Non-pharmaceutical treatments for irritable bowel syndrome
BMJ 2024; 387 doi: https://doi.org/10.1136/bmj-2023-075777 (Published 16 December 2024) Cite this as: BMJ 2024;387:e075777
- Xiao Jing Wang, gastroenterology physician1,
- Elyse Thakur, clinical health psychologist2 3,
- Jordan Shapiro, gastroenterology physician4
- 1Mayo Clinic Rochester, MN, USA
- 2Atrium Health, Charlotte, NC, USA
- 3Wake Forest University School of Medicine, Winston-Salem, NC, USA
- 4Gentle GI, Houston, TX, USA
- Correspondence to: X J Wang Wang.xiao{at}mayo.edu
Abstract
Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction that impacts a significant portion of the population and is associated with substantial morbidity, reduced quality of life, and economic impact globally. The pathophysiology of IBS is complex and incompletely understood, and the heterogeneity of IBS is reflected in the variety of pharmaceutical and non-pharmaceutical therapies utilized for the management of IBS. Given limitations with pharmaceutical treatments, many patients with IBS seek non-pharmaceutical options. Several non-pharmaceutical treatments such as the low FODMAP diet and brain-gut behavior interventions such as gut directed hypnosis and cognitive behavioral therapy are now considered standard of care and are part of all major guidelines for the treatment of IBS. However, challenges with access to and optimal implementation of these therapies remain. This review focuses on the current evidence for common non-pharmaceutical treatments for IBS, including the latest advances in dietary and brain-gut behavioral care, in addition other complementary and integrative health practices and emerging therapies.
Introduction
Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction characterized by abdominal pain and change in the consistency and/or frequency of stools. Pathophysiology mechanisms are thought to be multifactorial involving altered brain-gut axis, increased visceral hypersensitivity, and gut microbial dysbiosis, among others that interact to produce symptoms (fig 1). Symptoms range from mild and intermittent to severe and daily.
Pathophysiology of irritable bowel syndrome (IBS) is thought to be multifactorial, involving an interaction among factors including genetic predisposition, altered brain-gut axis, increased visceral hypersensitivity, increased mucosal permeability, bile acid malabsorption, gut microbial dysbiosis, altered mucosal immune function, and altered motility. The interplay of these alterations culminates in patient symptoms. Adapted from figures from Mayo Clinic Media Library and Dreamstime.com (image ID 113236410 ©Kateryna Kon)
Despite several treatment options and consensus guidelines for the treatment of IBS, patients and providers are challenged by high costs of pharmaceutical treatments and tolerability.1 Patient interest in non-pharmaceutical treatment is multifactorial, including preferences for more natural treatments and/or perception of greater safety.23 US based guidelines by the American Gastroenterological Association (AGA) for the pharmacological treatment of irritable bowel syndrome with diarrhea (IBS-D) and irritable bowel syndrome with constipation (IBS-C), which are not within the scope of this article, are available for guidance on available pharmaceutical treatment options.45 This review aims to highlight current and emerging non-pharmaceutical treatment options for IBS to aid general practitioners and gastroenterologists in expanding their clinical toolkit for this common disorder. Emerging treatments include novel treatment approaches that are promising but in need of further study. Emerging treatments that are derived from established approaches are discussed within the section; those that are novel are presented separately. International guideline consensus for non-pharmaceutical options, when included, is summarized in table 1.
Summary of non-pharmaceutical interventions for IBS in international guidelines
Epidemiology
IBS has a global prevalence of about 4% in adults with female predominance (5.2% in females v 2.9% in males) and declining prevalence with age (5.3% in 18-39 years old v 1.7% in those >65 years old).14 The Second Asian Consensus and Indian Society of Gastroenterology IBS guidelines report equal sex prevalence.1112 IBS does not increase mortality, but patients experience substantial morbidity with impaired quality of life.15 In a survey of 1885 patients with IBS, symptoms affected productivity 8.0 days with 1.5 days of missed school or work per month. In exchange for one month of relief from IBS, more than half of patients surveyed would give up caffeine or alcohol, 40% would give up sex, 24.5% would give up cell phones, and 21.5% would give up the internet for one month.16 Another study found that IBS patients would sacrifice 10-15 years of life expectancy for an immediate cure.17
A study of direct (eg, healthcare professional consultations) and indirect (eg, absenteeism, presenteeism, and productivity loss due to unpaid labor) costs found quarterly mean total costs per patient of $2444 (£1907; €2262), with indirect costs ($1525) greater than direct ones ($909). Mental healthcare visits made up a greater portion of direct care costs than gastroenterology visits.18 Health economics studies suggest that from a payor and utilization standpoint, targeting global symptoms with non-pharmaceutical options such as diet and cognitive behavioral therapy (CBT), as well as neuromodulators is more cost effective with similar health outcomes, largely because of prescription drug costs.19 From a patient perspective, insurance covered drug options are more cost effective owing to lack of reimbursement and out of pocket costs for many non-pharmaceutical options.20 Short and long term costs, including accounting for treatment durability, need to be considered when choosing a treatment plan.
Sources and selection criteria
We searched the literature utilizing PubMed from March 2013 to March 2023 searching “Irritable Bowel Syndrome” or “IBS” and “treatment” filtered by clinical trial, meta-analysis, randomized controlled trial, and systematic reviews in adult, human subjects. This initial search yielded 992 articles. A second search was undertaken of APA PsycINFO, EBM Reviews-Cochrane Central Register of controlled trials and systematic reviews, Embase, and Ovid MedLine from inception to 2023. These were cross referenced and added to the initial search for comprehensive review. This yielded a total of 1582 articles that were manually reviewed by at least two authors per article for relevance and rigor of the research conducted. The heterogeneous nature of non-pharmaceutical treatments and vast breadth of therapeutics that have been tried in the treatment of IBS meant that interventions included were selected on the basis of inclusion in currently available guidelines, availability of robust evidence, approval of the US Food and Drug Administration, and in consultation with patient advocates. Studies were included if they were primary randomized clinical trials (RCTs) or systematic reviews or meta-analyses. Randomized trials that were small in size were included and mentioned as such if study methodology was of high quality; low quality individual RCTs were not included. Pharmaceutical treatments, basic science studies, pediatric studies, case studies, and pathophysiology (non-treatment) studies were excluded. Narrative review articles were included to review references to primary trials, which were then included if relevant. In the case of highly relevant articles published after the search period, all three authors were required to agree on addition to the manuscript.
