What is Irritable Bowel Syndrome (IBS)?

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic abdominal pain, cramps, bloating, and altered bowel habits that may include diarrhea and/or constipation. As a functional disorder, it is not linked to tissue damage and is diagnosed by criteria related to key symptoms. Importantly, IBS should not be confused with inflammatory bowel disease (IBD), a broad term describing conditions characterized by chronic inflammation of the gastrointestinal tract.

IBS is very common and often contributes to reduced quality of life. IBS symptoms often can be improved with dietary and lifestyle changes along with nutrient supplementation. However, more serious cases may require drug treatment.

Nutrients & Irritable Bowel Syndrome

• Probiotics. As alterations in the gut microbiome can cause or exacerbate IBS symptoms, supplementation with probiotic bacteria or yeast may help rebalance it. Certain probiotic strains have clinical evidence for improving bowel frequency, abdominal pain, and other symptoms related to IBS.
• Ginger. Ginger may improve constipation by stimulating activity of a nerve-muscle complex that facilitates intestinal motility.
• Digestive enzymes. A comprehensive blend of digestive enzymes taken with meals can improve mealtime symptoms related to foods that commonly trigger IBS-like symptoms, such as lactose and beans.
• Artichoke. Artichoke supports healthy digestive function by promoting bile production. In one study, artichoke leaf extract almost eliminated abdominal pain, cramps, bloating, flatulence, and constipation in patients with IBS. A specific combination of artichoke and ginger extracts has also been shown to relieve bloating, pain, and other functional gastrointestinal symptoms.
• Melatonin. Melatonin, a multifunctional hormone, can be useful for more than just improving sleep. IBS patients taking melatonin had reduced abdominal pain, bloating, and overall IBS symptoms.

What Dietary & Lifestyle Changes Can Help IBS?

• Consider certain elimination diets (ie, low FODMAP or gluten-free diet); foods to avoid may include legumes, wheat, barley, rye, milk, certain fruits, and others.
• Get tested for and avoid foods that trigger high levels of IgG antibodies (ie, foods that cause sensitivities)
• Stress reduction techniques (eg, yoga, cognitive behavioral therapy, etc.)
• Engage in a regular form of low- to moderate-intensity exercise
• Consider acupuncture or hypnotherapy

What are the Signs & Symptoms of IBS?

• Recurrent abdominal pain or cramps typically related to defecation and associated with change in stool frequency or appearance
• Changes in stool could include constipation (in constipation-predominant IBS [IBS-C]) or diarrhea (in diarrhea-predominant IBS [IBS-D])
• Other symptoms not directly associated with the gastrointestinal tract may include headaches, backaches, lethargy, and anxiety or depression

What are the Risk Factors for IBS?

• Genetic predisposition
• Stress, anxiety, and/or depression
• Food sensitivities and intolerances
• Gastrointestinal infections
• Small intestinal bacteria overgrowth (SIBO)
• Intestinal inflammation
• Female gender and hormonal fluctuations
• Use of certain medications, including proton pump inhibitors and broad-spectrum antibiotics

How is IBS Treated?

• Diet and lifestyle interventions
• Bulking agents like dietary fiber and fiber supplementation
• Laxatives and stool softeners (eg, lubiprostone and polyethylene glycol)
• Antidiarrheals such as loperamide or bile acid sequestrants (eg, colesevelam)
• Antispasmodic medications (eg, pinaverium bromide)
• Serotonergic agents, which can be common classes of antidepressants (eg, tricyclic antidepressants [TCAs] or selective serotonin reuptake inhibitors [SSRIs]) or those that locally interact with serotonin receptors (agonists or antagonists) in the gut (eg, alosetron)
• Antibiotics to treat SIBO (rifaximin)

What are Some Novel & Emerging Therapies for IBS?

• Mesalazine, a drug used to treat inflammatory bowel disease, may also benefit patients with IBS
• Mast cell stabilizers (cromolyn or medications known as cromoglycates)
• Transcutaneous vagal nerve stimulation

Irritable bowel syndrome (IBS) is a very common functional gastrointestinal disorder. The estimated prevalence of IBS varies widely depending on which criteria are used and differ from country to country; about 10–15% of people in the United States are thought to be affected by IBS. Women are affected more frequently than men, and the condition is less common among people over age 50.^1-3 Because not everyone with symptoms possibly attributable to IBS seeks treatment, it is estimated that about 40% of individuals who would meet diagnostic criteria for IBS do not have a formal diagnosis.⁴

Typical IBS symptoms include recurrent abdominal pain (typically related to defecation), bloating, and varying bouts of diarrhea and constipation. The condition is generally associated with a reduced quality of life.^4,5 Importantly, IBS should not be confused with inflammatory bowel disease (IBD). IBD includes Crohn’s disease and ulcerative colitis, which are characterized by inflammatory lesions in the intestines.⁶

IBS can be diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixed (IBS-M), or unclassified. Subtype classification is important because the approach to treatment may vary depending on which IBS subtype an individual has. For instance, some medications are only approved for IBS-C while others only have approval for IBS-D.⁷

Many factors may cause or exacerbate IBS symptoms. For example, stress, anxiety, depression, food sensitivities, small intestinal bacterial overgrowth (SIBO), excessive exercise, and hormonal fluctuations are all associated with IBS.^8-13

Addressing psychological conditions in IBS patients is especially important because irritable bowel symptoms often persist despite drug therapy if these issues are not addressed.^14-21 Moreover, various strategies of dietary modification, targeting food intolerances and sensitivities, often lead to symptom improvement without the need for pharmaceutical interventions.^22-25

This protocol will discuss the causes of and risk factors for IBS along with its diagnosis and conventional treatment; emerging drug strategies will be examined as well. The important role of dietary and lifestyle modification will be reviewed, and evidence on nutrients that may alleviate IBS symptoms will also be summarized.

Probiotics

Probiotics are microorganisms that may provide health benefits to their host when administered at sufficient levels.²⁸ Probiotics, as a whole and when taken consistently, may help rebalance intestinal flora and alleviate IBS symptoms, and are recommended in the 2018 American College of Gastroenterology (ACG) guidelines for the treatment of overall IBS symptoms as well as the treatment of bloating and flatulence.²⁹ However, the 2021 ACG guidelines concluded that although probiotics are an important area of research for IBS treatment, there is still not yet enough evidence to recommend them for global IBS symptoms.³⁰ Certain probiotic strains, and blends of probiotics, have been clinically studied in individuals with IBS and shown positive effects.

A particularly important type of bacteria, Bifidobacteria, is found in reduced quantities in the gastrointestinal (GI) tracts of both constipation-predominant IBS³¹ and diarrhea-predominant IBS³² sufferers relative to healthy individuals.³³ Bifidobacterium longum BB536 is one specific strain of Bifidobacteria that has been well studied clinically and shown in various settings, including antibiotic use, to improve defecation patterns in both diarrhea and constipation. It has also been shown to help eliminate opportunistic GI pathogens and have beneficial effects on immune function.³⁴ Another specific Bifidobacteria strain shown to improve bowel symptoms, particularly in those struggling with constipation, is B. lactis HN019. A randomized controlled trial found that treatment with B. lactis HN019 at a dose of 10 billion colony forming units (CFUs) per day, taken for 28 days, increased stool frequency and reduced straining in a subgroup of patients with functional constipation who reported three or fewer bowel movements per week at baseline.³⁵ In another clinical trial of individuals with functional GI symptoms, B. lactis HN019 taken daily for 14 days was also shown to reduce transit time and relieve symptoms compared with placebo, with the higher daily dose of 17.2 billion CFUs being shown to be more effective than 1.8 billion CFUs.³⁶ Additional studies evaluating B. lactis HN019 in combination with different Lactobacillus strains have shown positive effects on GI symptoms related to constipation in as little as two weeks.^37,38

A combination of Lactobacillus paracasei IMC 502 and L. rhamnosus IMC 501 has been shown to improve bowel habits in clinical studies of healthy adults.^39,40 Although participants in these studies were not diagnosed with IBS, questionnaire responses indicated their bowel habits improved after two weeks of consuming the probiotic supplement. Specifically, subjects reported increased stool regularity and volume.⁴⁰ In another study, 20 billion CFUs of L. plantarum DSM 9843 were administered daily for four weeks to IBS sufferers. Flatulence resolved rapidly, and improvements in overall GI function remained long after supplementation was discontinued.⁴¹

A spore-forming bacteria known as Bacillus coagulans, which is extremely tolerant to harsh environments, including high temperature and stomach acidity,⁴² has also been shown to improve IBS symptoms in multiple clinical studies.^43-46 Specifically, B. coagulans MTCC 5856 at a dose of 2 billion CFUs per day, taken for 90 days, was shown to significantly improve bloating, vomiting, diarrhea, abdominal pain, and stool frequency in patients with IBS-D compared with placebo, also improving disease severity and quality of life.⁴⁶ A similarly designed study that tested 90 days of supplementation with B. coagulans MTCC 5856 in people with IBS and depression found improvements in depression and IBS symptoms compared with placebo.⁴⁷

