Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:

1. Describe the symptoms, differential diagnoses, and diagnostic criteria of irritable bowel syndrome.

2. Explain the potential role of neural, endocrine, immune, and metabolic alterations that affect irritable bowel syndrome symptoms.

3. Compare and contrast the different subtypes of irritable bowel syndrome and management strategies for treatment of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is characterized by recurrent abdominal pain and altered bowel habits that occur in the absence of organic gastrointestinal disease or structural or biochemical abnormalities.1 IBS is the most common functional gastrointestinal disorder, affecting up to 15% of the population worldwide, with onset commonly seen in early adulthood.1,2

Family history of IBS exerts a twofold to threefold increased risk. Research on twins has shown that genetic heritability ranges from 22% to 57%, with higher prevalence in monozygotic versus dizygotic twins.3 A female predominance of IBS exists at a ratio of 2:1 to males.4

Due to significant effects on health and quality of life, IBS is a leading reason for work absenteeism.5 The annual estimated costs associated with IBS in the United States range from $742 to $7547 per person with substantial indirect expenses related to lost work productivity.6

Pain associated with IBS includes recurrent abdominal bloating and distension, dyspepsia, and proctalgia fugax, marked by spasms and cramping of the rectum and anus.1,7 The pain is often diffuse and may be associated with increased peristalsis. Patients may report bowel movements that feel uncontrollable and/or urgent and that do not feel completely expelled, and may notice clear or white mucus with the stool. A significant number of individuals with IBS also have visceral hypersensitivity, characterized by increased sensation of pain to normal functions of the visceral organs.7

Pathophysiology of Irritable Bowel Syndrome

Early childhood adversity and psychological factors, including maladaptive stress, anxiety, and depression, and psychosocial effects on the neuroimmune axis, have been associated with IBS.8 However, the etiology of IBS is thought to be multifactorial, stemming from neural, endocrine, immune, and metabolic alterations, with increasing evidence on the role of the brain-gut axis and gut microbiome dysbiosis.

Abdominal pain, which is a key feature of IBS, involves peripheral and central sensitization of nociceptive pathways. Extrinsic innervation of the gastrointestinal tract occurs through the spinal afferent neurons and vagus nerve, whereas intrinsic innervation comprises the enteric nervous system with primary afferent neurons that regulate gastrointestinal motility.9

The enteric nervous system regulates neurohormonal, muscular, and secretory systems of the gastrointestinal tract and has 2 major regions:

1. The submucosal plexus, which controls neuroimmune interactions, absorptive, and secretory function of the mucosal epithelium, and intramural blood flow.

2. The myenteric plexus, which regulates intestinal motility.10

The stress neuroimmune axis has been implicated in IBS, with mixed findings suggesting that alterations in neurotransmitters, hormones, and inflammatory mediators influence IBS symptoms.8 In addition to psychological stress, commensal gut microbiota can influence levels of central neurotransmitters through the synthesis of precursors.

Bifidobacterium infantis has been shown to influence central serotonin [5-hydroxytryptamine (5-HT)] transmission by raising plasma tryptophan levels, whereas Candida, Streptococcus, and Enterococcus species can produce serotonin locally to influence sensory signaling.11-13Lactobacillus and Bifidobacterium species synthesize and release [gamma]-aminobutyric acid, and norepinephrine is produced by Bacillus and Saccharomyces species.14 Besides acting on local nociceptive fibers, these substances in the gut may signal the brain through the vagus nerve.

In addition to influencing the local neurochemical environment, increased intestinal permeability may trigger immune pathways, and certain bacterial species can disrupt normal digestion, intestinal motility, and induction of [mu]-opioid and cannabinoid receptors.15 Thus, the gut microbiome may also influence IBS symptoms.

In a systematic review of 16 articles involving 777 patients with IBS and 461 healthy controls, it was found that patients with IBS have lower [alpha]-diversity than healthy controls in fecal and mucosal samples.16 In the review, patients with IBS had increased Firmicutes, decreased Bacteroidetes, and increased Firmicutes/Bacteroidetes ratio at the phylum level in fecal microbiota, compared with healthy controls.

Another study that included 149 subjects (110 with IBS and 39 healthy subjects) sought to identify a microbiota signature associated with the severity of IBS symptoms using exhaled H₂ (hydrogen) and CH₄ (methane), oroanal transit time, severity of psychological and gastrointestinal symptoms, and fecal and mucosal biopsy samples analyzed with 16S ribosomal RNA.17 The authors found that IBS symptom severity was negatively associated with microbial richness, exhaled CH₄, presence of fecal methanogens, and enterotypes enriched with Clostridiales or Prevotella species. Differences in diet and medication use did not explain variation in the microbiota signature.

Several important considerations have been raised about research focused on the relationship between gut microbiota and IBS symptoms, including the need to untangle whether differences in the microbiota are a cause or result of IBS, and variation in gut microbiota due to geographic location.