Diet
Dietary management of IBS is important to patients and providers. Fiber, in dietary and supplement form, is a mainstay of treatment for IBS and is recommended in multiple guidelines as front line therapy for global symptom improvement as defined by the FDA as a primary outcome of IBS therapeutics (includes overall wellbeing and symptom severity).7 A survey found that more than 80% of IBS patients reported food related symptoms, with greater numbers of culprit foods reported in patients with more severe IBS.21 Therefore, restrictive or elimination diets are often tried. These diets range from specific food restrictions (eg, lactose free or gluten free diets), to larger dietary shifts such as the Mediterranean diet, the National Institute for Health and Care Excellence (NICE) dietary guidance, or a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet. In a survey of >1500 gastroenterologists, roughly 60% reported that patients link food with symptoms, and most utilized a trial and error approach or lactose/gluten-free diets. Fewer used the low FODMAP diet,22 often because of the lack of registered dietitian with suitable expertise. Although many variations of elimination and restrictive diets exist, this review is limited to diets recommended by guidelines and those with evidence in IBS treatment (table 2).
Diet guidelines
Fiber
Dietary fibers are a variety of non-digestible plant based carbohydrates that are not absorbed by the small intestine and differentially impact the digestive system depending on interaction with colonic microbiota,24 Insoluble fibers are found in peelings of fruits and vegetables, seed, whole grains, and wheat bran; they increase stool bulk while stimulating colonic motility and mucus production. This can contribute to common IBS symptoms such as bloating and abdominal discomfort.7 Soluble fiber is found in psyllium (synonymous with ispaghula husk), corn fiber, calcium polycarbophil, methylcellulose, oat bran, and the flesh of fruits and vegetables. Soluble fiber mixes with and holds water in the intestine, and can be categorized into viscous or non-viscous, short or long chain carbohydrates, and highly or minimally fermentable types. Short chained and highly fermentable fibers (eg, oligosaccharides) can trigger IBS symptoms through bacterial byproducts, but might also have beneficial effects as prebiotics.7 Soluble fiber comes in many forms including powder, gummies, wafers, and capsules to improve palatability. All forms might have sugar, artificial sweeteners, and/or fillers that can contribute to bloating and osmotic diarrhea.
The most often recommended soluble fiber for IBS is psyllium, which is viscous and minimally fermentable. Psyllium holds water in the lumen of the intestine and improves colonic transit without worsening IBS symptoms, especially in those with IBS-C. Psyllium might benefit patients with IBS-D because of its viscosity, as its gel-forming nature may add bulk to stools and reduce urgency. A systematic review and meta-analysis of 14 randomized controlled trials (RCTs) involving 906 IBS patients found a significant benefit of fiber in global symptoms of IBS (RR=0.86; 95% CI 0.80 to 0.94, NNT=10; 95% confidence interval (CI) 6 to 33), though the benefit was only seen in soluble fiber (RR=0.83; 95% CI 0.73 to 0.94, NNT=7; 95% CI 4 to 25) and not with bran (insoluble fiber) (RR=0.90; 95% CI 0.79 to 1.03).25 A more recent network meta-analysis of psyllium that included five RCTs and excluded two positive studies, however, found no benefit of psyllium over placebo (relative risk of failure to achieve global improvement 0.77 (0.58-1.02)), although only one of the included studies was considered low risk of bias.26 In a double-blind crossover trial, addition of dietary fibers did not alter symptom response in patients with IBS treated with the low FODMAP diet but did augment stool bulk and normalize low stool water content and slow transit.27
On the basis of this evidence, most international guidelines recommend soluble but not insoluble fiber for the treatment of global IBS symptoms. The AGA suggests a fiber intake of about 25 to 35 grams per day7 with slow increase to help prevent gas and bloating. Exceeding this goal is unlikely to improve and might worsen IBS symptoms.
Kiwifruit
Interest in both green and golden kiwifruit has arisen over the past few years from studies exploring the use of kiwifruit for the treatment of IBS-C. The first RCT compared two green kiwifruits per day with placebo capsules in IBS-C and healthy controls and found statistically significant decreases in colon transit time and increases in defecation frequency but no impact on pain.28 A more recent international multicenter RCT randomized healthy controls (n=63), patients with functional constipation (n=60), and patients with IBS-C (n=61) to consume two green kiwifruits or psyllium (7.5 g) daily. Kiwifruit consumption was associated with a significant increase in weekly bowel movements (P=0.0003) and reduced gastrointestinal discomfort (P< 0.0001).
Although evidence to support the use of kiwifruit as a treatment modality is limited given the small sample sizes, it is an encouraging example of dietetics, using food as therapy. The intervention is relatively safe and accessible, but it is important to note that some people might be allergic to kiwifruit or develop an oral allergy syndrome owing to cross-reaction in those allergic to birch tree pollen. Individuals with latex allergy might be more likely to have an allergy to kiwifruit.
NICE dietary guidance
Dietary recommendations by NICE were first released in 2008 and updated in 2017, focusing on optimizing eating habits and lifestyle changes.29 NICE guidance is less restrictive compared with many other dietary recommendations for IBS and includes many suggestions for behaviors such as having regular meals, taking time to eat, avoiding missing meals, and getting adequate exercise and relaxation, in addition to dietary changes/restrictions (table 2). NICE guidance recommends the low FODMAP diet if symptoms do not improve.
