Irritable Bowel Syndrome (IBS)

Definition, Etiology, PathogenesisTop

Irritable bowel syndrome (IBS) is the most common chronic disease of the small and large intestine, affecting ~10% of the total population. IBS is a symptom-based condition defined by the presence of abdominal pain associated with defecation or change in bowel habits in the absence of any other condition leading to these symptoms. The etiology is not well understood and is likely multifactorial. Inflammatory, environmental, psychological, and dietary factors as well as intestinal microbiota play an important role in the pathogenesis of IBS. Psychiatric conditions are prevalent, with increased rates of anxiety and depression compared with a healthy control population.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity, indirectness, and imprecision. Lee C, Doo E, Choi JM, et al; Brain-Gut Axis Research Group of Korean Society of Neurogastroenterology and Motility. The Increased Level of Depression and Anxiety in Irritable Bowel Syndrome Patients Compared with Healthy Controls: Systematic Review and Meta-analysis. J Neurogastroenterol Motil. 2017 Jul 30;23(3):349-362. doi: 10.5056/jnm16220. Review. PubMed PMID: 28672433; PubMed Central PMCID: PMC5503284.

Classification

According to the Rome IV criteria (see Diagnostic Criteria, below), IBS may be classified into 4 subtypes using the Bristol to determine stool consistency (see Figure 1 in Diarrhea). The scale ranges from 1 to 7, with 1 and 2 corresponding to hard stool; 3 to 5, normal consistency; and 6 to 7, loose and liquid consistency. The IBS subtypes are as follows:

1) IBS with predominant constipation (IBS-C): For >25% of the time stool type 1 or 2 and <25% of the time stool type 6 or 7.

2) IBS with predominant diarrhea (IBS-D): For >25% of the time stool type 6 or 7 and <25% of the time stool type 1 or 2.

3) IBS with mixed bowel habits (IBS-M): For >25% of the time stool type 1 or 2 and >25% of the time stool type 6 or 7.

4) Unclassified IBS (IBS-U) meets the diagnostic criteria for IBS but the bowel habits are not accurately described by any of the above subtypes.

IBS subtypes are not separate conditions and the quantity, intensity, and severity of symptoms may vary from patient to patient. Therefore, the IBS subtype should ideally be recategorized as the patient’s bowel habits change.

Clinical Features and Natural HistoryTop

The main symptom is abdominal pain, which may be constant or recurrent and usually is located in the hypogastric area or in the left lower abdominal quadrant; it may be sharp, spasmodic, and cause significant discomfort but almost never wakes the patient at night. The pain worsens after a meal and improves after bowel movement (either increasing or improving pain). Patients can also have diarrhea or constipation (or both). In most patients symptoms fluctuate over time.

In patients with diarrhea the stools are watery or semiliquid, rarely of increased volume. Bowel movements are more frequent and preceded by a fairly rapid urge to defecate; they occur after meals, in response to stress, and in the morning.

In patients with constipation, the frequency of bowel movements is reduced. The stools are hard, lumpy (or in a form of hard nut-like nuggets), and associated with strenuous defecation; a sense of incomplete stool evacuation is common after defecation.

Some patients experience alternating periods of diarrhea and constipation. In both subtypes the stools are typically of small volume. Other symptoms include bloating, presence of mucus in stool, nausea, vomiting, and heartburn.

DiagnosisTop

There are no known biomarkers for IBS diagnosis; therefore, this condition can only be recognized by its symptoms. The diagnosis of IBS requires the presence of specific gastrointestinal (GI) symptoms in the absence of any other GI disease. Physical examination is often normal. Some patients report tenderness in the hypogastrium or flanks.

Diagnostic Criteria

Establishing diagnostic criteria in IBS is important, as it provides a more standardized definition of IBS, which is essential not only for clinical practice but also for research. Since the first reports in 1972, the diagnostic criteria for IBS have evolved over time.

The most current Rome IV criteria include recurrent abdominal pain present on average ≥1 day per week in the last 3 months that fulfills ≥2 of the following:

1) Pain related to defecation (which either increases or improves the pain).

2) Pain associated with a change in stool frequency.

3) Pain associated with a change in stool form (appearance).

The criteria are fulfilled if the symptom onset occurred 6 months prior to diagnosis.

