients with functional constipation, loose stools are rarely present without laxative use. Although symptoms may be similar, these patients do not meet the full criteria for IBS-C. 


Functional Diarrhea

Functional diarrhea is characterized by loose or watery stools (>25% of stools) without predominant abdominal pain or bothersome bloating. These patients do not meet the criteria for IBS-D.

Functional Abdominal Bloating/Distension

Functional abdominal bloating (FAB) or distention (FAD) represent two different sets of signs and symptoms but are combined by Rome IV into the diagnostic entity of FAB/FAD. In patients with FAB/FAD, mild abdominal pain related to bloating and/or minor bowel movement abnormalities may be present. Symptoms of recurrent abdominal fullness, pressure, a sensation of trapped gas, and/or measurable increase in abdominal girth must be present. Abdominal bloating and/or distention predominates over other symptoms, occurring, on average, at least one day per week. These patients do not meet the diagnostic criteria for IBS, functional constipation, functional diarrhea, or postprandial distress syndrome. 


Abdominal pain is a hallmark of IBS; the absence of abdominal pain precludes the diagnosis of IBS. Pain can be present anywhere throughout the abdomen, although it is more common in the lower abdomen [3].

A history of disordered bowel habits (i.e., constipation, diarrhea, or both) should be identified, along with a temporal association with episodes of abdominal pain. Unpredictable bowel pattern (i.e., three or more different stool form types/week) reinforces the diagnosis of IBS-D. An increasing number of consecutive days without a bowel movement suggests a diagnosis of IBS-C.

Ask patients for specific information regarding bowel habits and stool characteristics, as this informs subtyping of their IBS. A diagnosis of unclassified IBS (IBS-U) is reserved for patients meeting IBS diagnostic criteria whose bowel habits cannot be accurately grouped into one of the three main subtypes; this group is uncommon. Difficulty in accurate subtyping can result from frequent changes in diet or medications or an inability to stop medications that affect GI transit. Subtyping should be based on the patient's reported predominant bowel habit on days with abnormal bowel movements. As noted, the BSFS should be used to record stool consistency [124].

Diagnosing patients with IBS-D or IBS-C is usually straightforward, but IBS-M can be more complex. A detailed history helps determine whether mixed bowel patterns originate from the underlying disease state or are a consequence of medical intervention. All prescription and over-the-counter medications and supplements with known influence on IBS symptoms should be considered. A stool diary helps identify patterns in the erratic bowel habits of many patients with IBS. Patients with IBS-M often report protracted periods when bowel movement is absent or appears with small, hard stools; this is followed by periods of multiple stools of variable consistency interpreted by patients as diarrhea. In most cases, this reflects IBS-C, and radiographic demonstration of fecal loading helps confirm clinical suspicion [5].

Non-Specific Symptoms

Common non-specific symptoms in IBS include abnormal stool frequency, abnormal stool form (BSFS types 1/2 or 6/7), excessive straining during defecation, urgency to defecate, feelings of incomplete evacuation, and mucus with bowel movements. Abdominal bloating is present in most patients with IBS and abdominal distention may be reported, but neither is required for an IBS diagnosis [3].

Patients with IBS frequently report that symptoms are induced or worsened by meals, although these symptoms are not specific to IBS. Many other functional GI (e.g., dyspepsia) and non-GI (e.g., migraine headaches, fibromyalgia, interstitial cystitis, dyspareunia) disorder symptoms are reported in patients with IBS; their presence supports an IBS diagnosis [3].

A physical examination should be performed for every patient evaluated for IBS. This reassures the patient and helps exclude organic etiology. Physical examination frequently reveals tenderness in the left lower quadrant over a palpable sigmoid colon. A rectal examination is warranted to rule out rectal disease and abnormal function of the anorectal sphincter (e.g., paradoxical pelvic-floor contraction during a defecation attempt), which may contribute to symptoms of constipation [125]. The presence of ascites, hepatosplenomegaly, or abdominal mass warrants further evaluation. An anorectal examination is mandatory to identify anorectal causes of bleeding, evaluate anorectal tone and squeeze pressure, and identify dyssynergic defecation [3].

Several diseases should be considered in patients with IBS symptoms, including celiac disease, inflammatory bowel disease, giardiasis, and dyssynergic defecation. When detailed history taking, physical examination, and/or routine laboratory testing results make it crucial to rule out a disease that requires diagnostic tests or functional studies not available in primary care, referral to a specialist is indicated.


Celiac Disease

Patients with IBS symptoms have a fourfold increased risk of biopsy-proven celiac disease [5]. However, the prevalence of celiac disease in patients with IBS symptoms varies by region, with European studies, but not American studies, demonstrating a higher prevalence of the disease. Routine celiac disease screening in patients with IBS becomes cost-effective with prevalence ≥1%. Given the potential long-term consequences of a missed celiac disease diagnosis, clinicians caring for patients with IBS should have a low threshold of suspicion, especially in patients with IBS-D [5,126].

Serologic tests for celiac disease should be performed in patients with IBS-D or IBS-M who fail empiric therapy. Upper GI endoscopy with duodenal biopsies should be performed if serologic tests for celiac disease are positive or clinical suspicion is high; duodenal biopsies can also identify tropical sprue, another mimic of IBS.

Microscopic Colitis

A small subgroup of patients with suspected IBS-D have microscopic colitis. Risk factors for microscopic colitis include age older than 50 years, nocturnal stools, weight loss, shorter duration of diarrhea, recent introduction of new medications, and comorbid autoimmune disease. When colonoscopy is performed in patients with suspected IBS-D, random colon biopsies should be obtained to rule out microscopic colitis [5,126].

Inflammatory Bowel Disease

Inflammatory bowel diseases, like Crohn disease, can mimic IBS symptoms during acute inflammatory flares. Nerve and muscle changes can persist following acute inflammation, even in remission. The underlying mechanisms may include altered gut permeability and persistent low-level immune activation, shown by cecal biopsies from patients with inflammatory bowel disease in apparent remission with ongoing IBS symptoms. Other mechanisms may include persisting alterations in enteric nerves and serotonin signaling. This information can help identify patients with inflammatory bowel disease and persistent IBS symptoms who may respond better to dietary restriction and other IBS treatments than to escalated immunosuppression [87,127,128].

Because even low-grade chronic inflammation can alter gut permeability and sensitize visceral afferent neurons, leading to aberrant motility and visceral sensitization, inflammatory bowel disease should be considered in all patients with IBS symptoms. IBS criteria are met by more than 33% of patients with inflammatory bowel disease, but the proportion of patients with inflammatory bowel disease and overlapping IBS symptoms with alarm features is unclear [5].

The pragmatic question is how often inflammatory bowel disease is ultimately identified in patients with typical IBS symptoms who lack alarm features. A prospective U.S. study of more than 900 non-constipated patients with IBS and healthy controls receiving colonoscopy found inflammatory bowel disease in less than 1% of patients with IBS and none in the controls. This argues against routine colonoscopy in patients with typical IBS symptoms who lack concerning features. Noninvasive biomarkers may be more cost-effective than colonoscopy for inflammatory bowel disease screening [5,129].