Saccharomyces boulardii is a well-studied probiotic yeast shown in several studies to improve diarrhea related to antibiotic use, traveler’s diarrhea, and recurrent Clostridium difficile infection.^48,49 Although clinical data on improvement of specific IBS symptoms is not particularly strong for S. boulardii as a monotherapy, multiple studies have shown that treatment with this probiotic yeast is efficacious for improving IBS-related quality of life.^50,51 Additionally, in people with IBS-D, S. boulardii has been shown to decrease the pro-inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor-alpha (TNF-α) and increase levels of the anti-inflammatory cytokine IL-10 compared with placebo in blood and the upper rectum.⁵⁰ Studies in other settings such as IBD have shown S. boulardii may play a role in resolving GI disease via improving the gut barrier integrity, a factor also implicated in IBS. It has also been shown to help resolve infectious diarrhea via increasing intestinal secretion of immunoglobulin A, which helps protect against infection.⁵²

Artichoke & Ginger

Artichoke. Artichoke leaf has been used since Roman times as a traditional medicine that supports digestive function. It has been shown to promote the production of bile that helps digest dietary fats and reduce spasms and flatulence. An extract of artichoke, standardized to the biologically active cynarin, was shown in a randomized controlled trial to significantly increase volume of bile secretion at 120‒150 minutes after administration compared with placebo.⁵³ Animal studies also support this traditional use of the plant.^54,55

In one study, two capsules of 320 mg artichoke leaf extract taken three times daily almost completely eliminated abdominal pain, cramps, bloating, flatulence, and constipation in study participants with IBS who also had nonspecific GI discomfort.⁵⁶ Further analysis revealed that artichoke leaf extract significantly improved quality of life in subjects with functional dyspepsia (ie, recurrent indigestion with no apparent cause).⁵⁷ Another study found that consumption of 320 or 640 mg of artichoke leaf extract daily for two months significantly attenuated IBS symptoms and improved quality of life.⁵⁸

Ginger. Ginger, often used to ease nausea and vomiting,⁵⁹ may also improve constipation by stimulating activity of the migrating motor complex, the nerve and smooth muscle complex that promotes intestinal motility (peristalsis) and defecation.⁶⁰ Acutely, treatment with 200 mg of ginger was shown to increase the activity of the migrating motor complex in response to a test meal.⁶¹ A lack of activity of the migrating motor complex may contribute to the state of dysbiosis known as SIBO, a factor in IBS for some.⁶⁰ The gingerols and shogaols found in ginger also have anti-inflammatory properties.⁶²

Combination (artichoke and ginger). Two clinical studies have looked at the effects of a specific combination of standardized extracts of artichoke and ginger on digestive health. In one multicenter, randomized, double-blind, placebo-controlled trial, the combination (containing 100 mg artichoke and 20 mg ginger extracts) was taken twice daily, before lunch and dinner, by individuals with functional dyspepsia.⁶³ After 14 days of treatment, the group receiving the combination had a significant improvement in symptoms versus no change in the placebo group. By the end of the study (day 28), a significant improvement was seen in nausea, bloating, and epigastric fullness, and pain in the artichoke/ginger-supplemented group. In a pilot, randomized, crossover study looking at the effect of acute supplementation of the artichoke/ginger combination on gastric volume, subjects’ after-meal gastric area was 24% smaller, with one capsule before the meal, compared with placebo.⁶⁴ A small group of these participants were evaluated at a later date and found to exhibit an even greater 38% reduction in post-meal gastric area compared with placebo after ingesting two capsules of the supplement prior to a meal.

Peppermint Oil/Caraway Oil

Peppermint oil is a natural antispasmodic. It is recommended by the ACG 2018 guidelines for the treatment of overall symptoms of IBS, shown in their analysis of seven randomized clinical trials to be significantly more effective than placebo with a number needed to treat of 4.²⁹ The number needed to treat, or NNT, is the number of people who need to receive an intervention in order to realize one occurrence of the outcome under study (in this case, improvement of IBS symptoms). In one study, an enterically coated preparation of 225 mg peppermint oil taken twice daily was shown to reduce all IBS symptoms by over 50% in three-fourths of the patients, whereas only 38% of the placebo group improved.⁶⁵ In another well-designed study, 187 mg of a similar peppermint oil product taken three times daily before meals for eight weeks led to a significant improvement over placebo with regard to abdominal discomfort, abdominal pain, and quality of life, but not in terms of diarrhea, constipation, or bloating.⁶⁶ IBS patients treated with peppermint oil in yet another study reported benefits including decreased abdominal pain, less bloating and flatulence, decreased stomach growling, reduced stool frequency, and improved stool consistency.⁶⁷ A meta-analysis of 12 randomized trials including 835 subjects concluded that peppermint oil improved global IBS symptoms and abdominal pain compared with placebo, with no difference in reported adverse effects.⁶⁸

Peppermint oil has also been studied in combination with caraway oil. In a double-blind placebo-controlled clinical study of 45 patients with non-ulcer dyspepsia, about half of whom had IBS, subjects in the treatment group received one enteric coated capsule, containing a combination of peppermint and caraway oil, three times daily for four weeks. While all patients complained of moderate-to-severe pain before treatment, 42% of patients in the treatment group were pain-free two weeks after taking the combination therapy versus only one patient in the placebo group. After four weeks of treatment, 63% of those in the treatment group were pain-free versus 25% in the placebo group and 89% in the treatment group showed improvement in pain intensity versus 45% in the placebo group.⁶⁹ A later trial by the same researchers found similar results—67% of functional dyspepsia patients given the peppermint/caraway oil mixture were described as much or very much improved after treatment for 29 days, compared to only 21% of those given placebo.⁷⁰ A possible adverse effect of peppermint oil is heartburn as it may have relaxant effects on the esophageal muscle.²⁹

Melatonin

Melatonin is a multifunctional hormone that exhibits a variety of beneficial effects in gastrointestinal disorders independent of its more widely known effects on sleep.⁷¹ Animal studies suggest production of melatonin in the GI tract by the enteroendocrine cells far exceeds pineal production of melatonin.^72,73 Melatonin receptors in the gut have been shown to play a role in motility, inflammation, and pain.⁷¹ Melatonin has also been shown to influence the gut microbiota composition, reducing the dysbiosis induced by stress and sleep deprivation in an animal study.⁷⁴

In one study of people with IBS and sleep disturbances, 3 mg melatonin taken prior to bedtime for two weeks significantly decreased abdominal pain and rectal sensitivity.⁷⁵ These findings were supported by another double-blind, placebo-controlled, crossover study in which 3 mg melatonin reduced abdominal pain and bloating in women with IBS.⁷⁶ In postmenopausal women, daily supplementation with melatonin, at a dose of 3 mg in the morning and 5 mg in the evening for a period of six months, significantly improved overall symptoms at four and six months compared with placebo in those with constipation-predominant IBS.⁷⁷ In a small study that examined a wider array of symptoms, besides improving bowel function, melatonin was associated with a 43% improvement in overall quality of life compared with 14% in the placebo group. Overall IBS scores improved by 45% among those taking melatonin compared with 16% in those taking placebo.⁷⁸

Vitamin D

Some evidence suggests vitamin D supplements may benefit some people with IBS, particularly those with vitamin D deficiency. In one study that randomized 88 people who satisfied the Rome IV criteria for IBS-D and who had vitamin D deficiency or insufficiency, subjects received either 1,250 mcg (50,000 IU) vitamin D3 or placebo weekly for nine weeks. All participants also received 135 mg of the antispasmodic drug mebeverine (Colofac) twice daily. Among 74 subjects who completed the study, IBS symptom severity and levels of the inflammatory mediator IL-6 decreased significantly in the vitamin D group compared with the placebo group and baseline.⁷⁹ Another randomized controlled trial found that 1,250 mcg (50,000 IU) vitamin D3 every two weeks improved some biomarkers related to inflammation and oxidative stress relative to placebo. The effect on certain inflammatory biomarkers (TNF-α and IL-17) was evident only in subjects with IBS-D, but changes in other inflammatory markers and in those related to oxidative stress were apparent regardless of IBS subtype.⁸⁰ In a six-month randomized controlled trial, 90 participants with IBS took either 1,250 mcg (50,000 IU) vitamin D or placebo every two weeks. Subjects who received vitamin D reported improved symptoms compared with those who received the placebo.⁸¹ A trial that enrolled 112 adolescents with IBS and low vitamin D levels found that supplementation with 50 mcg (2,000 IU) vitamin D daily for six months improved symptoms compared with placebo.⁸²

On the other hand, a trial in which 135 participants with IBS and low vitamin D levels took 75 mcg (3,000 IU) vitamin D or placebo daily for 12 weeks found no differences in symptom severity at the end of study period, despite a significant increase in serum vitamin D levels.⁸³

Although not all studies have found a benefit with vitamin D, supplementation is reasonable for those with IBS given the minimal cost and robust safety record of vitamin D. Supplementation may be especially pertinent for those with low vitamin D levels.⁸⁴