Diagnostic Tests

Tests are often performed to exclude organic causes of symptoms (Table 1) but are not required for IBS diagnosis. Commonly advised investigations include routine biochemical blood tests; complete blood count (CBC); thyroid-stimulating hormone (TSH); serologic testing for celiac disease (tissue transglutaminase [tTG] IgA antibodies and total IgA to identify IgA deficiency). All patients should undergo serologic testing for celiac disease irrespective of the IBS subtype. Routine stool tests for bacterial infections, parasitic infections (if diarrhea is predominant), and occult blood are not necessary. C-reactive protein (CRP) and fecal calprotectin testing may help exclude inflammatory bowel disease and is recommended in patients with diarrhea aged <45 years.

Colonoscopy or flexible sigmoidoscopy is performed in selected cases. Colonoscopy may be indicated in patients aged >50 years even without alarming symptoms or with persistent diarrhea despite empiric treatment (to exclude microscopic colitis) and in younger patients with alarming symptoms or positive fecal calprotectin test result. Endoscopy of the upper GI tract is performed in case of dyspepsia or positive serologic testing for celiac disease. A hydrogen breath test with lactose substrate can be performed if lactose intolerance is suspected but currently is not routinely recommended.

Differential Diagnosis

Before making a diagnosis of IBS, other causes of symptoms, particularly of recurrent diarrhea and constipation, should be excluded. IBS is a common condition and may coexist with other GI diseases.

TreatmentTop

Management involves nonpharmacologic and pharmacologic therapies. A stepwise approach is usually preferred. General outline of our management: Table 2.

Nonpharmacologic Treatment

Patient education is of key importance in the management of IBS. There are multiple nonpharmacologic therapies proposed, including lifestyle and dietary interventions, psychological treatment, prebiotics, and probiotics.

1. Diets: Patients with IBS often report worsening of symptoms after the ingestion of certain food components, and >60% of patients relate the occurrence of bloating and abdominal pain with consumption of certain foods, such as wheat and fermentable carbohydrates. Therefore, different elimination diets have been proposed to improve symptoms. It is worth noting that elimination diets are restrictive, expensive, and not easy to follow. The most common restrictive diets recommended in IBS:

1) Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet: Probably effective in relieving IBS symptoms.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to risk of bias and heterogeneity. Wang J,Yang P, Zhang L,Hou X. A Low-FODMAP Diet Improves the Global Symptoms and Bowel Habits of Adult IBS Patients: A Systematic Review and Meta-Analysis. Front Nutr 2021;8:683191. Doi: 10.3389/fnut.2021.683191. PMCID: PMC8417072. PMID: 34490319. Dionne J, Ford AC, Yuan Y, et al. A Systematic Review and Meta-Analysis Evaluating the Efficacy of a Gluten-Free Diet and a Low FODMAPs Diet in Treating Symptoms of Irritable Bowel Syndrome. Am J Gastroenterol. 2018 Sep;113(9):1290-1300. doi: 10.1038/s41395-018-0195-4. Epub 2018 Jul 26. Review. PubMed PMID: 30046155. A low FODMAP diet is often recommended for a period of 4 to 8 weeks. This is followed by the second phase, where different foods containing FODMAP are reintroduced every 6 days to identify symptoms triggered by specific types of food. This phase last 6 to 10 weeks. After this period >50% of patients with IBS follow the low FODMAP diet with a personalized approach, mostly reducing gluten or wheat to manage symptoms in the long-time perspective.

2) Gluten-free diet (GFD): There is insufficient evidence to recommend GFD as a first-line therapy in IBS.Evidence 3Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and heterogeneity. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291. Dionne J, Ford AC, Yuan Y, et al. A Systematic Review and Meta-Analysis Evaluating the Efficacy of a Gluten-Free Diet and a Low FODMAPs Diet in Treating Symptoms of Irritable Bowel Syndrome. Am J Gastroenterol. 2018 Sep;113(9):1290-1300. doi: 10.1038/s41395-018-0195-4. Epub 2018 Jul 26. Review. PubMed PMID: 30046155. However, the GFD is less restrictive and can be suggested for patients who recognize gluten as a trigger of their symptoms. A recent study suggested that the presence of antigliadin antibodies (AGAs) IgG may help identify patients with IBS-D that will benefit from a GFD, but there is no precise biomarker to identify patients that will respond to specific dietary therapies.

3) Elimination diet: There is some suggestion that an elimination diet based on the presence of IgG antibodies to specific food components could improve symptoms in IBS patients. However, the clinical evidence supporting the elimination diet in IBS is of very low quality and the intervention is currently not recommended.