Fecal calprotectin, a biochemical assay for intestinal inflammation, is a cost-effective choice in inflammatory bowel disease screening, although 33% of patients with inflammatory bowel disease and IBS-like symptoms show negative results. C-reactive protein levels of <0.5 mg/dL or fecal calprotectin levels of <40 mcg/g confer a ≤1% risk of inflammatory bowel disease in patients with typical IBS symptoms [5,130]. However, inflammatory bowel disease was found to develop two to three years after initial IBS diagnosis at rates far exceeding population norms, despite negative colonoscopy findings [31].

The American Gastroenterological Association (AGA) recommends that either calprotectin or fecal lactoferrin and C-reactive protein be checked in patients without alarm features and with suspected IBS and diarrhea symptoms to rule out inflammatory bowel disease [220]. If inflammatory markers are mildly elevated but the probability of inflammatory bowel disease is low, testing should be repeated before performing colonoscopy (unless other indications for colonoscopy are present). Inflammatory markers are not useful in patients with constipation-predominant symptoms.

Giardiasis

Giardia is a relatively common enteric parasitic infection that causes subacute-to-chronic watery diarrhea often accompanied by bloating, urgency, and excess flatulence. Infection is acquired from contaminated water sources in geographic regions scattered throughout the United States. Fluctuating symptoms and chronicity are common, leading to psychological stress and social disruptions not unlike that experienced by patients with IBS. Examination of stool for the parasite has variable sensitivity, but stool tests that rely on detection of Giardia antigen or subunit ribosomal RNA are highly sensitive and specific. This is a curable cause of GI symptoms, as the condition can be easily and effectively treated.

Bile Acids Diarrhea

As noted, perfusion of bile acids into the colon stimulates water and electrolyte secretion and accelerates transit. Evidence of bile acid malabsorption may be present in up to 33% of patients with IBS-D symptoms. Clinicians can empirically assess for bile acid malabsorption by initiating a bile acid sequestrant trial. Several tests can identify such malabsorption but are not widely available in the United States [5,92].

Dyssynergic Defecation

Dyssynergic defecation is an under-recognized, constipation-associated condition characterized by an inability to coordinate abdominal wall, anal sphincter, and pelvic floor muscles for normal defecation. Symptoms are non-specific and include abdominal pain, discomfort, and bloating. Intervention with biofeedback can improve bowel and abdominal symptoms. Thus, patients with medically refractory IBS-C symptoms should be referred to a specialist for evaluation of dyssynergia by digital rectal examination, anorectal manometry, balloon expulsion testing, or anorectal imaging [131,132,133].

There is no specific laboratory test that defines the presence of IBS; laboratory evaluation is used selectively to screen for other disorders in the differential diagnosis, principally in patients with IBS-D. In 2019, the AGA published a guideline to aid clinicians in choosing appropriate laboratory tests to exclude other diagnoses in the patient with functional diarrhea and IBS-D [209]. This guideline is applicable for the typical patient with chronic "watery" diarrhea of at least six weeks' duration, and is not intended to guide the evaluation of patients with a more complicated clinical profile, such as bloody diarrhea, recent foreign travel to regions endemic for enteric pathogens, or family history of inflammatory bowel disease or cancer. The AGA recommendations for laboratory testing in patients presenting with chronic diarrhea (IBS-D) are [209]:

The AGA suggests against the use of erythrocyte sedimentation rate or C-reactive protein to screen for inflammatory bowel disease and against testing for ova and parasites (other than Giardia) if there is no travel history or recent immigration from high-risk areas [209].

On initial evaluation, most patients with IBS should have a complete blood count to rule out anemia or screen for systemic signs of infection. In the absence of alarm symptoms or suspicion of abnormalities that other laboratory testing can confirm, no other testing is needed for diagnosis. However, the presence of alarm criteria requires further testing specific to the index alarm finding—colonoscopy in most cases [3,44].

Colonoscopy is indicated in the presence of alarm symptoms, family history of colorectal cancer, or persistent diarrhea that has failed empiric therapy. Biopsies of different segments of the colon may be required in patients with chronic diarrhea to rule out microscopic colitis. Colorectal cancer screening colonoscopy is indicated in patients 50 years of age or older (or 45 years of age or older in African Americans) in the absence of warning signs based on national recommendations.

With failure of empiric therapy, other diagnostic options in limited use include [3]:

Breath tests to rule out carbohydrate malabsorption may be useful in some patients with IBS symptoms and persistent diarrhea.

Concerning features that may suggest organic disease require assessment. Although the presence of these features may identify patients with organic disease, most will have negative evaluation findings, and concerning features are valuable for their negative (not positive) predictive value. IBS can be confidently diagnosed in patients who meet symptom-based criteria and lack concerning features, because extensive diagnostic testing is infrequently positive. However, the perspective of IBS as a diagnosis of exclusion remains widespread, and many healthcare professionals are uncomfortable relying solely on symptom-based criteria for its diagnosis [5,134].

Alarm criteria requiring further testing to rule out organicity include [3,44]:

Additional signs and symptoms that may suggest organicity are:

As discussed, psychosocial factors influence physiologic functioning of the GI tract (including motility, sensitivity, and barrier function), mediate pain experience and symptom behavior of the patient, and impact treatment selection and clinical outcome [15]. This makes psychosocial assessment a vital part of the evaluation of patients with IBS symptoms.

Primary care clinicians and gastroenterologists can use psychosocial screening to identify patients at risk for refractory symptoms, poor treatment response, or low quality of life. When overt psychopathology or moderate-to-severe symptoms are absent, visceral-specific anxiety, catastrophizing, somatization, and quality of life can be assessed to determine if comprehensive evaluation by a health psychologist or psychiatrist is indicated [55].

Clinicians should consider a brief psychosocial assessment for each patient with functional GI disorder, with the precondition that a satisfactory patient-clinician relationship is established earlier in the evaluation. A few specific questions on key psychosocial processes can be woven into routine history taking. If a patient asks about the relevance of this inquiry, a truthful response is, "I always ask my patients these questions as part of my initial assessment—it helps me determine the best way to help. The items may or may not apply to you." This psychosocial assessment will only be satisfactory if the patient is able to speak freely, which requires privacy, a lack of judgment or stigma, and sufficient time. Sensitive areas of discussion include abuse history, depressed mood, possible suicidal thoughts, and the nature of intimate relationships. These may require a second appointment for a full assessment.

The clinician should provide feedback about results of the overall evaluation and discuss treatment options, which can include medical and psychosocial approaches [55]. Consider referring patients with severe symptoms, previous treatment failure, poor treatment adherence, or marked disability to a clinician with special training in psychosocial assessment [55].

When a plausible explanation for a change in symptoms or treatment response in patients with an established IBS diagnosis is lacking, it is important to assess for an underlying causal condition. Following a new physical examination, time since the last diagnostic workup should be considered. Changes in epidemiologic characteristics of the family should be assessed and recorded. IBS can include phases where symptom severity changes, and patients may perceive they have an inadequately explored organic disease. With these considerations, additional diagnostic testing should generally be limited to the presence of alarm symptoms or signs [44].

Healthcare professionals who repeatedly perform unnecessary diagnostic studies to rule out pathologic disease, dismiss patient concerns, or do not collaborate effectively in patient care can promote a vicious cycle of symptom anxiety and health care seeking [2]. Effective provider-patient relationships can improve patient satisfaction, treatment adherence, symptom reduction, and other health outcomes. General guidelines can help optimize this relationship with patients with IBS [2]. Patient satisfaction is based on a perception of healthcare providers' humaneness, technical competence, interest in psychosocial factors, and provision of relevant health information; over-emphasis on biomedical issues can have a negative effect. In addition to verbal communication, engagement involves nonverbal communication such as good eye contact, affirmative nods, a gentle tone of voice, close interpersonal distance, and creation of a partner-like interaction.