Berberine

There is a multitude of mechanisms by which berberine, the yellow-orange alkaloid found in botanicals such as Oregon grape and goldenseal, may be useful in the setting of IBS. Berberine has well-documented antimicrobial effects and supports the integrity of the intestinal epithelial tight junctions.^85-88 In animals, it also has been demonstrated to have antinociceptive effects, reducing visceral hypersensitivity.⁸⁹

Berberine has been shown to be effective in human studies for the treatment of diarrhea of various etiologies. In patients with IBS-D, treatment with 400 mg of berberine hydrochloride twice daily for eight weeks significantly reduced the frequency of diarrhea, abdominal pain, and urgent need for defecation compared with placebo. Improvements were also seen in scores of IBS symptoms, IBS quality of life, and depression and anxiety versus placebo.⁹⁰ A retrospective study of a combination including berberine, guar gum (a galactomannan), and melatonin also found treatment was associated with significant improvements in functional diarrhea or IBS-D. After 30 days, diarrhea events were reduced by 50‒70%, and by 90 days they were reduced by 70‒80% with more than half of the subjects reporting normalized Bristol Stool Scale scores.⁹¹ Berberine, in its sulfate form, has also been shown to be effective for acutely improving diarrhea due to enterotoxigenic Escherichia coli.⁹²

A recent systemic review and meta-analysis out of China (a region in which berberine is widely used as a treatment for diarrhea) surveyed 38 randomized controlled trials in which berberine was used as a treatment for diarrhea of various origins, including infectious and non-infectious causes. Typically, berberine was given for a short period, similar in time to a standard course of antibiotics. Various other interventions were allowed in the studies selected and included antibiotics, probiotics, B vitamins, and montmorillonite (an absorbent clay) in addition to berberine. Overall, it was found that berberine improved clinical outcomes and shortened the duration of diarrhea compared to control interventions with no serious adverse events reported.⁹³

Although berberine has been studied and shown to have a high level of safety in human clinical trials, concerns about its long-term use have been raised on the basis of preclinical studies that suggest long-term berberine use, especially at high doses, may impair cellular metabolism in specific types of cells.^94-96 The implications of this preclinical research are yet to be determined by long-term human clinical trials, therefore Life Extension currently recommends short-term use of berberine when indicated.

Glutamine

Glutamine is the most abundant amino acid in the body and is an important fuel for the intestinal epithelial cells. Glutamine is considered a nonessential amino acid due to endogenous synthesis; however, in hypercatabolic states (such as severe burn wounds, infections, and surgery; and possibly also pregnancy, lactation, and substantial growth periods) it is often considered to be “conditionally essential.”^97,98 In periods of high physical stress such as these, the rate of glutamine consumption by the small intestinal mucosa exceeds the rate of production.⁹⁹ In these cases, glutamine has been shown to improve intestinal permeability.^100,101

Glutamine has been shown to be of clinical benefit in settings where intestinal repair is important, such Crohn’s disease and post-infectious diarrhea.^102,103 In individuals with IBS-D subsequent to enteric infection, a randomized controlled trial found that glutamine at a dose of 5 grams three times daily for eight weeks improved IBS severity scores meaningfully in almost 80% of individuals compared with only 5.8% of the placebo group achieving comparable improvement. Those in the glutamine group also saw highly significant improvements in daily bowel movement frequency, Bristol Stool Scale scores, and intestinal permeability. Intestinal permeability was normalized in the glutamine group but not in the control group.¹⁰²

Exercise, particularly at intense levels or in hot temperatures, has been shown to increase intestinal permeability.¹⁰⁴ In fact, 25‒50% of elite athletes are troubled by gastrointestinal symptoms.¹⁰⁵ Extreme temperatures and inadequate hydration further contribute to dysregulated GI function.¹⁰⁴ Glutamine has been shown in multiple clinical studies of athletes to help reduce or even prevent increased intestinal permeability related to intense exercise.^106-108

Digestive Enzymes

According to a 2012 national survey, the use of digestive enzyme supplements by individuals with IBS is common.¹⁰⁹ A comprehensive enzyme supplement commonly includes lactase for the breakdown of lactose, enzymes like xylanase, cellulase, and hemi-cellulase for the breakdown of plant substances, specific enzymes to facilitate the breakdown of gliadin, proteases to support digestion of proteins, lipase to improve digestion of fats, and alpha-galactosidase to help break down oligosaccharides found in foods like beans. Supplementation with specific digestive enzymes (eg, lactase) is a well-recognized intervention for the treatment of digestive symptoms associated with lactose intolerance.

Supplemental enzyme ingestion is also used as an intervention for symptoms associated with exocrine pancreatic insufficiency (EPI), which can have symptoms similar to IBS, particularly in its mild state.¹¹⁰ As EPI is typically diagnosed when pancreatic lipase falls below 10% of normal pancreatic output, many individuals may experience symptoms related to inadequate pancreatic output before this diagnostic threshold is breached.¹¹¹ Several diseases have been linked to EPI—reduced pancreatic elastase production (<200 mcg/g) was identified in about 40% of individuals with longstanding diabetes, while celiac disease and alcohol use are other potential contributing factors.^112-114 A comprehensive stool panel that includes assessment of digestive health measures (eg, elastase levels) and assesses for undigested fat can help determine if mild EPI is a contributing factor to mealtime symptoms attributed to IBS.

As there may be mild EPI, undiagnosed food intolerances or sensitivities, or sensitivities to high FODMAP foods, use of digestive enzymes as a dietary supplement may help improve mealtime-related symptoms of IBS.^115,116

Magnesium

Magnesium is an osmotic laxative with a long history of use for treating constipation.¹¹⁷ In females with mild-to-moderate chronic constipation, 500 mg magnesium oxide taken three times daily for 28 days significantly improved the frequency of spontaneous bowel movements (SBM), colon transit time, and Bristol stool consistency scores compared with placebo.¹¹⁸ Symptoms overall and constipation-related quality of life were also significantly improved. In adults with chronic constipation, 28 days of treatment with 1,500 mg magnesium oxide or 1,000 mg of senna (a stimulant laxative) per day significantly improved symptoms overall (68% and 69%, respectively) compared with placebo (almost 12%).¹¹⁹ Significant improvements in SBM and complete SBM were also seen in the active treatment arms compared with placebo.

Because mild abdominal discomfort can occur with higher doses of magnesium, it is best to gradually increase and/or divide doses during the day. In healthy individuals, the kidneys filter 2,000–2,400 mg of magnesium daily,¹²⁰ and there is little risk associated with the use of magnesium at doses commonly used for laxative purposes. However, excessive magnesium use, particularly by those with late-stage chronic kidney disease, can lead to hypermagnesemia.¹²¹ Those taking additional laxatives and using more than 1,000 mg magnesium per day are at greater risk of this complication.

Perilla Leaf Extract

Perilla frutescens is a plant in the mint family that is native to East Asia. Its leaves are rich in polyphenols and, in addition to being a flavorful and aromatic ingredient in many traditional foods, perilla leaf has been historically used in allergic, respiratory, and digestive ailments.¹²² In a randomized controlled trial, 47 participants with GI discomfort and reduced bowel movement frequency were treated with either perilla extract, 150 mg twice daily, or placebo for four weeks. All GI symptoms, including abdominal discomfort, flatulence, rumbling, fullness, and bloating, improved significantly in the perilla group. For bloating, the positive response rate in the perilla group was 83% compared with 57% in the placebo group.¹²³

Perilla may have several modes of action that contribute to its beneficial effects for digestive symptoms. Preclinical studies indicate perilla stimulates motility of the intestinal tract¹²⁴ and may relax intestinal muscle spasms.¹²⁵ Other studies found perilla extract inhibited the inflammatory response generally^126-128 and specifically in the large intestine in mice.¹²⁹

Stress, anxiety, and depression are known to be associated with changes in pain sensitivity, GI motility, and intestinal permeability via a complex network that connects the GI tract, brain, immune system, and microbiota.¹³⁰ In addition to preventing a stress-induced inflammatory response, an essential oil extract of perilla prevented depression-related behaviors in chronically stressed mice.¹³¹ Another study also noted a reduction in signs of stress-induced depression and a reversal of stress-induced changes in brain metabolism in mice treated with perilla essential oil. In this study, perilla extract compared favorably to fluoxetine (Prozac).¹³²

Activated Charcoal

Activated charcoal can be a useful palliative agent, especially for post-infectious IBS-D. It is used to enhance the elimination of toxic substances via the GI tract.^133,134 Due to its adsorbent nature, activated charcoal also helps the body eliminate immunogenic and toxic byproducts of infection, such as bacterial endotoxins.^135,136 Activated charcoal has been suggested as a palliative agent in the treatment of diarrhea due to its low rate of side effects compared with anti-diarrheal treatments.¹³⁷

A multicenter study of activated charcoal for the treatment of IBS, including approximately 60% who reported constipation as a symptom, found it was well tolerated and efficacious in nearly 80% of individuals after 12 weeks of treatment. Even the patients who began the study with severe and moderate constipation had substantial improvements. Flatulence, stool consistency, and abdominal distention were also reported to be improved.¹³⁸ Activated charcoal has also been studied and shown to be supportive in reducing the severity and frequency of chemotherapy-induced diarrhea.^139,140

Activated charcoal use may cause constipation in some individuals.^141,142 Stools also appear black with activated charcoal use which can be mistaken for blood in the stool.¹⁴³ Importantly, taking activated charcoal at the same time as prescription medications may reduce the amount of medication your body absorbs. Therefore, medications and activated charcoal should not be taken at the same time. If you are taking any medication, talk to your doctor before using activated charcoal.