2. Fiber: There is some evidence for the use of different fiber supplements in relieving IBS symptoms, including a modest benefit of psyllium. Bulking fibers that are minimally fermented can offer utility in modulating indices of bowel habit; slowly fermented fibers may enhance the activities of the gut microbiota. Recent studies suggest that the combination of both bulking and soluble fibers may reduce gas production and increase the tolerability of prebiotics in IBS; however, there is insufficient evidence to make this recommendation. Current recommendations suggest the use of soluble fiber, specifically psyllium, as first-line therapy, which should be started at a nominal dose and gradually titrated upward over weeks to a total daily intake of 20 to 30 g.Evidence 4Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and heterogeneity. Moayyedi P, Quigley EM, Lacy BE, et al. The effect of fiber supplementation on irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2014 Sep;109(9):1367-74. doi: 10.1038/ajg.2014.195. Epub 2014 Jul 29. Review. PubMed PMID: 25070054.

3. Prebiotics, probiotics, and fecal transplant:

1) Prebiotics refer to food components that remain undigested, such as fructo-oligosaccharides or inulin, and stimulate either the growth or activity of intestinal bacteria. There is no evidence for the positive effect of prebiotics in IBS.

2) Probiotics are live or attenuated microorganisms that may affect the composition or function of the gut microbiota and additionally may have anti-inflammatory and antinociceptive properties. Data have shown consistently that probiotic treatment is effective for IBS, although which individual species and strains are the most beneficial remains unclear. Probiotics help reduce symptom burden, abdominal pain, and duration or intensity of diarrheaEvidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Hungin APS, Mitchell CR, Whorwell P, et al; European Society for Primary Care Gastroenterology. Systematic review: probiotics in the management of lower gastrointestinal symptoms - an updated evidence-based international consensus. Aliment Pharmacol Ther. 2018 Apr;47(8):1054-1070. doi: 10.1111/apt.14539. Epub 2018 Feb 20. PubMed PMID: 29460487; PubMed Central PMCID: PMC5900870. and help reduce bloating or distension and improve the frequency and consistency of bowel movements.Evidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and heterogeneity. Hungin APS, Mitchell CR, Whorwell P, et al; European Society for Primary Care Gastroenterology. Systematic review: probiotics in the management of lower gastrointestinal symptoms - an updated evidence-based international consensus. Aliment Pharmacol Ther. 2018 Apr;47(8):1054-1070. doi: 10.1111/apt.14539. Epub 2018 Feb 20. PubMed PMID: 29460487; PubMed Central PMCID: PMC5900870.

3) Fecal transplant: Although this therapy seems to be promising, there is insufficient evidence of its efficacy in IBS.

4) Psychological treatment: Psychological interventions, such as cognitive behavioral therapy (CBT), hypnosis, and mindfulness-based therapies, have been designed and implemented effectively in IBS. CBT is the most widely studied psychotherapy and is currently suggested by some, when available, as first-line treatment for IBS.Evidence 7Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to risk of bias and imprecision. Ford AC, Lacy BE, Harris LA, Quigley EMM, Moayyedi P. Effect of Antidepressants and Psychological Therapies in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-Analysis. Am J Gastroenterol. 2019 Jan;114(1):21-39. doi: 10.1038/s41395-018-0222-5. PubMed PMID: 30177784. CBT is often provided by mental health practitioners, including counsellors, psychotherapists, psychologists, and psychiatrists.

Pharmacotherapy

When nonpharmacologic treatment has failed, pharmacologic therapies should be initiated, depending on the IBS subtype and predominant symptoms (Table 2).

1. IBS-C:

1) Water-soluble fiber, osmotic laxatives (polyethylene glycol, lactulose), and stimulant laxatives (bisacodyl, senna) are commonly used but generally do not influence the symptoms. They may be used as adjuvants when other symptoms have improved but constipation persists.Evidence 8Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and heterogeneity. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291.

2) Agents that target multiple symptoms in IBS-C are linaclotide and plecanatide (guanylate cyclase-C [GCC] agonists) or lubiprostone (a chloride channel activator). Plecanatide binding to GCC receptors is pH-dependent, which is why its activity is mostly confined to the proximal small intestine. Linaclotide binds to GCC receptors in a pH-independent manner and could be active throughout the small intestine and colon. In a recent systematic review, linaclotide, lubiprostone, and plecanatide were superior to placebo for the treatment of IBS-C. Linaclotide was ranked first in efficacy for abdominal pain and achieving complete spontaneous bowel movements and is recommended as first line-therapy in IBS-C.Evidence 9Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Black CJ, Burr NE, Quigley EMM, Moayyedi P, Houghton LA, Ford AC. Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis. Gastroenterology. 2018 Dec;155(6):1753-1763. doi: 10.1053/j.gastro.2018.08.021. Epub 2018 Aug 23. PubMed PMID: 30144426.