Mediterranean diet
The traditional diet consumed in Mediterranean countries emphasizes minimally processed, plant based foods, nuts and healthy fats, and limited amounts of red meat and refined grains. Previous research has shown a reduced prevalence of disorder of gut-brain interaction in children and adolescents more adherent to a Mediterranean diet, but had not studied impact on existing IBS symptoms.3031 A six week unblinded RCT of a Mediterranean diet (n=29) versus habitual diet (n=30) found that a greater proportion of people in the Mediterranean diet group had reduced gastrointestinal symptoms (24/29, 83% v 11/30, 37%, P<0.001), as well as improved depression scores. No differences were seen between groups in FODMAP intake at week six, gastrointestinal adverse events, or microbiome parameters.32 A cross-sectional, retrospective analysis of 106 patients with IBS and 109 healthy controls found that adherence to a Mediterranean diet was not associated with improved overall IBS symptoms, though certain pro- and anti-Mediterranean diet foods (table 2) were associated with more symptoms.33 This diet has many overall benefits23 but needs more evidence for use specifically in IBS.
Low FODMAP diet
The low FODMAP diet was first reported in a hypothesis paper in 2005, suggesting that reduction of certain fermentable short chain carbohydrates could improve symptoms of IBS by decreasing distention of the intestinal wall and reducing osmotically active compounds, thereby decreasing pain and diarrhea, respectively.34 Other research has highlighted the potential of high FODMAP foods, in susceptible individuals, to alter the microbiome, increase lipopolysaccharides that disrupt and cross the intestinal epithelial barrier, and subsequently activate mast cells, causing pain and diarrhea.35 The low FODMAP diet is delivered in three phases: elimination, reintroduction, and personalization.
The low FODMAP diet has been studied extensively as summarized in table 3. An older RCT comparing the low FODMAP with the modified NICE diet (mNICE) in IBS-D patients found no statistically significant difference in primary outcomes of adequate relief or composite outcome of pain and bowel movement changes.36 In secondary outcomes, the low FODMAP diet group had more abdominal pain responders and lower pain, bloating, consistency, and urgency scores.36 Post hoc analyses showed greater improvements in health related quality of life, anxiety, and activity impairment.42 A 2022 systematic review of 13 RCTs showed superiority of low FODMAP diet to habitual diet and all other dietary interventions.38 In primary care, an RCT showed superiority of the low FODMAP diet over antispasmodics as early as four weeks with results continuing at 16 week follow-up.39 A single center, single-blind, three-arm RCT with 294 patients showed a higher proportion of those following four weeks of low FODMAP diet and NICE guidance achieved symptom improvement by IBS-SSS (irritable bowel syndrome symptom severity scale) over baseline compared with fiber optimized diet or optimized medical management. Adherence was over 90% in all groups with limited adverse events.40
Studies related to low FODMAP diet
Most low FODMAP diet studies have only assessed the elimination phase of the three phase treatment. One randomized crossover trial of 50 IBS patients showed that the elimination phase led to reduced symptom severity and improved quality of life which was sustained through re-introduction.41
Restrictive diets carry risks of dietary deficiencies over time. In the low FODMAP diet, studies have shown fiber intake decreases during elimination but normalized after re-introduction.41 Post-hoc analysis of RCT data found both low FODMAP and mNICE diets resulted in decreased caloric intake, fewer daily meals, and fewer daily carbohydrates consumed. Patients on the low FODMAP diet had a decline in several micronutrients, but only riboflavin remained significantly decreased after correcting for calorie-adjusted nutrient intake. Fewer patients on the low FODMAP diet met the recommended intakes for thiamine and iron, and fewer in the mNICE met recommended intakes for calcium and copper.43 Micronutrient deficiencies are more likely with longer time in the elimination phase, emphasizing the importance of a three-phase approach.
The recent AGA Clinical Practice Update on the use of diet for IBS highlighted the importance of the three phases of the low FODMAP diet. The elimination phase is intended to last four to six weeks and might be considered a diagnostic test to determine if and how much FODMAPs contribute to an individual’s symptoms. If there is no improvement, then the prior diet should be resumed and other treatment options explored. Patients who respond to the elimination phase then enter the second, reintroduction, phase, during which foods from different high FODMAP groups are slowly added back to identify specific triggers. Careful monitoring of symptoms during this phase allows for development of the final, personalization phase where patients continue an individualized diet that maximizes diet variety and minimizes triggers. The guideline takes special care to recommend screening patients who are being considered for any elimination diet for eating disorders or disordered eating given the potential harm in this population.7 The rising awareness of avoidant restrictive food intake disorder (ARFID) has highlighted that disordered eating is a spectrum, and what begins as food restriction to avoid symptoms might lead to mealtime anxiety or full blown eating disorders.44
Given the costs (specialized foods, registered dietitian visits) and potential risks (micronutrient deficiencies, disordered eating) of a low FODMAP diet, researchers have sought to assess who is most likely to respond using baseline breath testing. A prospective cohort study using baseline hydrogen breath testing found an area under the curve for predicting low FODMAP diet response of 0.692 (95% CI 0.51 to 0.86, P<0.05) using a cutoff hydrogen level of 8 parts per million (sensitivity 66.7%, specificity 82.4).45 Studies utilizing other lactose or fructose intolerance breath testing are lower quality with unclear utility in IBS.46 Breath testing is not recommended by any guidelines for the prediction of response to the low FODMAP diet.
International guidelines generally support use of the low FODMAP diet with guidance from a registered dietitian, differing only in positioning of therapy (table 1). Further studies are needed to predict who will respond to dietary intervention.
Dietary and herbal supplements
Glutamine
The essential amino acid L-glutamine, thought to help maintain intestinal integrity, was studied in an eight week, double-blind, randomized, placebo controlled trial of 54 patients with post-infectious IBS.47 Symptom improvement by IBS-SSS was seen in 43/54 (79.6%) patients in the glutamine group and 3/52 (5.8%) of placebo (RR 63.8 95% CI 16.7 to 244.0; P<0.0001) with reduction in all secondary endpoints, including intestinal permeability, in the glutamine arm with no serious adverse events.