Zinc Carnosine

Zinc carnosine is a form of zinc backed by multiple studies suggesting it supports the health of the gut lining, improving the integrity of the tight junctions and protecting the intestinal villi from damage.^144,145 Increased intestinal permeability has been shown to be an issue in individuals with IBS-D and has been associated with visceral hypersensitivity.^146,147 Zinc carnosine also has some anti-inflammatory and antioxidant effects, which may lend to its usefulness in IBS.¹⁴⁸

In a crossover study in healthy volunteers, zinc carnosine at a dose of 37.5 mg twice daily was shown to ameliorate the increases in intestinal permeability induced by non-steroidal anti-inflammatory drug use.¹⁴⁵ In a randomized, controlled, crossover trial, at the same dose, zinc carnosine was shown to significantly reduce the increase in intestinal permeability seen with heavy exercise. Effects were greatest at the end of the study, with a 71% decrease in permeability after 14 days of treatment.¹⁴⁹

Collagen Peptides

Collagen is often purported to have a gut healing effect: numerous “gut healing” diets and collagen-enhanced products on supermarket shelves allude to this effect. However, human studies with collagen for this purpose are lacking as of mid-2021. Nevertheless, preclinical research from cellular and animal studies suggest collagen peptides may support gut integrity and reduce inflammation related to increased intestinal permeability. Specifically, in mice subjected to burn wounds, a setting known to increase intestinal permeability, at seven days post injury, treatment with collagen peptides had a greater effect than glutamine on reducing serum endotoxin levels (a marker of intestinal permeability) and the inflammatory markers TNF-α and IL-6.¹⁵⁰ Other research with this same animal model found a reduction in burn-induced intestinal permeability and disruption of tight junctions when collagen peptides were supplemented early after injury.¹⁵¹ Findings from cellular studies with Caco-2 cell monolayers (a common model for studying intestinal permeability) also suggest collagen peptides reduce intestinal permeability induced by the inflammatory trigger TNF-α.^152,153

Curcumin

Curcuma longa is well-known for its impact on inflammation and has been studied for numerous conditions in which inflammation plays a role, including IBS. A systemic review and meta-analysis of five randomized controlled trials found that curcumin did not have a significant impact on IBS symptoms; however, the studies were fairly heterogeneous as they included both variable doses and combinations including other nutrients.¹⁵⁴ It was noted that three of the five studies independently found positive and significant effects on IBS symptoms. In one large non-placebo-controlled trial included in the review, consumption of 72 or 144 mg Curcuma longa extract daily for eight weeks significantly reduced IBS prevalence and improved quality of life.¹⁵⁵

Additional Support

Stress-modifying natural therapies. Several natural compounds, including adaptogenic and nervine herbs (eg, Bacopa, holy basil, lemon balm, and ashwagandha) may benefit IBS sufferers by mitigating stress.

Research on Bacopa monnieri indicates it has adaptogenic effects and can significantly decrease stress-related anxiety.^156,157 In a 6-week, randomized, controlled trial, Bacopa (in combination with another herb) was found to be particularly beneficial in IBS-D.¹⁵⁸ More stress-reduction strategies are discussed in Life Extension’s Stress Management protocol.

Dietary considerations, such as reducing daily intake of caffeine and fatty foods, may benefit individuals with IBS.¹⁵⁹ Individuals with IBS are often aware of some foods that exacerbate symptoms; thus, they may be able to improve symptoms by avoiding those foods.¹⁶⁰ If one is not aware of specific food triggers, a food and symptoms diary may be useful in identifying specific contributors to symptoms.^161,162

Note: People who have ever had an eating disorder, among whom IBS is fairly common, should approach dietary restrictions judiciously as they may exacerbate eating disorder behavior.¹⁶³

Low-FODMAP Diet

A low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet is based on the hypothesis that poorly absorbed carbohydrates allow excess undigested carbohydrates to reach the lower GI tract (large intestine). There, undigested carbohydrates can stimulate the growth of microbes and/or are fermented, producing hydrogen gas, leading to bloating, flatulence, diarrhea, and constipation.^164,165 Theoretically, the restriction of fermentable foodstuffs deprives the gut microbiota of their energy source and results in decreased symptoms. However, the long-term effects of a low-FODMAP diet have not been well characterized, and beneficial microbiota, such as Bifidobacteria, also rely on FODMAPs as a food source—in fact, most prebiotics fall into the high-FODMAPs category.¹⁶⁶

Foods typically avoided on a low-FODMAP diet are those that contain high levels of fructo-oligosaccharides (eg, wheat, rye, onions, garlic, artichokes), galacto-oligosaccharides (eg, legumes), lactose (eg, milk), fructose (eg, honey, apples, pears, watermelon, mango), sorbitol (eg, apples, pears, stone fruits, sugar-free mints/gums), and mannitol (eg, mushrooms, cauliflower, sugar-free mints/gums).

A 2018 systemic review and meta-analysis supports the use of a low-FODMAP diet for the treatment of IBS, finding that adhering to the diet was associated with a reduction in global IBS symptoms compared with control, although quality of evidence was considered to be low.¹⁶⁷ In one study, subjects with IBS assigned to a low-FODMAP diet experienced significant improvement in their symptom response (ie, bloating, abdominal pain, and flatulence) relative to a standard diet group.¹⁶⁸ These results are supported by a later study showing that people with IBS guided to eat a low-FODMAP diet experienced a significant decrease in abdominal pain.¹⁶⁵

Reintroduction of foods as tolerated should be considered as long-term adherence to a low-FODMAP diet has been shown to lead to unfavorable changes in the gut microbiome.¹⁶⁶ In IBS patients who followed a low-FODMAP diet for three months, which led to significant improvements in symptom severity and quality of life, this initial symptomatic improvement was maintained after reintroduction of challenge foods (increasing fiber intake) for the next three months.²⁵

Gluten-free Diet

While a gluten-free diet is required for people with celiac disease, there is a wide spectrum of non-celiac gluten sensitivity symptoms that may present like IBS.¹⁶⁹ Gluten is found in grains (eg, wheat, barley, rye), breads, pasta, etc. Similar to the gluten-free diet, the low-FODMAP diet also restricts gluten. Both diets are used to manage food sensitivities, suggesting gluten sensitivity might be a more common contributor to IBS symptoms than previously thought.¹⁷⁰ Following a gluten-free diet also reduces dietary consumption of fructans, a FODMAP, which one small study pointed to as a factor possibly leading to IBS symptoms rather than gluten.²⁴

In one double-blind, randomized, placebo-controlled study of IBS sufferers who specifically did not have celiac disease, addition of gluten worsened abdominal pain, bloating, fatigue, stool consistency, and overall symptoms of IBS.¹⁷¹ However, as of mid-2021, only limited evidence supports adherence to a gluten-free diet as a strategy for the treatment of IBS symptoms.^167,172

Bulking Agents

Bulking agents (ie, dietary fiber and fiber supplements) are frequently used to treat IBS. Dietary sources of fiber include whole grains, oats, fruit, vegetables, beans, lentils, and nuts and seeds; psyllium husk powder is a common source of supplemental fiber. Insoluble fiber facilitates defecation by reducing transit time (the time it takes for the remains of ingested food to be excreted) while soluble fiber increases stool viscosity. A 2018 review and meta-analysis by the ACG found that fiber improved overall IBS symptoms. However, when broken down by fiber type, it was found that psyllium (mostly soluble fiber), and not bran (mostly insoluble fiber), was effective in treating IBS.²⁹

A potential side effect of fiber supplements is bloating and gas,⁵ which can exacerbate IBS for some individuals; thus, fiber intake should be increased gradually.

Additional Dietary Considerations for Irritable Bowel Syndrome (IBS)

In addition to the typical diet considerations discussed for the treatment of IBS thus far, certain additional consumables are also associated with IBS symptoms.