It is important to conduct the patient history using a nondirective, nonjudgmental, patient-centered approach. This involves active listening and asking questions based on the patient's thoughts, feelings, and experiences, instead of a preset agenda of questions. A good first step is to inquire regarding the reason for the appointment. Immediate reasons for a patient's visit may include [135]:

The next step is a careful physical examination and investigation. Although this obviously assists in diagnosis and assessment of new complaints, a well-conducted physical examination itself has therapeutic value [136].

In the course of clinical assessment, it is important to pay attention to patient concerns and understanding of their illness and to provide an explanation of the disorder that takes into consideration the patient's own perspective and beliefs about their condition. When plausible, one should point out the link between stressors and symptoms consistent with patient's views. Many patients are unable or unwilling to associate stressors with illness, but most understand the impact of illness-related stress on their emotional state.

Patients should be given therapeutic options and be involved in treatment decision-making. When possible, treatment recommendations should be consistent with patient interests. Identifying and responding realistically to the patient's expectations for improvement can strengthen rapport. However, it is also important to set consistent limits, especially as related to pain management and opioid use.

Finally, patients should be reassured that care will continue and that they should expect an ongoing relationship. It can help to let patients know that many treatment options can be explored to help control IBS.

Adherence is essential for the effectiveness of prescribed therapy, including dietary measures, lifestyle changes, and pharmacotherapy. A therapy regimen alone is often insufficient unless the patient understands and accepts the approach and agrees to follow it. This highlights the importance of a trust-based therapeutic relationship that promotes cooperation and empowers patient participation in decision-making and responsibility for self-care [44].

In addition to consideration of best-available therapeutic options, the following measures can facilitate patient engagement and adherence [44]:

The importance of regularity should be stressed for constipation management. Some patients only use medication intermittently for exacerbations, which is less effective. Other patients avoid laxatives altogether due to false beliefs that laxatives induce dependence or may be ultimately dangerous. 


Most patients with IBS are aware that their gastrointestinal symptoms are precipitated or made worse by eating certain foods. In 2022, the AGA published a clinical practice update on the role of diet in IBS management based on mounting evidence supporting diet modifications as a primary treatment for IBS symptoms [215]. To optimize patient education and clinical response, the AGA recommends referral to a registered dietician nutritionist for patients willing to collaborate and for patients who are not able to implement beneficial dietary changes on their own. Patients should attempt specific IBS diet interventions for a predetermined length of time (e.g., –four to six weeks); if there is no clinical response, the diet intervention should be abandoned in favor of another treatment alternative (e.g., different diet, medication, other mode of therapy) [215].

Dietary and Supplemental Fiber

Dietary fiber supplementation has long been the foundation of treatment in all patients with IBS, and IBS guidelines have consistently recommended dietary fiber by increasing fiber-rich foods or adding soluble fiber (usually Psyllium seed, but polycarbophil compounds may produce less flatulence) [44,118]. Soluble fiber is found in psyllium, corn fiber, calcium polycarbophil, methylcellulose, oat bran, and the flesh of fruits and vegetables; insoluble fiber is found in wheat bran, whole grains, and fruit and vegetable skins and seeds [215]. Guidelines recommend the use of soluble (but not insoluble) fiber for the treatment and improvement of global IBS symptoms. This recommendation is based on a systematic review and meta-analysis of 15 randomized controlled trials showing that soluble fiber may benefit patients with IBS, while causing only minor adverse effects [215].

While evidence indicates that poorly fermentable, soluble fiber has modest benefits in reducing global IBS symptoms in patients with IBS-C with mild constipation, insoluble fiber may worsen abdominal pain and distension and has little benefit in patients with IBS-D. Wheat bran, in particular, can exacerbate problems of abdominal distention, abdominal pain, and flatulence and should be avoided [3,5,44]. If fiber is indicated, initiate soluble fiber at a very low dose and gradually increase to total daily intake of 20–30 g [5].

Gluten Restriction

Dietary restriction of gluten may improve symptoms in some patients with IBS. Two small prospective studies in patients with IBS, in which celiac disease was carefully excluded, demonstrated global symptom improvement [97,98].

Dietary FODMAP Restriction

Numerous short-chain carbohydrates, including lactose, fructose, and polyols, can provoke IBS symptoms [84,143,144]. These short-chain fermentable carbohydrates are collectively termed FODMAPs, and there is direct evidence (using magnetic resonance imaging) that some FODMAPs may induce IBS symptoms via increased small bowel water content or increased colonic gas production [84,143,144].

FODMAPs promote poor absorption in the small bowel and rapid fermentation in the colon. FODMAP is an acronym for [87]:

The most common sources of FODMAPs in the western diet are wheat, onions, fruit in which fructose exceeds glucose (e.g., apples, pears), and processed food. Dairy products are important in those with lactose malabsorption.

True lactose intolerance may induce IBS-like symptoms, but only with relatively high lactose loads (20 g) that are easily avoidable. Psychological factors have a major influence on symptomatic responses to lactose intake [145,146].

Fructose is a monosaccharide abundantly present in many processed foods. The small bowel has a relatively limited absorptive capacity that particularly affects free fructose—the fraction in excess of the glucose that facilitates fructose absorption. High fructose loading can induce symptoms even in healthy individuals.

Polyols such as sorbitol, mannitol, and xylitol are naturally present in many fruits and vegetables and are added as artificial sweeteners to processed food products and pharmaceuticals. Polyols tend to induce bowel discharges from their stimulant effect on intestinal motility.

Dietary FODMAP restriction is associated with reduced fermentation and significant symptom improvement in some patients with IBS. In a randomized, controlled, single-blind cross-over trial, patients with IBS who had not previously tried dietary manipulation reported significant reduction in overall GI symptom scores compared with those on a standard Australian diet [87]. The complexity of the FODMAP diet makes implementation difficult, but this may be overcome by excluding only the major sources of FODMAPs (e.g., wheat, onions, dairy), avoiding processed food, and not focusing on items with small specific contribution [87]. Adding a gluten-free diet to patients with IBS already on a low FODMAP diet does not appear to offer additional benefit [147,148,149]. The AGA 2022 guideline recommends the low-FODMAP diet as the most evidence-based diet intervention for IBS [215].

Probiotics

Manipulation of intestinal microbiota has promise as a potential therapy for gut dysbiosis to ameliorate symptoms of IBS and restore health. The concept of probiotics is more than 100 years old, and modern research methods are establishing empiric support for the perceived benefits of probiotic bacteria, which mainly include Lactobacillus and Bifidobacterium species [150].

Probiotics have been generally defined as live micro-organisms that upon ingestion in specific and sufficient numbers confer unspecified health benefits to the host [216]. Selection is based on ability to survive in the GI tract, adhere to intestinal epithelium, and modulate intestinal flora. Potential benefits attributed to probiotics include improved general gut health; prevention of intestinal overgrowth and translocation (infection) of gut pathogenic bacteria; modulation or stimulation of immune responsiveness via immune cell proliferation; enhanced phagocyte activity; and increased production of immunoglobulin A [44,151].