A RCT of 50 IBS patients from two gastroenterology clinics found that patients on low FODMAP diet plus 15 g/day of glutamine had statistically significant changes with improvement in IBS-SSS, satisfaction with bowel habits, and less interference with community function compared with low FODMAP diet alone.48 Glutamine requires further study but might have an adjunctive role in certain patients.
Vitamin D
Vitamin D is a fat soluble vitamin with a primary role in the regulation of intestinal calcium/phosphate absorption and bone remodeling.49 The utility of vitamin D in IBS is mixed. Low vitamin D concentrations have been linked to increased intestinal permeability, alterations of the microbiome, inflammation, mood disorders, and reduced quality of life49 and deficiency has been associated with more severe IBS symptoms.50 An RCT of 116 patients comparing vitamin D supplementation with placebo showed improvements in IBS-SSS, IBS-QOL (Quality Of Life questionnaire), and total symptom scores (P< 0.05) in patients receiving vitamin D51 Another RCT of 74 people with IBS and vitamin D deficiency/insufficiency comparing vitamin D3 weekly versus placebo found significant improvements in IBS-SSS, and decrease in interleukin-6 values (P<0.01 and P=0.02, respectively).52 However, two systematic reviews and meta-analyses from 2022 – one with four RCTs (n=335)53 and the other with six RCTs (n=616)54—came to different conclusions. The first found that vitamin D is statistically significantly superior to placebo for the treatment of IBS and the second that it was associated with improvement in IBS-QOL but not IBS-SSS. Excess vitamin D supplementation can cause acute hypercalciuria and hypercalcemia, and chronic intoxication might lead to nephrocalcinosis, pain, and bone demineralization.55 Given the potential risks and conflicting results in trials, vitamin D supplementation can be considered for short term trial treatment with careful monitoring for toxicities.
Microbiome based therapeutics
Prebiotics and probiotics
Interest in manipulation of the gastrointestinal microbiome for the purposes of health date back more than a century and included concepts such as “intestinal auto-intoxication” which was thought to drive aging and illness.56 As alterations in the microbiome became linked to IBS, studies of probiotics for treatment increased and use became more common.5758 IBS, like many conditions, has broad patterns of microbial changes rather than a single microbiome signature, making hopes for precise, sustained microbiome manipulation to treat IBS an ongoing, unmet challenge and an area of active research.5960
Probiotics
Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.61 A systematic review and meta-analysis of 53 RCTs (n=5545) found that probiotics had beneficial effects on global IBS symptoms and abdominal pain. It was not possible, however, to conclude which species, strains, or combinations of probiotics to recommend.62 The 2020 AGA guideline for probiotic use across gastrointestinal disorders8 reviewed 76 RCTs with 44 different probiotic strains or combinations used to treat IBS. It found statistically significant heterogeneity in study design, outcome, and probiotics used, and evidence for publication bias, leading to no recommendation for clinical use of probiotics in children and adults with IBS outside of clinical trials. The authors suggested stopping probiotics use owing to cost and limited evidence to suggest lack of harm. Although the US based AGA and ACG guidelines for treatment of IBS do not recommend probiotics, the British Society of Gastroenterology (BSG) guidelines for the treatment of IBS acknowledge evidence limitations but advise interested patients to pursue a time limited trial (12 weeks) and discontinue if no improvement (weak recommendation, very low quality of evidence) (table 1).6
Prebiotics
Prebiotics are substrates selectively used by host microorganisms to confer health benefits. A systematic review and meta-analysis of 11 RCTs (n=729) found no differences in overall responders, severity of abdominal pain, bloating and flatulence, quality of life, or adverse events.63 The roles of prebiotics and probiotics in IBS is currently unclear.
Fecal microbiota transplant (FMT)
Given its success in microbiome restoration after infection with Clostridium difficile, FMT has been explored as a way of improving dysbiosis in IBS patients. A systematic review and meta-analysis of eight RCTs (n=472) found no statistically significant difference between the FMT and control groups for IBS symptom severity at any time point and that positive effects wear off over time with low success rates with attempted re-administration.64 A systemic review, pairwise meta-analysis and network meta-analysis of seven RCTs (n=470) showed no advantage of FMT over placebo in pooled analyses but found FMT via duodenoscope and nasojejunal tube were superior to placebo in subgroup analyses.65 The original efficacy study used a superdonor (a donor whose stool results in significantly more successful FMT outcomes than other donors) and suggested that this plays a more important role in FMT for IBS than in FMT for recurrent C difficile infection.66 Studies have shown that antibiotic pretreatment significantly reduces the engraftment of the FMT in patients with IBS-D67 and that patients with more severe IBS had greater response rates compared with those who have moderate IBS in a post-hoc analysis of a prior randomized trial of FMT v placebo.68
From a safety standpoint, a review of more than 1000 patients who received FMT for C. difficile infections found the incidences of serious adverse events including death and infection to be 3.5% and 2.5%, respectively. A 2019 FDA safety alert reported two cases of invasive extended-spectrum beta-lactamase producing Escherichia coli in patients receiving FMT; one case, in a neutropenic patient post-bone marrow transplant, was fatal.69 FMT was also linked to seven cases of Shiga toxin-producing E coli, which were undetected despite screening.70 Recommended screening protocols for FMT donors are rigorous, involving questionnaires of general health and habits as well as extensive stool testing.71
FMT has not shown statistically significant benefit in IBS and carries risk of serious adverse events including infection. Multiple international guidelines currently do not recommend FMT for IBS treatment (table 1). However, given patient interest72 and the role of dysbiosis in IBS, this remains an area of study as advancements in oral microbiome therapeutics progress.