Both decaffeinated and regular coffee have been shown to stimulate colon motor activity.¹⁸¹ Individuals who regularly drink coffee were shown to be more likely to have IBS than those who never drink coffee. Higher intake of caffeine was also associated with increased rates of IBS compared with low intake, although when separated by gender, the relationship only held in women.¹⁸²

Excessive consumption of alcohol was also associated with increased gastrointestinal symptoms in individuals with IBS, although only women were surveyed in this population study.¹⁸³

Stress Reduction

Stress associated with early life adverse events is implicated in the etiology of IBS¹⁸⁵; about 50% of individuals who seek IBS treatment have depression or anxiety.¹⁸⁶ This relationship appears to be bidirectional, meaning IBS may cause stress and stress may contribute to IBS symptoms. This cycle may be partially attributed to enhanced sympathetic nervous system (“fight or flight”) signaling in people with IBS relative to healthy controls.¹⁸⁷

IBS symptoms appear to respond positively to stress reduction. In one study, a meditation-based intervention known as mindfulness-based stress reduction (MBSR) reduced the severity of IBS and stress symptoms in IBS patients, although improvements in mood and quality of life were similar to those of a control group of IBS patients who were placed on a waiting list for MBSR.¹⁸⁸ Furthermore, psychological therapies—including cognitive therapy, dynamic psychotherapy, and hypnotherapy—may be of some benefit to those with IBS.²⁹ In a 2018 publication on the treatment of IBS, the ACG concluded, “IBS patients treated with psychological therapies were more likely to improve than patients not treated with psychological intervention,” finding a number needed to treat of 4. However, they noted significant design differences among the 36 randomized controlled trials surveyed.²⁹

For more specific discussion on stress-reduction techniques and nutrients that may be of benefit, see Life Extension’s Stress Management protocol.

Cognitive behavioral therapy. To those unfamiliar with it, cognitive behavioral therapy (CBT) may seem intimidating and like a momentous undertaking. However, this form of therapy is focused on specific behaviors and thought patterns related to a complaint, whether it be IBS, insomnia, or a problematic behavior. Multiple studies have looked at different ways of applying CBT as a treatment for IBS, including via telephone, a web-based program, and with very minimal sessions.^189,190 Treatment with home-based CBT was found to moderately to substantially improve gastroenterologist-rated IBS symptoms in almost 56% of individuals after two weeks, while IBS education only led to similar improvements in about 40% of participants.¹⁹⁰ Six months after the end of treatment (which totaled four sessions over four weeks), a significantly greater improvement was still seen in the group that received home-based CBT than in those who received IBS education.

Hypnotherapy. Hypnotherapy is often misrepresented as a single session in which one is “reprogrammed” to not engage in a behavior; however, it is actually a specific psychology practice that occurs over many sessions. IBS happens to be one medical condition for which this therapy has been studied as the mind-body connection is well established and recognized even by traditional gastroenterologists.²⁹ Similar to CBT, hypnotherapy also has the possibility of being performed remotely, and even can be done in a group.^191,192 In IBS patients who still had symptoms despite previous treatment attempts, 12 weeks of weekly hypnotherapy sessions (applied in a psychology practice setting) significantly improved IBS-related symptoms at three months compared with controls. Additionally, the improvements seen at three months were maintained at one year.¹⁹³

In a three-arm study comparing individual or group hypnotherapy to control (IBS educational support), both forms of hypnotherapy were significantly more effective than control for adequate relief of symptoms at three months when treatment ended, as well as at nine months later. For each intervention, six sessions occurred biweekly during the treatment period. Interestingly, in the per-protocol analysis, more participants in both hypnotherapy groups reported adequate relief at 12 months versus three months, when the sessions had just been completed.¹⁹⁴ Findings from both studies suggest the improvements were maintained after the course of treatment despite the fact that IBS is typically a chronic or recurrent condition.^194,195

Exercise

Although particularly intense exercise, especially in hot environments, can be a contributing factor to IBS (as discussed in section on causes and risk factors for IBS), exercise can also be beneficial for IBS patients. In one study, subjects who engaged in 20–60 minutes of moderate-to-vigorous physical activity 3‒5 days per week experienced a marked improvement in quality of life that was associated with reduced IBS severity.¹⁹⁶ Aerobic exercise at a lower intensity threshold and of shorter duration has also been shown in clinical studies to benefit those with IBS. Thirty minutes of treadmill exercise three times a week for six weeks significantly improved IBS symptoms and IBS-related quality of life compared with control (no prescribed exercise) and baseline in one small trial.¹⁹⁷ Another study considered possible mechanisms by which exercise may influence IBS, finding that low-to-moderate levels of exercise attenuated levels of inflammatory cytokines and oxidative stress while enhancing levels of antioxidants. The alterations of these parameters correlated with improvements in IBS symptoms.¹⁹⁸ Even walking regularly has been shown to improve symptoms of IBS, and it additionally had a positive effect on mood.¹⁹⁹

Yoga is another form of exercise that has been studied in the context of IBS, as well as numerous other stress-associated conditions. Compared with adhering to a low-FODMAP diet, engaging in a yoga session twice weekly led to similar improvements in IBS symptoms at 12 and 24 weeks. Of note, both groups were given guidance to only follow the prescribed intervention for 12 weeks; however, statistically significant benefits were still seen at 24 weeks.²⁰⁰ Another study compared three arms: yoga with limited conventional treatment, yoga with conventional treatment, and the control group. Yoga sessions occurred three days per week. Significant improvements were seen in IBS symptom severity and quality of life scores in both yoga groups compared with control. In the yoga groups, there also were significant improvements in several other parameters, including flexibility and autonomic function, which correlated with a reduction in medication and supplement use.²⁰¹ A systemic review and meta-analysis of six trials considering yoga as a treatment for IBS also found a beneficial effect over conventional treatment, with improvements in bowel symptoms, IBS severity, and anxiety, as well as other parameters. However, the authors noted major flaws in the study methods that prevented them from making a strong conclusion that yoga should be recommended for individuals with IBS.²⁰²

Acupuncture

Several clinical trials suggest acupuncture may alleviate IBS symptoms.^203-207 A multicenter, randomized, controlled trial found acupuncture (18 sessions) was significantly more effective than standard pharmaceutical treatments (polyethylene glycol [PEG] given at 20 g/d for constipation-predominant IBS or pinaverium bromide given at 150 mg/d for IBS-D) for reducing IBS symptom severity scores on all domains after six weeks of treatment. Post-hoc analysis also suggested the responder rate with acupuncture remained higher than among those receiving pharmaceutical treatment 12 weeks after the intervention was completed.²⁰³ Another study compared treatment with acupuncture at specific points (noted to be key for treatment of diarrhea) to treatment with pinaverium bromide in people with IBS-D. After six weeks of treatment and at the three-month follow up, IBS-quality of life and symptom severity scores in the acupuncture group were significantly better than baseline. At both six weeks and three months, symptom severity scores were significantly lower in the acupuncture group than those treated with pinaverium bromide, while quality of life scores were significantly higher in the acupuncture group at three months.²⁰⁴ Two meta-analyses also found acupuncture to be more effective than pharmaceutical treatment of IBS, and to have the least severe side effects; however, there was no difference in symptom severity or quality of life when comparing acupuncture to sham acupuncture.^208,209

The cause(s) of IBS are not clear.²¹⁰ Stress, GI tract hypersensitivity, altered gut microbiota, intestinal inflammation, genetics, and food sensitivities may all be involved.^211-213 One theory proposes that altered serotonin metabolism within the GI tract and/or abnormalities in pain perception pathways cause hypersensitivity to abdominal sensations or pain.¹⁸⁶ Other hypotheses suggest stress-induced inflammation, gastroenteritis, and a history of traumatic events may contribute to the development of IBS.^185,213,214

Disrupted Gut-Brain Communication

Some evidence suggests alterations in the bidirectional communication between the brain and gut may contribute to IBS symptoms.^215-218 The mechanisms behind these phenomena are unclear, but some studies have identified altered autonomic and central nervous system function in individuals with IBS.^219-221 Studies also point to the gut microbiome as a mediating factor in altered gut-brain communication in the context of IBS.²¹⁵ Additional studies employing magnetic resonance imaging to examine the brains of people with IBS have identified some structural changes and heightened visceral stimuli response that may contribute to enteric hypersensitivity.^222-224

Stress and anxiety appear to contribute to gut hypersensitivity via modulation of neural pain-processing pathways by glucocorticoid hormones, which are also called “stress hormones.”²²⁵ Moreover, alterations of the microbiome have been observed in mood disorders, which frequently also present with IBS symptoms; these microbiome changes may contribute to both IBS and mood disorders.^226-229 Persistent systemic and neuroinflammation may be another factor in altered gut-brain communication and IBS symptoms.²¹²

Several studies suggest impaired gut-brain communication may stem from altered levels of chemical messengers called neurotransmitters. Levels and activity of the neurotransmitter serotonin in particular appear to be somewhat abnormal in people with IBS.^230,231 Serotonin affects intestinal motility and may be a factor in visceral hypersensitivity and intestinal permeability.^232-236 Enteric serotonin levels are regulated by the serotonin reuptake transporter (SERT). An increase in SERT expression leads to lower enteric serotonin levels and contributes to constipation-predominant IBS (IBS-C), while a decrease in SERT expression increases serotonin levels in the gut and can be a factor in IBS-D.²³⁷