The reported potential benefit of probiotics in managing IBS could occur through multiple mechanisms. Bifidobacterium infantis 35624 led to significant improvements in abdominal pain/discomfort, bloating/distention, and/or bowel movement difficulty (vs. placebo) in two randomized controlled trials of patients with IBS [152,153]. A 2016 meta-analysis that included 43 clinical trials using different products found probiotics to offer benefits for global IBS symptoms, pain, bloating, and flatulence. However, the reliability of these findings is limited by the variability of IBS diagnostic criteria and symptom measurement methods in published randomized controlled trials [154]. Despite growing scientific and commercial interest, studies assessing probiotics for the treatment of IBS and other GI disorders have been varied, including differences in the strain and dose of microbes used, as well as the research methodology and differences in reporting of end points and outcomes [216].

In 2020, the AGA published guidelines on the use of probiotics for several gastrointestinal disorders, including IBS. After reviewing a total of 76 randomized controlled trials that used 44 different probiotic strains or combination of strains, the AGA made no recommendations for the use of probiotics in children and adults with IBS. The review found that many studies examining this question are marked by significant heterogeneity in study design, outcome, and probiotics used [217].

Prebiotics/Symbiotics

Prebiotics are food products that promote proliferation of bifidobacteria and other species potentially associated with anti-inflammatory effects (e.g., oligofructose, inulin, galacto-oligosaccharides, lactulose, breast milk oligosaccharides). Prebiotics do not seem particularly effective in IBS, possibly due to fermentation products that may themselves stimulate IBS symptoms. Trials for prebiotics are few in number, and no definite conclusions can be drawn [84].

Symbiotics aim to simultaneously produce synergic pro- and prebiotic effects, but evidence has not substantiated their theoretical benefits in IBS. Further evidence is required to establish the role of prebiotics or synbiotics in IBS [84].

CBT refers to a family of psychological treatments rather than a specific technique. CBT is derived from behavior theories that focus on learning processes and cognitive theories that emphasize faulty cognitions or thinking processes. These same learning processes are used to help patients gain control and reduce symptoms of IBS. Cognitive theory views external events, cognitions, and behavior as interactive and bidirectional, with primary emphasis on how patients process information about their environment, self, and the future. Cognitive factors, especially the way people interpret or think about stressful events, can intensify the impact of events on patient response. Emotional, physiologic, and behavioral responses to life events will be problematic to the extent that thought processes are faulty. Clinically modifying patient thinking can change behavior and emotional and physical well-being. Cognitive changes can occur by teaching patients to systematically identify cognitive errors generated by automatic thinking, or by providing experiential learning that systematically exposes patients to the situations that cause discomfort [55,157].

Unlike traditional, insight-oriented "talk therapy," which identifies the root causes of a problem, CBT focuses on teaching people how to control their current problems by identifying the thoughts and behaviors that are maintaining them. CBT requires active patient participation during and between sessions and patient responsibility for learning symptom self-management skills. With IBS, CBT can include a combination of techniques such as self-monitoring, cognitive restructuring, problem solving, exposure, and relaxation methods [55].

Self-Monitoring

Self-monitoring is the ongoing, real-time recording of problem behaviors. In IBS, the focus of self-monitoring is internal and external triggers and the thoughts, somatic sensations, and feelings that usually accompany flare-ups. Self-monitoring provides clinically relevant information with which to structure treatment and serves as a useful therapeutic strategy by increasing patient awareness of triggers and contributing factors [55].

Cognitive Strategies

Cognitive strategies are designed to modify thinking errors that bias information processing (e.g., tendencies to overestimate risk and magnitude of threat or underestimate one's ability to cope with adversity). These self-defeating beliefs are clinically important because they are believed to moderate excessive stress experiences. Negative beliefs are identified, and the patient works with the healthcare provider to challenge and dispute them. This involves examining the accuracy of beliefs in light of available evidence and replacing biased beliefs with more logical and constructive cognitions [55].

Problem Solving

Problem solving refers to an ability to define problems, identify solutions, and verify their effectiveness once implemented. The intervention is rooted in the problem-solving model of stress, which acknowledges that a causal relationship exists between health and stressors. Using this model, the health or mental health professional teaches patients how to effectively apply the steps of problem solving to actively cope with stress [55,158].

Relaxation Procedures

Various relaxation techniques are effective in managing IBS symptoms, and relaxation procedures have long been a staple of psychological treatments for functional GI disorders. These techniques, including progressive muscle relaxation, breath work, and meditation, are designed to directly modify autonomic arousal believed to aggravate GI symptoms [159].

Progressive muscle relaxation training involves systematically tensing and relaxing selected muscle groups throughout the body, from forehead to feet. This exercise helps patients dampen physiologic arousal and achieve a sense of mastery of physiologic self-control over previously uncontrollable and unpredictable symptoms [55,160].

In breathing retraining, the patient is taught to take slow, deep breaths and focus on bodily sensations during exhalation. This technique is based on the idea that patients with stress-related physical ailments develop inefficient respiratory patterns (e.g., shallow chest breathing), which, if chronic, can intensify physiologic arousal and increase somatic complaints [55,161].

Meditation is a self-directed practice that can emphasize focused breathing and mindfulness. Mindfulness is defined as purposefully paying attention in the moment without judgement. This nonjudgmental acceptance of thought processes allows the practitioner to achieve a state of calmness, physical relaxation, and psychological balance. In mindfulness meditation for IBS, the patient disengages him/herself from the ruminative thoughts considered core aspects of pain and suffering by developing a nonreactive, objective, present-focused approach to internal experiences and external events as they occur [55,162]. Small studies have indicated that engagement in a mindfulness-based stress reduction program can ameliorate IBS symptoms, reduce stress, and improve patients' quality of life, with continued improvements evident after six months [163].

Hypnosis

In hypnosis, a therapist typically induces a trance-like state of deep relaxation and/or concentration using strategically worded verbal cues suggestive of changes in sensations, perceptions, thoughts, or behavior. Most hypnotic suggestions are designed to elicit feelings of improved relaxation, calmness, and well-being. Hypnotic suggestions in IBS are "gut directed," meaning suggestions are conveyed that are incompatible with aversive visceral sensation. Hypnosis might include a suggestion to feel a sense of warmth and comfort spreading throughout the abdominal area [55,164]. Hypnosis has shown some benefit in decreasing IBS symptoms in adults [165].

Exposure Therapy

Exposure therapy is designed to reduce catastrophic beliefs about IBS symptoms, hypervigilance for IBS symptoms, fear of IBS symptoms, and/or excessive avoidance of unpleasant visceral sensations or situations by helping patients confront maladaptive thoughts and beliefs in a systematic manner. Exposure can include interoceptive cue exposure (i.e., the patient repeatedly provokes unpleasant sensations) or situational/in vivo exposure (i.e., feared situations or activities are confronted). Through exposure treatments, patients learn the stimuli that led to fear and avoidance are neither dangerous nor intolerable and that fear will subside without resorting to avoidance, a behavior that reinforces fear and hypervigilance in the long-term [166,167]. In an experimental study of 13 patients with IBS, 70% improved on measures of GI symptoms, pain catastrophizing, and quality of life following 12 sessions of exposure therapy [168].

Efficacy of Psychological Treatments

Periodic meta-analyses conducted over the past two decades have consistently demonstrated that psychological therapies, as a class of treatments, are at least moderately effective for relieving symptoms of IBS when compared with a pooled group of control conditions. The Internet has been used as a treatment delivery platform to give a larger proportion of patients with functional GI disorder access to, and engagement in, therapy than would have been feasible through clinic-based treatment alone [169,170,171].