A recent systematic review of 22 publications evaluating the gut microbiome in patients with IBS found that it is important to examine both increased and decreased levels of certain bacteria to differentiate patients with IBS from healthy controls.18

The authors of the review found that, compared with healthy controls, patients with IBS had increased family Enterobacteriaceae (phylum Proteobacteria), family Lactobacillaceae, and genus Bacteroides; and decreased uncultured Clostridiales I, and genera Faecalibacterium and Bifidobacterium.

The authors noted that many of the studies did not address sex and age comparisons between patients with IBS and controls, which could influence variation in the gut microbiome.

In addition, a systematic review and meta-analysis of 10 studies from China and 7 studies from other regions around the world found that differences in gut microbiota associated with IBS were specific to whether the patients were from China or other regions.19

Although there are many unanswered questions regarding the role of the gut microbiome on the etiology of IBS, investigation continues on how it may inform diagnosis and treatment. Presently, there is inconsistent evidence that baseline gut microbiota can serve as an accurate predictor of weight loss or glycemic response in obesity or as a predictor of IBS symptom improvement in response to dietary intervention.20

Diagnosis of Irritable Bowel Syndrome

A thorough medical, family, and psychosocial history and physical examination should be performed for the patient presenting with suspected IBS.1 When ascertaining the patient's medical history, include dietary triggers and personal stressors, which are often related to the onset of symptoms.

Anxiety, depression, and posttraumatic stress have a significant influence on IBS but are more predictive of inflammatory bowel disease symptoms.21 In addition, negative cognitive coping, such as catastrophizing, can have a significant influence on quality-of-life outcomes.22

Inquire about rectal bleeding, unintentional weight loss, and family history, and preventive health measures the patient has taken. This inquiry can identify any high-risk screening that may need to take place, such as for colon cancer.

Other differential diagnoses to consider include gastrointestinal cancers, inflammatory bowel disease, microscopic colitis, infectious diarrhea, and celiac disease (Table 1). Inflammatory bowel disease encompasses a group of conditions characterized by inflammation of the gastrointestinal tract, with the primary types being Crohn's disease and ulcerative colitis. Crohn's disease most often affects the large and small intestines but can also occur in the mouth, esophagus, stomach, colon, and anus. In comparison, ulcerative colitis primarily affects the colon and rectum.

Table 1. Differential Diagnoses of Irritable Bowel Syndrome

General workup includes blood work for complete blood count and electrolytes to assess for anemia or elevated white blood cell count, which are typically present with inflammatory bowel disease, infectious causes, or celiac disease.23 C-reactive protein and erythrocyte sedimentation rate will also be elevated with these disorders.

Stool guaiac may be positive in gastrointestinal cancer, inflammatory bowel disease, or infectious causes, and both fecal calprotectin and fecal leukocytes are present with inflammatory bowel disease, infectious diarrhea, and celiac disease. Colon cancer screening with colonoscopy should be performed for patients with a family history, rectal bleeding, or unintentional weight loss.

Positive serologic testing for celiac disease should be further assessed with esophagogastroduodenoscopy and small bowel biopsy. In addition, IBS has been linked to atopy and autoimmune disease, including asthma, allergies to food, pollen, and animals, scleroderma, psoriasis, rheumatoid arthritis, and diabetes mellitus.24 Thus, careful assessment and possibly workup of related conditions should be pursued.

Diagnostic criteria for IBS were updated in 2016 with the publication of the Rome IV criteria, which specify that, to meet the criteria, the individual must have symptoms of recurrent abdominal pain for an average of at least 1 day per week for the previous 3 months and symptom onset at least 6 months before presentation.25 Abdominal pain associated with at least 2 of the following criteria must also be fulfilled:

* Defecation (with either improvement or worsening of pain);

* Change in stool frequency; and

* Change in stool form or appearance.

Subtypes of IBS are used as a foundation to select treatment strategies and include constipation predominant (IBS-C), diarrhea predominant (IBS-D), mixed (IBS-M), or unclassified (IBS-U). The Bristol Stool Form Scale (BSFS) assists to classify individuals into the subtypes (Table 2).

Table 2. Subtypes of Irritable Bowel Syndrome

For this reason, it is useful to have individuals who present with symptoms of IBS keep a diary for several months to track their symptoms, patterns of bowel movements, and classification of bowel movements according to the BSFS.

General Approach to Treatment

In individuals without red flag conditions (Table 3) and symptoms that do not significantly affect quality of life, a reasonable first step is to keep a dietary and symptom diary with removal of gas-producing foods and avoidance of lactose. Although lactose intolerance can be diagnosed with a lactose breath test, individuals can react to other components in milk. Thus, even if having a negative breath test, the patient may benefit from a trial of avoiding milk and reduction of other lactose-containing foods.