Dysbiosis

One consistent finding associated with both IBS-D and IBS-C is dysbiosis —a pathogenic alteration in the gut microbiota which can cause or exacerbate IBS symptoms in a variety of ways.^31,238 Dysbiosis is associated with increased intestinal permeability (often referred to as “leaky gut”) whereby pathogens, toxins, or undigested foods that are not usually absorbed are able to pass into the bloodstream. This can trigger abdominal pain and altered bowel habits. Dysbiosis can also lead to aberrant immune system activation, resulting in the release of cytokines that increase abdominal pain perception and alter bowel habits.²³⁹

People with IBS produce an abnormally high amount of gas in response to certain foods, particularly those high in fermentable carbohydrates, and this may be attributed to dysbiosis.²⁴⁰ Increased gas formation results in an increase in abdominal bloating, abdominal pain, and flatulence that can often be reversed by avoiding those foods.¹⁶⁸ Studies have also determined that the gut microbiota may alter levels of neurotransmitters and steroid hormones, another mechanism possibly linking anxiety and depression with IBS.²⁴¹

Small intestinal bacterial overgrowth (SIBO) is a condition characterized by overgrowth of microbes in the small intestine. As a result, fermentation of food begins before it has been thoroughly digested and absorbed, which can lead to gas formation.^242,243 The formation of gases (typically hydrogen, but also methane) after consumption of a fixed amount of carbohydrates and their exhalation via respiration is typically used for the diagnosis of SIBO; however, the gold standard for diagnosing SIBO is microbial investigation of fluids collected from the small intestine.²⁴⁴ SIBO is more common in people with motility disturbances, low stomach acid production, and bowel obstruction.²⁴³ The prevalence of SIBO in IBS varies across studies, but estimates range from about 20‒84%.^10-12 A 2018 systematic review and meta-analysis found SIBO to exist in IBS 38% of the time, being more common in females, older people, and those with IBS-D.²⁴⁵

Obesity is a risk factor for the development of SIBO, and the link has been shown to be unrelated to alterations in bowel transit time or stomach pH.^246,247 Other risk factors for SIBO include proton pump inhibitor use, chronic pancreatitis, immunodeficiencies, altered anatomy, small intestinal disease (including IBD and celiac disease), and chronic liver disease.^248,249

Intestinal Inflammation

Historically, the presence of intestinal inflammation was considered a differentiator between IBS and IBD, only being a factor in the pathology of IBD. Now, intestinal inflammation is recognized as a factor in IBS. However, inflammation in IBS is distinctly different from the inflammatory profiles of IBD.^210,212,250 Increased numbers of lymphocytes, mast cells, and eosinophils have been shown in different regions of the intestine in individuals with IBS, while elevated levels of proinflammatory cytokines have also been shown both locally in the gut and systemically.^210,251-254 These activated immune cells release inflammatory mediators including nitric oxide, histamine, proteases, and tryptase, which studies suggest contribute to increased intestinal permeability, pain, and other IBS symptoms.^210,255,256

Food Intolerances & Sensitivities

Food intolerances and sensitivities may have a role in IBS. Please see the “Dietary Considerations” section of this protocol for further exploration of this topic.

Gluten sensitivity. Gluten is a protein component of some grains, especially wheat. Sensitivity to gluten is common and is associated with a spectrum of symptoms ranging in severity from minor skin conditions to severe GI compromise in the case of celiac disease, which should be ruled out as a cause of symptoms.^257-260 Some evidence suggests gluten sensitivity potentially contributes to IBS symptoms; however, gluten-containing foods also often contain fructans, which may cause the symptoms.^24,260,261 A population survey of 1,002 individuals in the UK self-reporting gluten sensitivity (with the possibility of celiac disease ruled out) found that 20% of them met the Rome III criteria for IBS compared with 3.9% of those not reporting gluten sensitivity.²⁶² Although evidence is not yet strong enough to support a recommendation that all IBS patients avoid gluten, findings from at least one study indicate that using a blood test to detect IgG antibodies against components of wheat may help identify patients with IBS-D who are likely to respond positively to a gluten-free diet.²⁶³ Individuals who are HLA-DQ2 or HLA-DQ8 positive (at risk for celiac disease but not diagnosed with the condition) have also been shown to have altered bowel movement frequency and increased intestinal permeability with gluten consumption and may want to avoid gluten.²⁶⁴

Carbohydrate malabsorption. Lactose, the sugar found in dairy products, is broken down by the enzyme lactase, found on the mucosal lining of the intestine. Reduced levels of this enzyme lead to lactose intolerance, which manifests with symptoms similar to IBS after the consumption of lactose-containing dairy. Lactose intolerance can be present from birth, develop with increasing age, or arise secondary to GI infection or other stress that affects the brush border lining of the intestine.²⁶⁵

Fructose, a sugar naturally found in fruits, can also contribute to IBS-type symptoms if poorly absorbed. In one study of 209 individuals with IBS symptoms, of the 80 individuals diagnosed with IBS by the Rome II criteria, 31 were found to have fructose intolerance by a positive fructose breath test.²⁶⁶ High-fructose foods include fruit juices, apples, grapes, watermelon, and honey. Processed foods sometimes contain added fructose; this added fructose may be listed on labels under various names, including high-fructose corn syrup, agave syrup, or simply “fructose.”

Sugar alcohols are also a common trigger for IBS symptoms. These include xylitol, sorbitol, mannitol, and erythritol. Sugar alcohols have a sweet taste and a lower caloric value than sugar, so they are commonly added to foods intended to be lower calorie or to support healthy blood sugar. At high doses, sugar alcohols can lead to IBS-type symptoms in both individuals with IBS and healthy subjects.²⁶⁷

Post-infectious IBS

It is not uncommon for IBS to arise following a GI infection. This is called post-infectious IBS, or PI-IBS, and occurs in up to about 30% of individuals who contract an acute GI infection.^268,269 PI-IBS is not limited to bacterial and parasitic infections, but also can be secondary to viral gastroenteritis.²⁷⁰ Symptoms of PI-IBS typically resemble IBS-D and can be present for several months after the infection.^269,270

Irritable bowel symptoms are thought to arise following enteric infection due to inflammatory damage to the gut epithelium, which increases intestinal permeability and alters levels and activity of digestive enzymes found in the brush border lining. Additional factors that may contribute to development of PI-IBS include alterations in intestinal flora, bile malabsorption, and altered levels of immune responders that influence serotonin levels.^268,270-274 Some estimates suggest as many as one-third of all IBS cases may arise post-infection.²⁷⁵

Sex Hormones

As women are twice as likely as men to be affected by IBS, numerous studies have looked at the role sex hormones may play in the condition.²⁷⁶ In general, intestinal transit times may be slower in women, even more so during the luteal phase (after ovulation) of the menstrual cycle, and women are more likely to experience constipation-predominant IBS.^3,277 Women also often experience worsening of IBS symptoms around menstruation, which coincides with natural changes in sex hormone levels.²⁷⁸ Evidence regarding the effect of menopause and associated changes in hormone levels on IBS frequency and severity is mixed.^279-282

There are several possible mechanisms by which hormonal variations could influence IBS susceptibility or severity. For instance, differing expression of estrogen receptors in the GI tract among women compared with men may be a factor, as estrogen may relax gastric muscle cells.²⁸³ Also, testosterone may have antinociceptive effects and may influence pain and temperature sensation in the GI tract. Sex steroids influence the GI microbiome, which may play a role as well.²⁸⁴

Studies assessing the effects of hormone replacement therapy (HRT) in women with IBS are generally lacking. However, some observational evidence suggests HRT may be associated with increased IBS risk.²⁸⁵ More studies are needed to clarify the potential role of sex hormones in IBS and assess the influence of HRT in this context.

Exercise

Although physical activity is often prescribed as a lifestyle intervention for treating IBS, intense exercise can be a factor contributing to it. In endurance athletes, IBS often goes undiagnosed, and symptoms are worse during training and competition.⁸ Factors that can contribute to IBS in athletes are increased intestinal permeability due to heat and/or intense exercise, acute psychological stress, and immune activation.^104,286,287

Medications that may Contribute to IBS

Certain medications may contribute to the development of IBS. Proton pump inhibitors (eg, omeprazole [Prilosec]), which are used to treat heartburn, can alter intestinal barrier function and affect the intestinal microbiota; and these drugs are known to have a positive association with IBS.²⁸⁸ Similarly, many common analgesics, such as non-steroidal anti-inflammatory drugs, can damage the intestinal epithelium, an important barrier against harmful substances. This tissue damage may compromise intestinal permeability.^289,290 Although broad-spectrum antibiotics are designed to target systemic infections, antibiotics are known to alter the colonic microbiota. Indeed, a retrospective study showed that the use of broad-spectrum antibiotics, particularly macrolides (eg, erythromycin) or tetracyclines (eg, tetracycline, doxycycline), was associated with IBS development.²⁹¹

Although medications that interact with serotonin receptors are at times used for the treatment of IBS, they also can contribute to it. For example, tricyclic antidepressant drugs like amitriptyline inhibit peristalsis and may worsen IBS-C.²⁹² Antidepressant medications also can contribute to diarrhea.²⁹³ Opiate pain medications are also well-known for their constipating effects.²⁹⁴

The cardinal symptoms of IBS are abdominal pain (typically related to defecation) and altered bowel habits.^295,296 Pain or discomfort associated with IBS typically “flares” for several days intermittently.