3) Lubiprostone is a prostaglandin derivative and selective chloride channel activator, which facilitates transport of chloride, sodium, and water into the intestinal lumen. It has been shown to improve IBS-C symptoms, including bloating, bowel frequency, and stool consistency.

4) For patients with IBS-C and predominant pain, antispasmodics (dicyclomine, pinaverium, and trimebutine) have been proposed, as they relax intestinal smooth muscle.Evidence 10Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291.

5) Antidepressants, including selective serotonin reuptake inhibitors (SSRIs)Evidence 11Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity and indirectness. Ford AC, Lacy BE, Harris LA, Quigley EMM, Moayyedi P. Effect of Antidepressants and Psychological Therapies in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-Analysis. Am J Gastroenterol. 2019 Jan;114(1):21-39. doi: 10.1038/s41395-018-0222-5. PubMed PMID: 30177784. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291. and tricyclic antidepressants (TCAs),Evidence 12Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Ford AC, Lacy BE, Harris LA, Quigley EMM, Moayyedi P. Effect of Antidepressants and Psychological Therapies in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-Analysis. Am J Gastroenterol. 2019 Jan;114(1):21-39. doi: 10.1038/s41395-018-0222-5. PubMed PMID: 30177784. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291. are also widely used for IBS treatment, although in doses lower than those used in depression.

6) Prokinetics, such as prucalopride, are an alternative option for the treatment of constipation. Although prucalopride was shown to be effective in idiopathic constipation, the body of evidence for its use in IBS-C is weaker and the agent is not recommended in IBS.Evidence 13Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291.

The cost of prescription medications can be a barrier to treatment access in clinical practice.

2. IBS-D:

1) Diet modification: A low FODMAP diet.

2) Pharmacotherapy:

a) Loperamide, a mu-opioid receptor agonist, decreases diarrhea by slowing intestinal transit and reducing fluid secretion into the intestinal lumen. It is not recommended for continuous use,Evidence 14Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias, heterogeneity, and imprecision. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291. although it may be useful in specific situations in selected patients.Evidence 15Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias, heterogeneity, and imprecision. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291.

b) Probiotics.Evidence 16Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and heterogeneity. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291.

c) Eluxadoline is a new therapeutic agent with mixed opioid effects (affecting mu-opioid, kappa-opioid, and delta-opioid receptors).Evidence 17Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and imprecision. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291.

d) Rifaximin is a nonsystemic broad-spectrum antibiotic approved in some countries for IBS-D in adults. The mechanisms of action of rifaximin in IBS are not well understood but may be associated with altering the microbiome and thus reducing gas production. In a recent consensus statement, there were concerns related to the recommendation of rifaximin for the treatment of IBS related to the potential antibiotic resistance and high cost associated with this therapy.

e) Antidepressants, especially TCAs, are widely used to target pain in IBS-D, as they are associated with decreased colonic transit.

f) Diphenoxylate/atropine (in North America available as Lomotil) combines the mu-opioid receptor agonist effect (diphenoxylate) and anticholinergic effect (atropine).

3. IBS-M:

1) A low FODMAP diet, probiotics, and TCAs can be offered to these patients. Treatment will be adjusted according to the predominant symptom of diarrhea or constipation.

2) Ensure the patient is not affected by “pseudo–IBS-M” with overflow diarrhea (feces becoming so hard they cannot be expelled with fecal fluid flowing around the blockage), which requires treatment targeting constipation.

4. Treatment of other symptoms in all patients with IBS:

1) Flatulence: Simeticone 80 mg tid; dimeticone 100 mg tid.

2) Postprandial pain: Hyoscine 10 to 20 mg before meals, peppermint oil (recommended for improving IBS symptoms, particularly in patients with pain).Evidence 18Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity and indirectness. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019 Apr;2(1):6-29. doi: 10.1093/jcag/gwy071. Epub 2019 Jan 17. PubMed PMID: 31294724; PubMed Central PMCID: PMC6507291.

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