Table 3. Red Flag Conditions in the Differential Diagnosis of Irritable Bowel Syndrome

Removal of gas-producing foods entails avoiding beans, broccoli, brussels sprouts, cabbage, fructose, pork, and wheat germ. As IBS has a benign course, patients should be encouraged to continue with the dietary changes, focusing on removal of foods that trigger symptoms.1,23

Stress reduction, adequate sleep, and routine moderate exercise have also been found to improve symptoms.26

In patients who do not improve with reduction in gas-producing and lactose-containing foods, and lifestyle changes, the option of referral to a dietician-monitored diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) can be considered (Table 4). FODMAPs are poorly absorbed in the digestive system, and as they pass through the colon, they are fermented by bacteria that produce short-chain fatty acids and gas. The increase in short-chain fatty acids increases the acidity of the colon, and thus, the diversity and abundance of different bacteria.

Table 4. Foods That Are Low and High in FODMAPs

Referral to a dietician to monitor a low-FODMAP diet is recommended to guide the patient in avoiding ingestion of high-FODMAP foods and selecting alternatives over a period of 8 to 12 weeks, which is then followed by a reintroduction of certain foods to identify triggers. In a review of 6 randomized controlled trials (RCTs) comparing low-FODMAP diet with placebo for patients with IBS, the intervention has been found to be feasible and effective in reducing symptoms with an approximate 70% response rate.27

In addition, a meta-analysis of 10 studies comparing a low-FODMAP diet with a standard IBS diet found that both diets reduced symptoms. However, participants in the low-FODMAP group had a significant improvement (P = 0.002) in general symptoms compared with participants in the standard diet group.28 The authors reported that a dietician-monitored low-FODMAP diet can provide more improvement of symptoms as compared with a traditional IBS diet.

Another review of dietary interventions for patients with IBS that evaluated 11 systematic reviews and meta-analysis reported that probiotic therapy has been shown to be safe and effective in improving overall IBS symptom scores and abdominal pain, although no recommendation could be provided on specific species, strains, or combinations, due to the variability among studies.29

On the other hand, 2 systematic reviews found no evidence to support the clinical use of prebiotics for IBS symptom management.

Of interest, investigators studying the influence of sex and psychosocial factors on visceral hypersensitivity in healthy young volunteers found no evidence to support that sex differences, anxiety, or chronic stress contribute to altered visceral sensitivity.³⁰ However, other factors may affect response to dietary interventions. Among 165 patients with IBS who were exposed to a low-FODMAP diet, it was found that patients with concomitant joint hypermobility syndrome had a more significant improvement in pain, bloating diarrhea, and constipation compared with patients with nonjoint hypermobility syndrome.31

Pharmacologic Management of IBS

Medications are used to treat constipation or diarrhea-specific symptoms and general symptoms of abdominal pain and spasms. Antispasmodic treatment used to antagonize acetylcholine at the muscarinic receptors and relax smooth muscle include dicyclomine 20 to 40 mg by mouth up to 4 times per day or hyoscyamine 0.125 to 0.25 mg by mouth as needed every 4 hours.

Selective serotonin reuptake inhibitors and tricyclic antidepressants can also be used to reduce symptoms of pain and spasm. Peppermint oil capsules work by relaxing smooth muscles and reducing gastric motility and can be taken by mouth at 0.2 to 0.4 mL 3 times per day, although it can have the side effect of heartburn.

For patients with constipation-predominant IBS (IBS-C), nonsoluble fiber supplements can be used to soften the stool at 25 to 30 g by mouth per day. Polyethylene glycol 3350 is used to increase stool water retention at a dose of 17 g each day to 4 times per day but does not improve bloating or pain. Patients should be encouraged to stay hydrated by consuming adequate water intake.1

If constipation continues to be an issue despite these therapies, linaclotide may provide relief of constipation, but may not affect bloating or cramping. It is taken 30 minutes before the first meal of the day. For women, lubiprostone is another option, and is taken twice daily (Table 5).

Table 5. Medications for Treatment of IBS-C

Patients with IBS-D may benefit from preprandial loperamide to decrease the number of loose stools. If loperamide does not provide substantial relief, the addition of a bile acid sequestrant, such as cholestyramine, colestipol, or colesevelam, may provide more consistent relief of symptoms. Female patients have the option of using a 5-HT type 3 antagonist-alosetron-although it does have a black box warning for ischemic colitis.1,23

For men and women with IBS, the use of ondansetron is indicated for reducing symptoms of nausea and vomiting (Table 6).1

Table 6. Medications for Treatment of IBS-D

Although some medications provide potential benefit in reducing global symptoms, they may not reduce pain (such as laxatives or antidiarrheals), whereas antispasmodics and antidepressants can help to reduce pain sensitization.32