Other symptoms not directly associated with the GI tract have been reported in some IBS patients, including headache, backache, anxiety or depression, and lethargy.^297,298

Diverticulitis (inflammation/infection of small pouches in the digestive tract) is more common with IBS and can be problematic if not appropriately treated; however, IBS does not increase risk for serious conditions like colon cancer nor is it associated with increased mortality.^186,299,300

Diagnosing IBS is complex and often involves multiple tests to rule out several other diseases that may be associated with IBS-like symptoms, such as^{30,160,301-303}:

• hyper- or hypothyroidism
• celiac disease
• lactose or fructose malabsorption
• IBD
• giardia or other enteric infection
• microscopic colitis
• diverticulitis
• colon cancer and/or pancreatic cancer

A complete blood count and blood chemistry panel may be ordered as well to assess for anemia or other abnormalities.

The specific criteria used to diagnose IBS have changed over the years and currently the Rome IV criteria is most widely used. The Rome IV criteria are more restrictive than previous versions, so not as many people meet the diagnostic criteria for IBS as used to be the case.¹ The Rome IV criteria does not include abdominal discomfort and requires a higher frequency of abdominal pain (at least one day per week vs. three days per month) than Rome III for diagnosis. Although bloating is also a very common symptom, it is not required for diagnosis.³⁰

According to the Rome IV criteria, a diagnosis of IBS requires recurrent abdominal pain, (on average, at least one day per week during the past three months) with at least two of the following characteristics:

1. related to defecation
2. associated with a change in stool frequency
3. associated with a change in stool appearance

As different treatments may be indicated for those with constipation-predominant IBS (IBS-C) versus diarrhea-predominant IBS (IBS-D), knowledge of which subtype a patient experiences can be useful. By the Rome IV criteria, IBS is considered IBS-C if more than 25% of bowel movements are classified as Bristol Stool Scale Types 1-2 and less than 25% are Types 6-7. The subtype IBS-D is the opposite of this with more than 25% of bowel movements classified as Bristol Stool Scale Types 6-7 and less than 25% being Types 1-2. In Rome IV classification, these criteria are only applied during days with abnormal bowel movements (ie, during flare-ups).³⁰⁴

IBS treatment aims to alleviate predominant symptoms, such as diarrhea, constipation, or abdominal cramping.⁵ Dietary and lifestyle strategies, discussed at length in their respective sections of this protocol, are usually suggested as first-line interventions in the conventional treatment of IBS, particularly in those with mild or intermittent symptoms.³⁰⁵ The therapeutic options discussed in the remainder of this section may be implemented in addition to dietary and lifestyle changes based upon the characteristics of each case.

Laxatives

Laxatives that draw water into the colon are often used by clinicians to treat constipation-predominant IBS (IBS-C).^5,306 These treatments typically provide rapid relief, but are not recommended for long-term use as they can cause electrolyte imbalances by enhancing the excretion of fluids.³⁰⁷ The most common laxatives work by osmosis, that is, they draw fluid into the intestine producing softer stools that are easier to pass.

Polyethylene glycol. Polyethylene glycol (PEG, commonly prescribed as MiraLAX) is one of the most studied laxatives; it has a better side effect profile compared with lactulose (another osmotic laxative).³⁰⁸ However, possible side effects of PEG are bloating and abdominal pain, and dosing should be gradually increased to help lessen their likelihood. Treatment of patients with IBS-C with PEG has been shown to significantly improve spontaneous bowel movements, stool consistency, and severity of straining within 28 days compared with placebo.³⁰⁹

Lubiprostone. Lubiprostone (Amitiza) is a prostaglandin E1 analog that stimulates fluid secretion into the intestine by directly and selectively acting on the chloride receptor ClC-2.³¹⁰ Lubiprostone is indicated for IBS-C in the United States.^306,311 Lubiprostone has been shown to act quickly to facilitate defecation, relieve discomfort, and resolve abdominal pain.^310,312 A meta-analysis of studies including 1,366 patients with IBS-C found that lubiprostone improved spontaneous bowel movements at all time points assessed between one week and three months, also significantly improving abdominal pain especially after one month of treatment initiation.³¹³

Linaclotide. Linaclotide (Linzess) activates a receptor in cells on the intestinal surface called the guanylate cyclase 2C receptor, which stimulates intestinal fluid secretion and softens the stool making it easier to pass. Linaclotide is effective in attenuating IBS-C, chronic constipation, and abdominal discomfort. Linaclotide was approved by the Food and Drug Administration (FDA) in 2012 for the treatment of IBS-C; however, as long-term risks are unknown, it is limited to use in patients unresponsive to PEG. In two large randomized clinical trials, linaclotide safely and effectively treated bowel and abdominal symptoms associated with chronic constipation.³¹⁴ In patients with IBS-C, linaclotide was shown to significantly improve IBS-C including symptoms of abdominal pain, complete and spontaneous bowel movements, bloating, straining, and stool consistency. Diarrhea was the most common adverse effect, leading to study discontinuation by 5.7% of participants.³¹⁵

Tegaserod. Tegaserod (Zelnorm, Zelmac) is a 5-hydroxytryptamine-4 (5-HT4) partial agonist that has been studied and shown to accelerate small bowel transit time and colonic emptying. 5-HT4 receptor agonists stimulate colonic motility by increasing peristalsis and the release of neurotransmitters, which also can modulate visceral hypersensitivity.³¹⁶ In patients with IBS-C, tegaserod taken twice daily was shown to significantly improve abdominal discomfort, bloating, and constipation compared with placebo.^317,318 Common adverse events are diarrhea, headache, abdominal pain, and flatulence.³¹⁹

Anti-diarrheal Medications

There are several different medications used to mitigate the diarrhea of IBS. These medications rely on a variety of mechanisms to decrease peristalsis and prolong transit time, including interacting with opioid receptors, acting as a bile acid sequestrant, and antagonizing serotonin receptors.

Eluxadoline. Eluxadoline (Viberzi) is a mixed opioid receptor agonist and antagonist approved for the treatment of diarrhea-predominant IBS (IBS-D), although it is contraindicated in individuals who do not have a gallbladder and have a history of biliary disorders, pancreatitis, or alcohol use disorder, among other things. A review of three clinical trials, including 3,235 patients with IBS-D, found eluxadoline was significantly superior to placebo for the treatment of IBS-D and significantly improved stool consistency.^29,30

Loperamide. Loperamide (Imodium, among others) is another antidiarrheal agent that interacts with opioid receptors to inhibit peristalsis and increase transit time. It also has antisecretory activity and reduces fluid and electrolyte loss.^320,321 Loperamide has been shown to be effective for reducing stool frequency and improving consistency; however, the results are mixed with regard to its impact on pain.^322,323 In two ACG position papers (2018 and 2021) on the management of IBS, loperamide is not recommended as a first-line therapy due to the limited trials and small number of patients included, as well as its inability to improve global IBS symptoms.^29,30

Bile acid sequestrants. Bile acid sequestrants (eg, cholestyramine [Prevalite], colestipol [Colestid]) also can be effective for the treatment of diarrhea. It has been shown that a substantial percentage of individuals with IBS-D have bile acid malabsorption which can be the cause of functional diarrhea.³⁰⁵ In a randomized controlled trial of 24 patients with IBS-D, the bile acid sequestrant colesevelam (Welchol) significantly increased ascending colon emptying time by four hours compared with placebo; however, overall colon transit time was not significantly increased. Treatment with colesevelam significantly improved ease of stool passage and was associated with a somewhat firmer stool consistency.³²⁴ In an eight-week, randomized, open-label, controlled trial of patients with varied subtypes of IBS, treatment with colestipol significantly improved IBS symptoms.³²⁵

Alosetron. Alosetron (Lotronex), an antagonist of the 5-HT3 serotonin receptor, is used in females to treat severe IBS-D that is unresponsive to other treatments.^5,186,326 By blocking the 5-HT3 receptor, alosetron modulates visceral sensation and reduces colonic motility.³²⁷ A meta-analysis of 14 randomized controlled trials found that alosetron or cilansetron, another 5-HT3 antagonist, were more effective than placebo or mebeverine (an anti-spasmodic agent) for improving abdominal pain and discomfort and IBS symptoms overall in patients with non-constipated IBS or IBS-D.³²⁸ In one randomized clinical trial in women with severe IBS-D, alosetron was found to have significant beneficial effects versus placebo on numerous markers of quality of life (eg, emotional and mental health, sleep, energy, etc.) as well as workplace productivity.³²⁶ However, alosetron may cause significant side effects including severe constipation and loss of blood flow to the colon, although the latter is fairly uncommon.^328-330