Brain-gut behavior interventions
Brain-gut behavior therapies
Brain-gut behavior therapies (BGBTs) include classes of therapeutic approaches that incorporate techniques that directly target modifiable psychosocial and physiological processes that dysregulate the brain-gut axis (fig 2).7374 Cognitive behavioral therapy (CBT)75 and gut directed hypnotherapy (GDH)76 are the most evidence based BGBTs for IBS, both with durable treatment response after therapy completion.777879Other emerging approaches include self-management training, mindfulness based stress reduction, psychodynamic-interpersonal therapy, and emotional awareness and processing approaches.7480 Factors such as anxiety and depression,81 learned behaviors and early life adversity have been shown to impact stress sensitivity, which can disrupt brain-gut processing and negatively impact gastrointestinal related pain pathways, visceral hypersensitivity, and gastrointestinal motility.82 When IBS symptoms become severe, this increases disease burden and hinders health related quality of life.14 Brain-gut behavior therapies can address coping deficits,83 reduce arousal, and improve self-regulation.84 These approaches are particularly effective when integrated in gastroenterology practice settings and administered by mental health professionals specifically trained in psychogastroenterology.8485 ACG guidelines conditionally recommend that BGBTs can be used to treat global IBS symptoms for patients who do not have severe psychiatric comorbidities but this is based on low quality evidence.9
Conceptual model of why and for whom brain–gut behavior therapies best work on the basis of hypothesized targets. Thicker lines represent greater evidence supporting target engagement for a technique. Adapted from Burton Murray H, Ljótsson B. Future of brain–gut behavior therapies: mediators and moderators Gastroenterol Clin N Am 2022;51:723-39
Cognitive behavioral therapy is a skills based approach that aims to target cognitive, affective, and behavioral processes, which trigger and/or exacerbate IBS symptoms. Skills training can incorporate a combination of relaxation strategies, cognitive restructuring, problem solving/emotion focused coping skills, exposure, and behavioral changes. Contextually based CBT approaches, such as acceptance and commitment therapy (ACT), are emerging BGBTs that incorporate techniques that target psychological flexibility and enhance behaviors that align with a patient’s values.74 One quasi-experimental study of ACT showed improvement in depression and psychological capital in IBS patients.8687 Gut directed hypnosis, delivered over a set series of spaced sessions, involves a deep state of relaxation and focused attention that increases receptivity to suggestion. A recent systematic review and network meta-analysis of 41 RCTs (n=4072) found CBT (self-administered, minimal contact, or face to face) and GDH to be the most efficacious of several psychological therapies. In patients with refractory symptoms, CBT and GDH were more efficacious on a pooled relative risk of remaining symptomatic than education, support, or routine care controls in regard to their effect on IBS symptoms, but no single form of psychotherapy was superior to another.88
Self-management training programs target self-efficacy74 and have been shown to have a positive impact on IBS health outcomes. For example, a systematic review and meta-analysis of 10 RCTs (n=886) demonstrated that compared with controls guided self-help interventions (GSH) for IBS had a medium effect size for the decrease in IBS symptom severity (SMD=0.72; 95% CI 0.34 to 1.08) and a large effect size for the increase in patient’s quality of life (SMD=0.84; 95% CI 0.46 to 1.22).89 Similarly, a systematic review of minimal contact psychological treatments for symptom management of IBS found that minimal contact interventions reduced IBS symptom severity and improved quality of life.90 Mindfulness, a therapeutic technique involving conscious, judgment-free awareness of the present moment, has been shown to reduce IBS symptom severity and improve stress related outcomes in an RCT.91 Psychodynamic-interpersonal therapy approaches aim to improve interpersonal functioning through the development of a collaborative patient-provider relationship92 and have been shown to be effective in improving IBS symptoms (such as diarrhea and intermittent abdominal pain) in an RCT. Other emerging emotion focused interventions include emotional awareness training, which in RCT alongside symptom oriented medical treatment, was more effective at reducing abdominal pain in patients with IBS as compared with medical treatment alone.93 Another RCT showed that written expressive disclosure, involving four brief writing sessions about deep thoughts and feelings about IBS, improved pain self-efficacy and reduced healthcare utilization compared with controls.94 Similarly, a RCT of a brief, emotional awareness and expression therapy intervention that targeted emotional avoidance in patients with a history of trauma and emotional conflicts, reduced IBS symptom severity and improved quality of life in patients with IBS.95 Other emerging transdiagnostic approaches that target emotional dysregulation from a CBT approach, including the Unified Protocol for Emotional Disorders, have been adapted for IBS, demonstrating a statistically significant decrease in depression, anxiety, stress, and gastrointestinal symptoms and statistically significant improvements in emotion regulation among patients with IBS, although larger RCTs are needed to confirm these findings.96
Despite robust evidence of benefit, widespread adoption of BGBTs has been limited by access, cost, provider expertise, time required, and patient related factors (eg, stigma). Traditionally, CBT is administered face to face in an individualized or group format, but advances in technology have allowed for development of minimal contact or self-administered delivery. This has prompted studies exploring alternative delivery mechanisms including in group sessions or in digital delivery. RCTs have shown benefit for group CBT compared with waitlist controls in drug refractory IBS,97and both group and individually nurse administered GDH were effective at improving IBS symptoms, psychological symptoms, and quality of life for patients with IBS.98
Digital delivery of psychologically based therapies
Digital therapeutics, which allow self-administration of therapeutic tools have been developed to increase access for BGBTs. Mahana IBS, an unguided web based CBT program which is no longer available, was the first FDA cleared digital therapeutic for IBS, and demonstrated promise for improving IBS symptom severity as well as psychological factors in pilot trials.99 A subsequent multicenter RCT showed that two digital applications of CBT: telephone based CBT (TCBT) and web based Mahana IBS (WCBT) had statistically significant improvements in IBS symptom severity, quality of life, and mood, at 12 months. Compared with treatment as usual (TAU) (IBS-SSS=205.6) IBS symptoms were 61.6 (95% CI 33.8 to 89.5) points lower (P<0.001) in TCBT on the IBS-SSS and 35.2 (95% CI 12.6 to 57.8) points lower (P=0.002) in WCBT. Compared with TAU (Work and Social Adjustment Scale (WSAS) score=10.8), WSAS was 3.5 (95% CI 1.9 to 5.1) points lower (P<0.001) in TCBT and 3.0 (95% CI 1.3 to 4.6) points lower (P=0.001) in WCBT. Compared with TAU (mean Hospital Anxiety and Depression score=15.0 (SD=7.2), scores were an estimated 2.8 (95% CI 1.5 to 4.1) points lower (P<0.001) in the TCBT and 2.3 (95% CI 1.0 to 3.7) points lower (P=0.001) in the WCBT,100 with sustained benefits at 24 months.101 This provides further evidence for CBT as one of the most durable IBS treatment options. A similar CBT based app, Zemedy, has also been shown to significantly reduce IBS symptom severity and improve quality of life in the treatment group compared with a waitlist control group in a crossover RCT (F1,79=20.49, P<0.001, Cohen d=1.01, and F1,79=20.12, P<0.001, Cohen d=1.25, respectively).102
Digitally delivered GDH has also been developed. A retrospective evaluation of n=190 patients with self-reported IBS who completed Nerva, a GDH app, showed 64% responded positively, defined as a >30% reduction in abdominal pain.103 An RCT of digital GDH delivered by another app, Regulora, showed 30.4% of patients met primary endpoint (abdominal pain response, defined as ≥ 30% reduction from baseline in average daily abdominal pain intensity 4 weeks post treatment) but changes were not statistically significant over muscle relaxation control (P=0.5352).104 Although an RCT (n=20) showed that web based hypnotherapy was slightly less effective than face-to-face treatment on the primary outcome (65% of subjects had a 50 point or more reduction in the IBS symptom severity score versus 76%, respectively), access to care was improved.105 Overall, these alternative delivery methods improve patient access and allow additional care options with similar patient outcomes but evidence quality is still low.