Rifaximin, a broad-spectrum antibiotic, has also been evaluated for treatment of IBS (primarily in nonconstipated subtypes) and demonstrates a significant improvement in global symptoms at a dose of 550 mg by mouth 3 times per day for 14 days.33 Recurrence of IBS symptoms is a concern with rifaximin and the use of the second and third courses is being investigated along with the role of other antibiotics for treatment of IBS.33,35

Alternative and Complementary Treatment of IBS

Other treatments have been examined for efficacy in improving symptoms of IBS. A total of 21 RCTs related to IBS-D were included in a meta-analysis to evaluate the effects of acupuncture and Chinese herbal medicine (CHM) compared with control participants who received Western medicine or Western medicine combined with CHM.35

The meta-analysis found that acupuncture and CHM resulted in more favorable outcomes in abdominal pain, distension/discomfort, diarrhea, physical strength, and sleep quality (P values ranging from 0.03 to 0.00001) compared with patients in a matched group treated with standard Western medicine.

A network meta-analysis of 29 studies involving 9369 patients suggested that acupuncture was superior to pharmacologic treatment in terms of efficacy in reducing symptoms and severity of side effects in patients with IBS-D.36

A review of 17 RCTs including 1806 participants compared acupuncture with sham acupuncture on symptom severity or health-related quality of life.37 None of the RCTs found acupuncture to be superior to sham acupuncture on these outcomes. Tongxieyaofang (TXYF) is a prescription of traditional Chinese medicine that has been used widely to treat IBS-D and consists of 4 main ingredients: Bai Zhu (white atractylodes rhizome); Bai Shao (white peony root); Chen Pi (orange peel); and Fang Feng (ledebouriella root).

A meta-analysis involving 1556 patients who received TXYF and 1506 who received standard treatment was conducted to examine the clinical effective rate.38 Compared with probiotics, pinaverium bromide, trimebutine, and oryzanol, the clinical effective rate was significantly improved with TXYF treatment, although there were no significant associations with abdominal pain, stool frequency or form, or total symptoms.

A small number of studies have examined the effect of hypnotherapy on symptoms of IBS.39 Although a review of these studies found that hypnotherapy was well tolerated and no side effects were reported, there is insufficient evidence to support any conclusions about effectiveness.

Experimental use of fecal microbiome transplantation (FMT) for the treatment of IBS has led to conflicting results.40 One RCT demonstrated that 65% (36/55) of patients with IBS had relief of symptoms 3 months after a single fecal transplantation by colonoscopy, compared with 43% (12/28) of patients in the placebo group.41

In another study evaluating FMT capsules for 12 days, a greater reduction in symptoms was seen in the placebo group (n = 23) compared to the FMT group (n = 22) at 3 months even though increased diversity of the gut microbiome was achieved.42 As these were small studies that used different means of FMT administration, several large-scale studies are underway to further examine the efficacy of FMT for treatment of IBS.

Management and Coordination of Care for IBS

Addressing behavior and lifestyle changes during IBS treatment can be a significant challenge, particularly for individuals with limited access to specialist care. For patients who want to pursue a low-fat or low-FODMAP diet, consultation and coordination of care may be available through web-based or telehealth programs.43-45

Some programs provide access to psychotherapy or dietician-led interventions. In a 3-arm RCT assessing telephone-delivered cognitive-behavioral therapy (CBT), web-based CBT, or minimal therapist support and treatment as usual, 558 patients with refractory IBS were assessed over 12 months.46 The study found that both telephone- and web-based CBTs were superior to treatment as usual on the symptom severity score and on the work and social adjustment scale at 12 months. Another avenue for improving IBS outcomes is through self-management programs that provide knowledge and skills for managing chronic conditions and support from health care professionals. A comprehensive self-management intervention, developed and evaluated by an interdisciplinary team, has shown that it can provide sustainable changes in behavior, including dietary change, beyond 1-year follow-up.47

Conclusion

IBS is a chronic condition with a key feature of recurrent pain that can significantly affect functioning and quality of life. The main diagnostic criteria of IBS are related to symptom duration and frequency. The treatment of IBS should entail a biopsychosocial approach, addressing the psychological, spiritual, social, and physiological domains of the individual.

Lifestyle behaviors for managing stress, diet, sleep, and exercise are important for optimizing the management of symptoms. Many pharmacologic treatments are available to treat general symptoms and subtypes of IBS. Through careful monitoring of symptoms that evolve in response to diet, and other lifestyle choices, the symptoms of IBS can be reduced. Assisting patients in this journey may require support, such as through self-management programs that offer knowledge and skills for monitoring, goal-setting, and problem-solving, to make a significant impact on symptom reduction.

More personalized strategies of treating IBS are currently under investigation through research on the gut microbiome and use of multimodal strategies based on the unique characteristics of the individual.

References