Medications for Abdominal Pain & Bloating

Antispasmodic medications. Antispasmodic medications can help reduce the pain and discomfort associated with IBS and may be used on an as-needed basis, but generally are not taken long-term. Antispasmodics relax the intestinal smooth muscle of the lower GI tract and thus may reduce not only pain but also fecal urgency.³³¹ There are several different commonly used medications that fall into this category. The 2018 ACG position paper on the management of IBS recommends the use of antispasmodics for overall symptom management, finding from the review of 26 randomized controlled trials that the use of antispasmodics (including 13 different medications) significantly improved IBS symptoms with the number needed to treat being 5. Of the different antispasmodic medications, otilonium bromide (Spasmomen, among others) and pinaverium bromide were the most studied with both being shown to be effective for treatment of IBS with a low number needed to treat of 5 and 4, respectively. While the other antispasmodic medications were less studied, all were found to be more effective than placebo with a low number needed to treat.²⁹ However, in their 2021 guidelines, the ACG recommends against antispasmodics available in the United States, namely dicyclomine (Bentyl), hyoscyamine (Levsin, among others), and hyoscine (Scopolamine), due to lack of evidence supporting their efficacy.³⁰

Antidepressants. Although best known for the treatment of mood disorders, antidepressants are another class of therapeutic agents that can be used in IBS treatment.³⁰⁶ As previously described, serotonergic signaling can affect not only motility but also visceral hypersensitivity. Tricyclic antidepressants (TCAs) have central analgesic effects as well as peripheral anticholinergic effects which also may slow transit time; thus, they may not be an appropriate choice for constipation.³³² In addition to TCAs, selective serotonin reuptake inhibitors (SSRIs) are the second-most-studied category of antidepressants used in the treatment of IBS. The 2018 and 2021 ACG position papers recommend TCA use for overall symptom improvement, while SSRIs are only weakly suggested in the 2018 guidelines, based on the low quality of evidence for their use.^29,30

While a 2015 meta-analysis of 12 randomized controlled trials found treatment with antidepressants improved global IBS symptoms, a subgroup analysis found only TCAs, not SSRIs, were effective.³³³ However, in the analysis of seven randomized controlled trials discussed in the 2018 ACG position paper it was found that SSRIs were effective for reducing IBS symptoms although there was significant differences in study design in the trials assessed.²⁹ The ACG noted that due to the high rate of mood disorders in this population, providers still may elect to use these medications. There is a fairly high rate of adverse effects associated with antidepressant medications, particularly TCAs, which includes drowsiness and dry mouth. That said, lower doses of these medications are typically used to treat IBS than are used in mood disorders, which may lessen these effects.^29,334

Antibiotics. Although not broadly applied as a general treatment for IBS, the non-absorbable antibiotic rifaximin (Xifaxan) has become recognized in recent years as a treatment for non-constipated IBS patients—particularly when bloating is a symptom.²⁹ Rifaximin has been substantially studied and shown to be effective as a treatment for SIBO, which has been shown to be present in a high percentage of patients with IBS.^245,335 A meta-analysis of five trials in which rifaximin was used for the treatment of IBS found that, compared with placebo, it was effective for reducing global symptoms of IBS, and significantly improved symptoms of bloating. However, the number needed to treat was fairly high at approximately 10. Adverse events (including diarrhea) and discontinuation rates were similar between the treatment and placebo groups, and there were no reports of C. difficile -associated diarrhea.³³⁶ The 2021 ACG position paper recommends rifaximin use in IBS-D due to its improvement of abdominal pain and stool consistency and reduction of global IBS symptoms.³⁰

Evidence points to low-level inflammation and immune system activation as possible factors in IBS pathology.^{210,253,254,337,338} Thus, medications directed at addressing these and related factors have been investigated as possible treatments for IBS.

Mesalazine

The aspirin-like anti-inflammatory drug mesalazine (also known as mesalamine and 5-aminosalicylic acid [5-ASA]), which is used in the treatment of IBD,³³⁹ has successfully relieved IBS symptoms in clinical trials.³⁴⁰ In a trial of 360 subjects with varying types of IBS who were treated with 500 mg mesalazine four times daily or standard therapy for 28 days, mesalazine led to significant reductions in pain and symptom duration in most IBS subtypes. In addition, the treatment normalized stool patterns among subjects with IBS-D and lessened infiltration of immune cells into bowel mucosa.³⁴¹ In a placebo-controlled study of 148 patients with diarrhea-predominant IBS (IBS-D), treatment with 1,500 mg mesalazine daily was associated with a significantly greater portion of responders (defined as patients having improvements in both abdominal pain and stool consistency for ≥2 months) at three months.³⁴² However, in a 2016 study where the dosing was 2,000 mg twice daily, no benefit was seen for improving abdominal pain or stool consistency in patients with IBS-D.³⁴³ In the 2018 ACG position paper, the use of 5-ASAs, based on low quality of evidence, was weakly recommended against for overall symptom management in IBS; however, they also suggested these medications should be further studied based on existing clinical findings.²⁹

Mast Cell Stabilizers

Research suggests increased levels of mast cells and their activation and release of intracellular molecules (including histamine, tryptase and other proteases, serotonin, nitric oxide, and numerous cytokines and chemokines) may play a role in the pathogenesis of IBS.³⁴⁴ Thus, medications known as mast cell stabilizers have been investigated as a treatment for IBS in preclinical and clinical research with positive findings. Due to the various compounds they release when activated, mast cells are thought to be a factor in diarrhea and increased visceral sensitivity.³⁴⁵ One clinical trial assessed this specifically, finding that treatment with ketotifen, a mast cell inhibitor and antihistamine, for eight weeks increased the threshold for discomfort in IBS patients with increased visceral sensitivity. Ketotifen also significantly decreased abdominal pain and other IBS symptoms and improved quality of life scores.³⁴⁶

Multiple clinical studies with different cromoglycates (eg, disodium cromoglycate, cromolyn) have also shown improvements in IBS symptoms, mostly in patients with IBS-D. Findings of interest, in addition to improvement in overall symptoms, stool consistency, and abdominal pain, were that these mast cell stabilizers may decrease intestinal permeability and mucosal tryptase release, as well as alter the expression of genes associated with immune response and mucosal barrier function.³⁴⁷ However, most of the clinical studies were small and uncontrolled. In one large, unblinded, uncontrolled study of patients with IBS-D, improvement in symptoms with cromolyn were similar to that of individuals following an elimination diet (67% vs. 60% improvement, respectively). It was noted that response rates in both groups were greater in those having positive skin tests for dietary antigens.³⁴⁸

Numerous nutritional interventions, including essential fatty acids, vitamin D, carotenoids (eg, astaxanthin), palmitoylethanolamide (PEA), quercetin, and curcumin also help reduce mast cell activity and thus may be helpful in certain individuals with IBS.³⁴⁹

Serine Protease Inhibitors

Proteases (enzymes that break peptide bonds in proteins) are released by mast cells as well as other lymphocytes, intestinal cells, and the gut microbiota. The majority of these proteases are classified as serine proteases.³⁵⁰ The gut microbiota also produces protease inhibitors, exerting a regulatory effect on protease activity in the gut.³⁵¹ High levels of serine protease activity have been seen in fecal samples of IBD patients as well as individuals with IBS.^256,352-354 In mice, application of fecal supernatants from IBS-D patients increased perception of pain and colonic paracellular permeability, both of which were prevented by serine protease inhibitors.²⁵⁶ High fecal protease activity in IBS patients has been shown to be associated with symptom severity, higher intestinal permeability, and reduced microbial diversity.³⁵³ Additional animal models have also shown serine protease inhibitors have promise for improving this potential factor that may contribute to the development of IBS as well as its symptoms.^355,356

Transcutaneous Vagal Nerve Stimulation

Transcutaneous vagal nerve stimulation (tVNS) is a novel non-invasive technique by which the FDA-approved practice of vagus nerve stimulation is being applied to a variety of common conditions. Studies have been done showing its efficacy in conditions including migraines, symptoms of lupus, post-stroke motor recovery, and atrial fibrillation.^357-360 Its origins lie in the medical practice of invasive vagal nerve stimulation which is used in managing severe, treatment-resistant depression and epilepsy.³⁶¹ Human studies have also shown it has potential to intersect with the stress axis and thinking patterns, both of which may impact symptoms of IBS.^362-364

One small, open-label, pilot study looked at the impact of tVNS on IBS. In women with IBS (nine who completed the trial), the application of tVNS was shown to significantly improve symptoms of IBS at three and six months, although there were no changes in measured variables (transit time, blood cytokines, and fecal calprotectin).³⁶⁵ Specific to GI function, tVNS also has been shown in humans to induce gastric slowing by reducing myoelectrical signaling, reduce the development of and reverse established acid-induced esophageal hypersensitivity, improve gastrointestinal symptoms in Parkinson’s disease, and improve biomarkers related to postoperative ileus.^366-369