Other complementary and integrative health approaches
Peppermint oil (Mentha piperita)
Peppermint oil has antispasmodic properties that have been well studied for the treatment of IBS and is suggested for relief of global IBS symptoms as a conditional recommendation in the ACG9 as well as the BSG guidelines.6 A recent systematic review and meta-analysis that included 10 RCTs (n=1030) found peppermint oil more efficacious than placebo for global IBS symptoms (RR of not improving=0.65; 95% CI 0.43 to 0.98, NNT=4) and abdominal pain (RR of not improving=0.76; 95% CI 0.62 to 0.93, NNT=7).106 The peppermint oil group experienced more adverse events, which were predominantly mild symptoms of reflux, dyspepsia, and flatulence (RR of adverse event 1.57; 95% CI 1.04 to 2.37, NNH=14.5).106 Patients should be counseled about GERD as a potential side effect.6
Cannabis (Cannabis sativa)
Cannabis sativa (“marijuana”) is frequently used for recreational and medicinal purposes, with the first medicinal uses dating back to 4000 BC. The C sativa plant contains over 400 compounds, though the psychoactive cannabinoids, Δ-9 tetrahydrocannabinol (Δ-9-THC) and cannabidiol (CBD) are the best understood.107 These interact with the body’s endocannabinoid system, which consists of endogenous substrates, receptors, and enzymes for production and degradation of substrates.108
A small study using chewing gum containing 50 mg of CBD for the treatment of IBS found no difference in symptoms between treatment and placebo arms.109 A database study of 31 272 patients ages 15 to 54 years of age admitted for IBS showed an increased risk (adjusted OR 1.41, 95% CI 1.32 to 1.50) of hospitalization in patients using cannabis compared with those not using it.110 No studies of the whole cannabis plant on patients with IBS have been conducted at this time, in part owing to its controlled status in many parts of the world.
Several cannabis derivatives are being studied including dronabinol, a synthetic Δ-9-THC,111112113114 and olorinab, a highly selective peripherally acting cannabinoid 2 receptor agonist, both with no statistically significant benefits seen in IBS over placebo.115 Therefore, despite increased access and patient interest, the risks of cannabis based treatments for IBS outweigh benefits based on current trials. Their use is not recommended in the Joint Consensus of Italian Societies guidelines.10
Traditional medicine practices
The Second Asian Consensus guidelines12 suggests that traditional Chinese medicine could be helpful for some patients with moderate evidence based on a meta-analysis of 14 RCTs of traditional Chinese medicine in IBS-D patients with improvement of global IBS symptoms, abdominal pain, and diarrhea.116 A formulation called Tongxie Yaofang has been studied the most among numerous formulations with 23 trials in 1972 IBS-D patients.12 In a multicenter RCT of 1044 Chinese patients with IBS, Tongxie Yaofang was superior to placebo (79.3% responders v 31.9%) and similar to pinaverium (73.6% responders, chi squared >0.05) for treatment of abdominal pain.117 A network meta-analysis showed non-inferiority between traditional Chinese medicine and antispasmodics in global IBS symptom relief.118
Other ancient herbal medicine practices with evidence in IBS include Ayurvedic medicine,119 and Japanese Kampo agents including rikkunshito and keishikashakuyakuto.120 The Second Asian Consensus suggests Kampo could be considered effective with low grade evidence.12 More data are needed to recommend these formulations in global populations.