A 2016 meta-analysis investigated the duration of sustained benefit gained from psychological therapy in reducing GI symptoms in patients with IBS. Forty-one trials recording data from 2,290 subjects (1,183 assigned to therapy, 1,107 assigned to a control condition) were analyzed. Compared with a mixed group of control conditions, psychological therapies had a medium size effect on reducing GI symptom severity immediately after treatment. On average, subjects receiving psychotherapy had greater post-therapy reduction in GI symptoms than individuals assigned to a control condition. After short-term follow-up (1 to 6 months after treatment) and long-term follow-up (6 to 12 months after treatment), this beneficial effect remained significant and medium in magnitude [172].

For the most part, the efficacy of psychological therapies for IBS has been demonstrated from studies conducted as freestanding clinical trials; less clear is the effectiveness of psychotherapy approaches within the context of general clinical practice. To assess this further, a systematic review was made of the types and effects of psychological treatments for IBS conducted in gastroenterology clinic settings. In an analysis of seven eligible studies comparing psychological treatments to controls, IBS symptoms improved significantly among patients in cognitive and behavioral therapies, mindfulness-based stress reduction, guided affective imagery, and emotional awareness training [210].

The choice of antidepressant agent is determined by the patient's predominant symptoms, disease severity, presence of comorbid anxiety or depression, prior experience with medications in the same class, and patient and prescriber preference. The three broad antidepressant classes most often used in IBS are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-noradrenalin reuptake inhibitors (SNRIs) [55].

Tricyclic Antidepressants

TCAs such as amitriptyline, imipramine, desipramine, doxepin, and trimipramine are the most widely used psychotropic agents for treating neuropathic (e.g., postherpetic neuralgia, diabetic neuropathy) and functional (e.g., fibromyalgia) pain syndromes. Their analgesic effect is thought to be independent of antidepressant mechanisms and effects because TCAs can benefit patients with diverse pain syndromes in whom psychopathology is modest or absent and because they are often effective for pain at low (sub-psychiatric) doses [106,175,176].

In general, TCAs are the first antidepressant choice for pain in non-constipated patients with IBS due to their dual mechanism of action (serotonin and norepinephrine reuptake inhibition). Nortriptyline or desipramine is better tolerated than amitriptyline or imipramine due to fewer anti-histaminergic and anti-cholinergic effects. The usual starting dose is 25–50 mg at night and can be titrated up as needed up to about 150 mg/day, while carefully monitoring side effects and/or blood levels. Typically, lower doses than the full antidepressant dose are effective for visceral pain if no psychiatric comorbidity is present [55].

In one study, amitriptyline 10 mg/day in patients with IBS-D significantly improved overall IBS symptoms, reduced frequency of loose stool and feelings of incomplete defecation, and led to complete response (remission) in some [165,177].

SSRIs

SSRIs are less effective for pain and are less commonly prescribed as monotherapy for IBS. Review papers have arrived at different conclusions concerning SSRI utility in IBS treatment, with some authors concluding no convincing evidence has been reported for functional GI disorders and others reporting beneficial effects for overall IBS symptoms [3,93,165].

The American Gastroenterological Association (AGA) suggests against using selective serotonin reuptake inhibitors for patients with IBS.

(https://www.gastrojournal.org/article/S0016-5085(22)00391-2/fulltext Last Accessed: November 18, 2022)

Strength of Recommendation/Level of Evidence: Conditional recommendation/low-quality evidence

However, SSRIs are considered useful in patients with high levels of anxiety that contribute directly to IBS exacerbations and symptom severity. SSRIs and SNRIs have a more narrow therapeutic range, and therefore, the doses used for the treatment of pain are closer to the doses used for mood and anxiety disorders. Starting doses are usually within the lower range of the psychiatric dose (e.g., citalopram 20 mg or duloxetine 30 mg) and titrated up as needed [173,174,178].

A systematic review of SSRIs found benefits over placebo for overall IBS symptoms. Several clinical characteristics, including the predominant stool complaint, presence of insomnia, or comorbid anxiety, can influence antidepressant selection for individual patients with IBS [165].

SNRIs and Other Psychotropics

For SNRIs, especially venlafaxine, higher doses (≥225 mg) are usually required to attain effective analgesia because the noradrenergic mechanism of action is only evident at these doses. If nausea and weight loss are concerns, the addition of a low dose (15–30 mg) of mirtazapine can be helpful.

Atypical antipsychotics, such as quetiapine, are only recommended for patients with severe, refractory IBS, especially if severe anxiety and sleep disturbances are also present and the patient has failed to respond to other centrally acting agents. A low starting dose of 25–50 mg is recommended and can be titrated up as required [173,174].

Augmentation, or the use of a combination of drugs from different classes in submaximal doses instead of one drug at a maximal dose, is common in psychiatry and is increasingly used in the treatment of functional GI disorders. Examples of augmentation include adding buspirone to an SSRI, TCA, or SNRI to enhance therapeutic effect, or adding a low-dose antipsychotic (e.g., quetiapine) to a TCA or SNRI to reduce pain and anxiety and improve sleep. If there is a component of abdominal wall pain associated with the GI pain, pregabalin or gabapentin can be added to a TCA or SNRI [173,174].

Combination Antidepressant and Psychological Treatment

Combining antidepressants with psychological therapy can be an effective augmentation strategy. Antidepressants can improve pain and vegetative depression symptoms, and psychological therapy improves higher cortical functioning, including coping, reappraising maladaptive cognitions, and adapting to previous losses and trauma. Psychotherapy can optimize medication adherence, while antidepressants can sufficiently increase physical and psychic energy to improve the level of engagement in therapy. The difference in effect size with combined treatment can exceed 50% compared to either treatment alone [106,179,180,181].

Although drugs work faster and are readily available, psychological treatments have several advantages. They are safe and effective, their effects persist beyond the duration of the treatment, and they may be more cost-effective. Potential barriers to the use of psychological approaches in the treatment of IBS are a longer treatment duration, the need for patient motivation, and limited availability and access to a mental health professional trained in IBS treatment [55,182].

Careful patient selection, initiation at a low dose with gradual escalation, monitoring for side effects, and a good patient-clinician relationship are important for medication adherence and, by extension, therapeutic response. In particular, eliciting and addressing any potential concerns/barriers to taking psychotropic medications for IBS, discussing potential side effects, setting realistic expectations, and involving the patient in decision making result in improved adherence [55,174].

Loperamide is a synthetic, peripheral-acting mu opioid receptor agonist with limited ability to penetrate the blood-brain barrier (and therefore limited abuse potential). It decreases peristaltic activity, inhibits secretion, increases water and ion absorption, reduces colonic transit, and increases resting anal sphincter tone. This results in reduced fluid and electrolyte loss and improved stool consistency [93,183]. Loperamide is available over the counter.

Diphenoxylate is another mu opioid receptor agonist, but unlike loperamide, it can cross the blood-brain barrier and is therefore combined with atropine to reduce abuse potential. Both of these agents are effective in reducing diarrhea in general, but research for the treatment of IBS-D is not well developed [93].