Other herbal formulations
There are numerous herbals and supplements used by patients for the treatment of IBS, some of which have been studied in literature. These include curcumin, fennel,121 turmeric,122 caraway oil,123 melatonin,124 aloe,125 ginger,126 berberine hydrochloride,127 and mixed agents such as STW5, which has shown efficacy in functional dyspepsia.128129
Acupuncture
Acupuncture, a Chinese technique dating back more than 2000 years,130 utilizes the insertion of thin needles into specified acupoints along 12 energy channels (“meridians”) to balance the flow of energy throughout the body. This technique has been studied in animal and human models of IBS with the goal of improving inflammation, visceral hypersensitivity, and central sensitization through change in functional connections, regulation of gut motility,131132 modulation of serotonin response,133 and downregulating overexpression of substance P and vasoactive intestinal peptide in IBS-C populations.134135
A 2006 Cochrane review136 comprising six individual trials, found acupuncture was not superior to sham acupuncture (RR 1.28 (95% CI 0.83 to 1.98, n=106), but was superior to herbal medications (RR 1.14, 95% CI 1.00 to 1.31, n=132) and as an addition to psychotherapy compared with psychotherapy alone (RR 1.21 (95% CI 1.03 to 1.39, n=100). The overall quality of the trials, however, was low with significant heterogeneity, preventing conclusive assessment. Since then, multiple studies and meta-analyses have been conducted trying to clarify the benefit of acupuncture in IBS. A 2014 meta-analysis137 of six RCTs (2000-2012), one with positive and five with no benefit in IBS, found a pooled benefit to acupuncture (OR 1.75(1.24 to 2.46)). Updated meta-analyses suggest acupuncture and sham acupuncture both performed better than drugs (including alosetron and rifaximin) with fewer side effects138139 with combination of acupuncture and medicines having higher benefit than acupuncture alone.139140 Impact was greater in IBS-D compared with all subtypes,138 and short term acupuncture treatment showed durable impact at 12 months, but not at 24 month follow-up.141 Overall, the quality of evidence supporting acupuncture remains low142 with no statistically significant differentiation between true and sham acupuncture.143
One challenge of evaluating the utility of acupuncture is heterogeneity in acupoints selected, which can vary depending on individual patient symptoms or vary between studies in similar patient populations. This led to a Delphi expert consensus group to establish acupuncture best practices to standardize treatment.144 In addition, sham acupuncture in trials is sometimes performed with blunt needling at the same acupoints as true acupuncture, effectively delivering acupressure, which has shown benefit on its own for symptom treatment,145146 bringing into question whether this is a true control.
Given this evidence, the utility of acupuncture remains unclear with a possible positive effect and low risk for adverse events. Studies suggest acupuncture might have a role as an adjunctive therapy to medications or psychotherapy with 12 month durability.141 Due to lack of benefit over sham, the Canadian Association of Gastroenterology guidelines do not recommend offering acupuncture for global IBS symptoms13; no mention is made in other guidelines thus far.
Electroacupuncture
Electroacupuncture is an emerging therapy that involves the use of small electric currents applied to acupuncture needles with the aim of enhancing the therapeutic effect of acupuncture. A RCT of 96 functional constipation patients in China compared electroacupuncture with mosapride with the electroacupuncture group showing improved weekly spontaneous bowel movements, stool consistency and ease of defecation with partial improvement in quality of life.147 A single blinded randomized trial of electroacupuncture v sham in women with constipation suggests that treatment with electroacupuncture enhances parasympathetic nervous system activity as measured by heart rate variability.148 The role of electroacupuncture in treatment of IBS remains unclear but holds promise given improvement in other constipation subtypes.
Mind-body interventions
Mind-body interventions, a complementary and integrative health approach, target “interactions among the brain, mind, body, and behavior, with the intent to use the mind to affect physical functioning and promote health.”149 Mind-body interventions utilized for IBS therapy include general exercise, yoga and tai-chi or qi-gong.
Exercise
Exercise in general has been shown to improve IBS symptoms through a variety of mechanisms with potential long term durability (>5 years).150 Low to moderate intensity aerobic exercise was shown in a RCT of 109 women to attenuate inflammation and signs of oxidative stress correlating with improvements in IBS symptoms.151 In patients with cognitive bias or poor coping styles, exercise combined with CBT seems to improve IBS symptom scores as well as coping and cognitive bias.152 A systematic review of 14 RCTs (n=683) showed statistically significant benefit for patients with IBS across a variety of aerobic and static activity, but studies had significant bias.153 A Cochrane review (11 RCTs, n=622) of physical activity including yoga, treadmill exercise, or generalized support to increase physical activity for the treatment of IBS concluded that physical activity might improve symptoms but not quality of life or abdominal pain with the quality of evidence deemed very low.154 The BSG guidelines strongly recommend regular exercise as a first line treatment for global IBS symptoms (weak quality evidence).6
Meditative movement (yoga/qi-gong)
Meditative movement practices, which combine postures/movements with meditation practice, can be used for stress sensitive disorders such as IBS. Yoga, originating in India, is among the most popularized meditative movement practice and involves three main components: asanas (physical postures), pranayama (breathwork), and dyhana (meditation). Yoga is hypothesized to correct parasympathetic underactivity in stress related disorders,155 and modulate stress induced immune responses,156 which improve IBS symptoms. Other forms of meditative movement include qi-gong and its martial arts form, tai-chi, both of which were developed in China thousands of years ago. Both involve postures and gentle movements conducted with mental focus, meditation, and breathing strategies to promote relaxation.
A systematic review of six RCTs of yoga for IBS found yoga to be more beneficial than conventional care, with statistically significant decreases in bowel symptoms, IBS symptom severity, and anxiety with improvements in quality of life, global symptoms, and physical functioning. No statistically significant differences were found between yoga and exercise, suggesting yoga to be equally effective as other movement practices. Yoga was concluded to be safe and feasible, with no adverse events in studies that reported safety data.157 Studies were deemed heterogeneous and had methodologic limitations, limiting generalizability and interpretation of implications. In line with increasing interest in digital health, virtual yoga programs were also shown in RCTs to be safe and feasible, with positive impacts on IBS symptom severity from baseline to follow-up in the yoga group but not in the advice only control group. There were no statistically significant differences between groups in symptom severity, but statistically significant improvements were seen for quality of life, fatigue, and perceived stress in the yoga group compared with control.158
From the success of yoga, other meditative movement therapies have emerged for treatment of IBS including tai-chi, and qi-gong. A virtual tai chi program was piloted for IBS-C patients in one single-arm trial and was found to be feasible with high satisfaction among completers, and statistically significant improvement in symptom severity from baseline to follow-up. Secondary outcomes were positive including improvements in other IBS symptom scoring measures, IBS related quality of life, measured abdominal diameter, and leg strength.159 Further studies are needed to draw conclusions.
Meditative movement might have benefit compared with other forms of meditation for this population because, in addition to increased activity, it downregulates the central nervous system, which challenges stagnation and arousal, both of which are potential factors in gastrointestinal dysregulation. Although many informal resources exist, further empirical research is needed to understand clinical utility
Physical/manual manipulations and biofeedback
Physical therapy, including manual manipulations, myofascial release, pelvic floor rehabilitation and biofeedback, have an important role in management of musculoskeletal and myofascial pain conditions, many of which are comorbid with IBS.