Several small randomized controlled trials of loperamide in IBS-D have shown reduced bowel frequency and improvements in stool consistency, urgency, and subjective overall response. Pain outcomes were mixed, with reduced pain intensity or increased nightly abdominal pain both reported in separate trials [3,183]. However, loperamide may improve quality of life by allowing the planning of trips and socializing, which anxious patients with IBS-D often avoid for fear of fecal urgency or even incontinence [87].

Adverse effects with loperamide or diphenoxylate are rare, but include bladder dysfunction, glaucoma, and tachycardia. These may be more likely with diphenoxylate due to the atropine constituent [93].

As discussed, the underlying pathophysiology in some patients with IBS-D is bile acid perfusion into the colon, and bile acid sequestrants are used as treatment for these patients. Cholestyramine is the agent generally considered first-line treatment for IBS-D with bile acid diarrhea [3,183]. Other options include colesevelam and colestipol. Cholestyramine granules are often poorly tolerated due to poor taste and adherence to the teeth [93].

Antibiotics have traditionally been used as adjunctive IBS treatment. However, they are associated with systemic side effects, and there are concerns of promoting antibiotic-resistant microbes [184].

Rifaximin is a synthetic antibiotic derived from rifamycin and has anti-microbial activity against Gram-positive, Gram-negative, aerobic, and anaerobic bacteria. It is not absorbed by the intestinal mucosa, allowing intraluminal activity without systemic circulation and effects [185]. Rifaximin targets the GI tract to reduce gas-producing bacteria and alter the predominant bacterial species; it may also reduce mucosal inflammation and visceral hypersensitivity [93].

The AGA suggests using rifaximin (over no drug treatment) in patients with IBS-D.

(https://www.gastrojournal.org/article/S0016-5085(22)00391-2/fulltext Last Accessed: November 18, 2022)

Strength of Recommendation/Level of Evidence: Conditional recommendation/moderate-quality evidence

In 2015, rifaximin was approved by the FDA for the treatment of IBS-D in adults [93]. Clinical trials have demonstrated that rifaximin improved IBS-associated symptoms of bloating, flatulence, stool consistency, and abdominal pain. The drug showed a side-effect profile similar to placebo. Some patients experience relief of IBS symptoms after a course of rifaximin, while others require retreatment at the same dosage [184,186]. Improvement in symptoms relative to placebo showed a gradual reduction over time, but significant improvement persisted for 10 weeks after the treatment course [3]. The usual dosage is 550 mg three times per day for 14 days [93].

Clinical experience suggests that many rifaximin responders eventually develop recurrent IBS symptoms. Data from re-treatment patients suggest that second and third courses produce efficacy similar to the initial course. The role of other antibiotics in IBS treatment remains unknown, but antimicrobial resistance with repeated courses of systemically absorbed antibiotics is a concern [5]. Overall, rifaximin appears to be safe and beneficial as a management option for IBS-D, although optimal dosing and treatment duration and potential resistance require further study [184,186].

Serotonin (5-HT) plays an important physiologic and pathophysiologic role in regulating GI function [187]. As such, 5-HT3 receptor antagonists (5-HT3RAs) can be effective treatment for IBS-D by slowing transit, reducing bowel frequency, normalizing stool consistency, and reducing urgency—a key symptom that impairs quality of life in patients with IBS-D [87].

Randomized controlled trials have found the potent, selective 5-HT3RAs alosetron and cilansetron may be effective in the treatment of IBS-D. However, alosetron was voluntarily withdrawn due to postmarketing reports of ischemic colitis (a potentially serious class-wide adverse event) and complications of constipation, while cilansetron was never marketed [187]. Alosetron was subsequently reintroduced to market and is currently available for women with severe IBS-D refractory to conventional therapy under an FDA Risk Evaluation and Mitigation Strategy program [188]. Alosetron is effective at relieving pain and reducing stool frequency and rectal urgency in women with IBS-D [3].

The 5-HT3RA ramosetron has also been studied as IBS-D therapy but has not received FDA approval. Ramosetron reduces defecation induced by corticotropin-releasing hormone and inhibited colonic nociception in preclinical studies. In randomized controlled trials of patients with IBS-D, ramosetron increased patient rates of global IBS symptom relief. In trials limited to male patients with IBS-D, ramosetron was as effective as mebeverine (an agent approved outside the United States) in improving stool consistency, relieving abdominal pain/discomfort, and improving health-related quality of life. Ramosetron shows a lower incidence of constipation versus other 5-HT3RAs and has not been associated with ischemic colitis [187]. In data stratified by sex, women reported significant relief of IBS symptoms only after two months, while men reported significant relief of IBS symptoms at all time points. Reasons for these differences are unknown [21].

The much less potent 5-HT3RA ondansetron (4 mg/day, range 2–6 mg/day) has also been found highly effective at improving stool consistency, reducing stool frequency, and reducing urgency. In one study, 70% with ondansetron (versus 16% with placebo) reported adequate IBS-D symptom relief. Worth noting is that ondansetron has been used for more than two decades without reports of ischemic colitis and has an excellent safety record; these features are important for IBS therapy selection [87].

Eluxadoline was approved in 2015 for IBS-D treatment in adults. This drug has therapeutic activity as a mixed mu-opioid receptor agonist and delta-opioid receptor antagonist, a novel mechanism of action developed to control GI function and decrease GI pain while mitigating the constipating effects of unopposed mu receptor agonist activity [21,87].

FDA approval of eluxadoline was based on two multi-center, multi-national randomized controlled trials with 2,426 patients with IBS-D receiving twice-daily eluxadoline (75 mg or 100 mg) or placebo for 26 weeks. Therapeutic response was defined as concurrent improvement in diarrhea (using the BSFS) and abdominal pain. In both trials, the proportion of patients with reduced abdominal pain and improved stool consistency was significantly higher with eluxadoline than placebo, at both doses. Eluxadoline reduced IBS-D symptoms in men and women, and efficacy was sustained over six months with the 100-mg, twice daily dose. The most common adverse events were nausea (8%), constipation (8%), and abdominal pain (5.0%) [189,190].

A small but definite risk (0.3%) of acute pancreatitis resulted from sphincter of Oddi spasm; all patients who developed this adverse effect had a history of cholecystectomy or significant ethanol consumption. According to the 2022 AGA guidelines, eluxadoline is contraindicated in patients without a gall bladder or those who drink more than three alcoholic beverages per day [218].

In patients with IBS-D, jejunal mucosal biopsies have shown mast cell activation and hyperplasia, providing the theoretical basis for possible benefits with mast cell stabilizers [191]. Disodium cromoglycate and ketotifen act primarily by stabilizing the plasma membrane of mast cells and have been evaluated in the treatment of IBS-D [93].

In a six-month trial of disodium cromoglycate for IBS-D, jejunal biopsies showed reduced release of tryptase and reduced expression of toll-like receptor 2 and 4, and patients showed clinical improvement of bowel function [192]. In an earlier trial of patients with IBS-D with food intolerance, disodium cromoglycate (250 mg, four times per day) plus exclusion diet was associated with prolonged symptomatic benefit compared with exclusion diet alone [193,194].

Ketotifen is a mast cell stabilizer with antihistamine properties that showed substantial improvement in patients with IBS despite no effect on mast cell parameters [195]. Further research suggests the effects mediated by histamine-blocking properties, and ketotifen may also be used in the treatment of abdominal pain-predominant IBS.

Muscarinic type 3 (M3) receptor antagonists have beneficial effects in chronic diarrhea that include delayed small bowel and colonic transit, reduced rectal sensitivity, and reduced enterocyte secretion [93]. Preliminary evidence suggests greatest benefit with otilonium in IBS-D, with benefits shown in increased sensory thresholds to colonic volume and pressure, and reduction in abdominal pain [93,196]. Otilonium is investigational in the United States.

Patients with IBS-D have increased gut permeability, and symptomatic patients with IBS have decreased intestinal glutamine synthetase levels. In a preliminary report of a placebo-controlled trial of 10 g glutamine three times per day in 61 patients, the glutamine arm was associated with improved abdominal pain, bloating, and diarrhea and restored intestinal permeability [93,197].

During clinical development, rifaximin and eluxadoline demonstrated significant improvement in IBS-D endpoints versus placebo. In the absence of comparative randomized controlled trials, direct comparisons of alosetron, rifaximin, and eluxadoline efficacy cannot be made, but general efficacy estimates suggest similar and responses using outcome measures of adequate relief and combined improvements in abdominal pain/stool form. Clinical use of these agents is suggested to follow a sequential scheme that considers patient symptoms and severity, prior medical history, mode of action, cost, availability, managed care coverage, and adverse event profiles [198]. The AGA guideline on the pharmacologic management of IBS-D recommends that selection of medication should be individualized, taking into account the dominant clinical features and individual patient's needs and preferences. A decision tool is offered based on a tiered approach, as follows [218]:

If abdominal pain persists and/or psychological symptoms supervene, the AGA recommends adding (or switching) to low-dose TCA or SNRI and/or brain-gut behavior therapies (e.g., CBT, hypnosis) [218].

Osmotic laxatives contain nonabsorbable ions or molecules that retain water in the bowel lumen. Polyethylene glycol (PEG), lactulose, and magnesium salts are most commonly used. Osmotic laxatives are generally useful to treat constipation but can promote or worsen abdominal pain and distension in IBS and are not recommended [44].

Stimulant laxatives promote water and electrolyte secretion in the colon or induce colonic peristalsis. They include diphenylmethanes (phenolphthalein, bisacodyl, sodium picosulfate) and anthraquinones (Senna, bearberry, Aloe vera). While useful for constipation, they can worsen abdominal pain and distension in patients with IBS [44]. In patients with IBS-C, a randomized controlled trial of PEG vs. placebo found stool frequency, stool consistency, and straining were improved, but abdominal pain and bloating were unimproved during the four-week study [142].

Secretagogues act through different pharmacologic mechanisms to stimulate chloride release into the intestinal lumen, which stimulates intestinal fluid secretion to counteract constipation symptoms in IBS-C [200]. The most commonly used agents are lubiprostone and linaclotide.

Lubiprostone

Lubiprostone is a prostaglandin-derived fatty acid that activates intraluminal chloride channels and chloride ion secretion. This leads to a passive influx of water and sodium, which increases intestinal peristalsis and colonic laxation and decreases intestinal stool transit time. Lubiprostone does not affect pain thresholds during rectal distension [5,87].

In patients with IBS-C, lubiprostone has proven effective in reducing constipation symptoms, but reduction of abdominal pain is much more modest (7% greater than placebo) and generally develops after one month of therapy. Side effects mostly involve mild-to-moderate nausea and diarrhea, and lubiprostone should be taken with food to limit dose-dependent nausea [3,5].

Lubiprostone is approved for the treatment of chronic constipation and opioid-induced constipation for men and women at 24 mcg twice daily, and for IBS-C in women at 8 mcg twice daily. No dosage adjustment is required in patients with impaired renal function [44]. Additional research may expand its clinical use [87,199].

Linaclotide

Linaclotide binds and activates guanylate cyclase C (GC-C) receptors expressed locally on the luminal surface of intestinal epithelium. GC-C receptor activation increases cyclic guanosine monophosphate concentrations, which activates the cystic fibrosis transmembrane conductance regulator to stimulate secretion of chloride and bicarbonate into the intestinal lumen. This leads to increased intestinal fluid and accelerated stool transit [87,189].

The AGA recommends using linaclotide (over no drug treatment) in patients with IBS-C.

(https://www.gastrojournal.org/article/S0016-5085(22)00391-2/fulltext Last Accessed: November 18, 2022)

Strength of Recommendation/Level of Evidence: Strong recommendation/high-quality evidence

In patients with IBS-C, randomized controlled trials have shown highly similar results across studies. Improvements in constipation, abdominal pain, discomfort or bloating, and stool consistency were 15% to 30% greater compared with placebo. These benefits persisted for 26 weeks. Diarrhea was the most commonly reported adverse event, occurring in 16.3% of patients receiving linaclotide, compared with 2.3% of patients receiving placebo. Efficacy and safety were similar in elderly and middle-aged adults [44,87,186]. Patients should take linaclotide (290 mcg) 30 to 60 minutes before breakfast to minimize the chance of diarrhea [5]. In consideration of additional evidence, the AGA 2022 guidelines make a strong recommendation for the use of linaclotide, noting that a network meta-analysis ranked this agent first in efficacy among secretagogues for IBS-C [219].

While lubiprostone and linaclotide led to improvements in stool frequency, constipation severity, and abdominal pain/discomfort in IBS-C, higher costs and adverse effects generally limit these agents to second-line therapy in IBS-C [201].

Plecanatide

Plecanatide is a nonabsorbed 16-amino acid peptide that, like linaclotide, stimulates GC-C receptors on intestinal epithelium, and via the same mediators causes secretion of fluid and electrolytes into the lumen of the bowel. Plecanatide is FDA-approved for treatment of IBS-C and chronic idiopathic constipation at a dosage of 3 mg once daily [219].

In two large phase 3 clinical trials of 12 weeks' duration, a total of 1,632 patients with IBS-C were randomized to treatment with plecanatide (814 patients) or placebo (818 patients). Patients treated with plecanatide showed greater IBS-C symptom relief (27.4%) than those receiving placebo (16.9%), as measured by meeting a predetermined responder end point for IBS-C [219]. Plecanatide demonstrated a higher success rate compared with placebo for improvement in abdominal pain, stool frequency, bloating, straining, and global measures of treatment satisfaction. Diarrhea was the most common side effect, reported by 4.3% of patients receiving plecanatide compared with 1.2% of those receiving placebo.

Tenapanor

Tenapanor is a first-in-class, small-molecule inhibitor of the intestinal sodium/hydrogen exchange isoform 3, which is expressed on the surface of the small bowel and colon and is responsible for the absorption of sodium. Tenapanor decreases absorption of sodium and phosphate and increases secretion of water into the intestinal lumen. This agent is FDA-approved for treatment of IBS-C at a dosage of 50 mg twice daily [219].

In three randomized controlled trials of 12 weeks' duration (688 patients in the treatment group and 684 in the placebo group), a greater proportion of patients with IBS-C taking tenapanor (58.1%) reported adequate relief of IBS symptoms compared with placebo (41.1%) [219]. Tenapanor demonstrated a higher success rate compared with placebo for improvement in abdominal pain. Diarrhea was the most common side effect, resulting in discontinuation of medication in 6.6% of patients in the tenapanor group compared with 1.1% in the placebo group.

5-HT4 receptors are expressed on enteric neurons and in cardiac tissue. 5-HT4 receptor agonists (5-HT4RAs) facilitate fast excitatory cholinergic synaptic transmission between enteric neurons, which stimulates GI motility and increases fluid in the gastrointestinal tract. [93]. Tegaserod is the only FDA-approved 5-HT4 receptor agonist for the treatment of IBS; because of early trial cardiovascular adverse events in men and older women, this agent is only approved for use in adult women younger than 65 years of age with IBS-C [219,220]. It is contraindicated in patients with more than one cardiovascular risk factor.

Prucalopride, mosapride, and three other 5-HT4RAs (velusetrag, naronapride, and YKP10811) are in development for IBS-C treatment. These drugs have greater cardiovascular safety compared with older 5-HT4RAs due to higher specificity at intestinal 5-HT4 receptors and low intrinsic activity in cardiac muscle. These agents are expected to show efficacy in IBS-C, but this awaits confirmation by large randomized controlled trials [93].

The 2022 AGA guideline on the pharmacologic management of IBS-C recommends that selection of medication be individualized, taking into account the dominant clinical features and individual patient's own needs and preferences. A decision tool is offered based on a tiered approach [219]:

If abdominal pain persists and/or psychological symptoms supervene, the AGA recommends adding (or switching) to low dose TCA or SNRI and/or brain-gut behavior therapies (e.g., CBT, hypnosis) [219].

Abnormal contraction of smooth muscle within the colon and the GI tract underlies pain and other IBS symptoms in some patients, providing the rationale for using agents that relax smooth muscle [21]. Spasmolytics fall into three groups based on mechanism of action [44,202]:

A review of 23 randomized controlled trials using various antispasmodics found that these agents improved IBS symptoms to a greater extent than placebo, but efficacy of individual antispasmodics varied. Only otilonium (investigational), hyoscine bromide, cimetropium bromide, pinaverium bromide, and dicyclomine showed significant improvements beyond placebo [196,203].

Antispasmodic drugs with anticholinergic or calcium-channel blocking mechanisms are used for relieving diarrheal symptoms, abdominal pain and distension, and spasms in all IBS subtypes. However, anticholinergic agents may be better tolerated in patients with IBS-D [5,183]. Otilonium and hyoscine have the best evidence of efficacy, and otilonium bromide is the most effective agent in preventing IBS symptom recurrence. Some patients with IBS have an exaggerated gastrocolic reflex that is in part cholinergic-mediated, and spasmolytics may be best suited for postprandial abdominal cramping and loose stools in these patients [5].

The most commonly reported adverse effects associated with spasmolytics include dry mouth, dizziness, and blurred vision; serious adverse events are rare. Spasmolytics with greater anticholinergic activity are more likely to induce blurred vision, urinary retention, constipation, and dry mouth. Anticholinergics should be avoided in the elderly and in patients with a history of acute myocardial infarction or hypertension. Use during pregnancy and breastfeeding is not recommended [5,44].

Peppermint oil possesses a calcium-channel blocking mechanism and is classified as an antispasmodic [5]. The spasmolytic properties of peppermint oil may modulate pain by attenuating visceral hypersensitivity [44]. Two systematic reviews found peppermint oil superior to placebo in the management of IBS pain [203,204]. A 2014 review evaluated five trials enrolling a total of 482 patients and showed a statistically significant positive effect of peppermint oil over placebo [203].

Although peppermint oil is typically well tolerated, with no significant side effects reported with standard doses (250–750 mg two to three times/day), some patients may experience reflux symptoms, and allergic reactions, heartburn, and headache have been described [5]. Peppermint oil is available over the counter, and enteric-coated capsules are preferred [44].

Linaclotide (290 mcg daily) demonstrated improvement in abdominal pain in two large, phase 3 studies in IBS-C, with one trial extending treatment out to 26 weeks [93].

As discussed, antidepressants are commonly used to treat pain symptoms associated with chronic functional GI disorders, including IBS. In a Cochrane review, the TCAs desipramine (25–100 mg at bedtime) and amitriptyline (10–50 mg at bedtime) demonstrated some global improvements of abdominal pain [93].

Pregabalin, an a2d ligand that inhibits release of a number of excitatory neurotransmitters, may alleviate visceral pain in patients with IBS [106,205]. Pregabalin increases distension sensory thresholds to normal levels in patients with IBS with rectal hypersensitivity. Studies are in progress to evaluate efficacy in centrally mediated abdominal pain syndrome (formerly termed functional abdominal pain syndrome) [93].

Ketotifen

Ketotifen is a mast cell stabilizer with antihistamine properties. An eight-week randomized controlled trial showed evidence of improved pain, bloating, flatulence, diarrhea, quality of life, sleep, and sexual functioning in patients with IBS-D, despite lack of reduction in mast cell mediators [195]. The underlying mechanism of action was identified as histamine H1 receptor antagonism, which helped prompt further study of H1 receptor antagonists in patients with IBS [206].

Ebastine

Evidence suggests disordered GI motility, psychosocial distress, and visceral hypersensitivity converge on common pathways, including transient receptor potential cation channel subfamily V (TRPV). TRPV expressed on sensory neurons throughout the gut produces pain when activated by inflammatory mediators [207].

Researchers examined colorectal biopsies of patients with IBS and found greater TRPV-4 metabolite levels, which correlated with abdominal pain and bloating severity, and significantly greater nervous tissue and nerve growth mediators [207]. From these discoveries and results of ketotifen in the treatment of IBS, the histamine H1 receptor antagonist ebastine was studied for possible effects on visceral pain and hypersensitivity in 56 patients with IBS, randomized to ebastine (20 mg/day) or placebo. Over 12 weeks, a significant reduction of abdominal pain was found with ebastine compared to placebo and to baseline. Significantly more patients treated with ebastine (vs. placebo) had at least considerable relief of symptoms (46% vs. 12%) and lower mean abdominal pain scores (0–100 scale: ebastine 38, placebo 62). Quality of life was significantly improved on all IBS-QOL subscales in the ebastine group compared with baseline and placebo [206,207].

Hypersensitive and normosensitive subgroups did not differ in ebastine response. Visceral pain response, as measured by rectal distension, had no association with clinical response, showing barostat findings as an invalid outcome measure. Most importantly, this study suggests H1-receptor blockade may represent an effective treatment for IBS abdominal pain regardless of subtype. This is encouraging given the lack of targeted treatments for visceral hypersensitivity and abdominal pain in IBS [206,207].

Fecal microbiota transplants have been used in the last decade for severe cases of Clostridioides difficile infection, with success rates greater than 90%. Fecal microbiota transplants may be a therapeutic option for severe refractory IBS or inflammatory bowel disease, but current FDA regulations limit use to the treatment of severe C. difficile infection [208].

In a randomized, double-blind placebo-controlled trial involving 52 adult patients with moderate-to-severe IBS, fecal microbiota transplantation successfully altered gut flora in patients with IBS, but patients in the placebo group experienced greater symptom relief after three months than did patients in the treatment group [211]. The authors concluded that altering gut microbiota is not an effective means of obtaining symptom improvement in patients with IBS. A 2019 literature review and meta-analysis, conducted to evaluate the combined outcome of improvement in global IBS syndrome, found no significant difference at 12 weeks in fecal microbiota transplantation versus placebo [212].

Concerns over introducing pathologic organisms must be addressed before fecal microbiota transplant is approved in clinical management of inflammatory bowel disease. An example is the case of a female patient with C. difficile infection who received fecal microbiota transplant from an obese person and subsequently became obese herself [208].