A 2014 systematic review evaluated five studies (n=204) utilizing osteopathic manipulation for IBS, finding pronounced short term benefits in IBS symptoms compared with sham or standard of care.160 Like acupuncture, studies of osteopathic manipulation utilize varied, individualized approaches, and lack standardized symptom severity or secondary outcome measures,160 making findings difficult to generalize and interpret. Except for a small RCT on micro-physiotherapy which showed improvement in IBS over sham,161 other manual therapies have evidence in comorbid pain conditions such as fibromyalgia162 but not in IBS.
A Cochrane Review of RCTs (n=300) assessed multiple biofeedback mechanisms including thermal (skin temperature, four trials), rectosigmoid (rectal manometry/barostat, one trial) , heart rate variability (pulse oximetry, two trials), and electrocutaneous biofeedback (two trials), all aimed at helping patients control their bodily processes (eg, heart rate, breathing) with the goal of modulating response. This review found high or unclear risk of bias in all studies with overall uncertain benefit of biofeedback for IBS symptoms.163 Further studies are required to understand which modality has benefit in IBS treatment.
Other emerging therapies
Polymethylsiloxane polyhydrate
Polymethylsiloxane polyhydrate (Enterosgel) is an orally consumed intestinal adsorbent that is classified as a medical device with no pharmacological action. Enterosgel was shown in vitro to bind bacterial toxins, endogenous and exogenous substances, immune proteins, and bile acids.164 In a RCT of 105 primary care patients with acute diarrhea, the Enterosgel group had shortened duration of diarrhea compared with the control (27 hours v 39 hours, HR 1.74 (95% CI 1.06 to 2.87), P=0.03) with no adverse events.165 A multicenter RCT of 440 patients with IBS-D showed that Enterosgel performed better than placebo in the composite primary outcome of pain reduction and stool consistency score (37.4% vs 24.3% (OR 1.95, NNT=8, P=0.002) and decreased stool urgency and frequency. Sixty per cent of patients reported adequate relief of symptoms with no increase in adverse events.166 This over-the-counter therapeutic can be considered for treatment of IBS-D and warrants further investigation.
Vagal nerve stimulation
Auricular nerve stimulation utilizes electrocutaneous stimulation at the auricular branch of the vagal nerve to achieve vagal nerve modulation, potentially impacting gut barrier function and inflammatory response to improve visceral hypersensitivity.167168 Trials have shown improvement in quality of life and IBS pain scores as well as number of spontaneous bowel movements in an IBS-C cohort.169
A percutaneous auricular nerve stimulator (IB-STIM) has received FDA clearance for use in adolescents with functional abdominal pain related disorder of gut-brain interactions on the basis of a randomized, sham controlled trial (n=115): 81% of the treatment group (versus 26% of sham group) showed global symptom improvement after three weeks of treatment with greater reduction of worst pain scores compared with sham (P<0·0001). The effect was sustained at 12 weeks follow-up. Side effects included ear discomfort, adhesive allergy, and syncope.170 This product is not yet available for adult IBS populations.
Vibrating capsule
An ingestible vibrating capsule (VIBRANT) has been approved for treatment of chronic idiopathic constipation (CIC) based on study data showing improvement in number of complete spontaneous bowel movements, straining, stool consistency, and quality of life compared with placebo capsule171 with similar results in a functional constipation population.172 Early evaluation of this capsule in patients with IBS-C and chronic constipation did not show statistically significant improvement in overall colonic transit compared with sham but at least 25% of the patients experienced increase in colonic transit speed.173 The utility of the vibrating capsule for IBS-C treatment requires further study.
Virtual reality
The use of virtual reality as a therapeutic tool has been studied over the past decade, with benefit in management of acute and chronic pain through proposed mechanisms of distraction, decreased sensitization, and management of symptom driven mood disturbance.174 Virtual reality for IBS treatment is being studied with programming specifically targeted to gut directed causes of pain, combining educational content, CBT techniques, and exposure therapies within an immersive virtual environment. Early studies show patient acceptance of the treatment modality with further studies on efficacy and mechanism of action currently under way.175
Guidelines
Table 1 contains a summary of international guidelines for non-pharmaceutical interventions in IBS.
Conclusion
Treatment of IBS has evolved over the past two decades with more options and evidence for non-pharmaceutical treatments (fig 3). International guidelines support the use of diet based interventions as front line therapy from increased soluble fiber to more general dietary changes (eg, NICE guidance, low-FODMAP diet). Guidelines overall support psychological and behavior based interventions with caveats to patient selection and differing suggestions for where these should be positioned. complementary and integrative health therapies including peppermint oil and traditional herbal based interventions are gaining acceptance with mixed recommendations in guidelines. Microbiome based therapies are similar with overall limited evidence and mixed support from guidelines for probiotic use and consensus that FMT is not currently recommended for IBS treatment. Continued areas of research and development blend traditional and modern techniques and include electroacupuncture, percutaneous vagal nerve stimulators, intestinal binders, vibrating capsules, digitally delivered psychotherapies, and virtual reality.
Irritable bowel syndrome is a multifactorial illness and should be approached in a multidisciplinary manner with a complement of therapeutic modalities to address that patient’s individual symptom phenotype. Therapeutic options include pharmacologic (drug) options, complementary and more “natural” products, diet based interventions, and those focused on mind-body interventions, spanning the spectrum of cognitively focused to more movement focused. Emerging therapies with devices and more invasive interventions can also have a role in treatment. Adapted from National Center for Complementary and Integrative Health. Complementary, Alternative, or Integrative Health: What’s In a Name? https://www.nccih.nih.gov/health/complementary-alternative-or-integrative-health-whats-in-a-name
IBS is a heterogeneous disorder and many of the non-pharmaceutical approaches aim to provide personalized therapy for patients within a standardized framework, leading to challenges in standardizing and interpreting research for many of these interventions. Future research directions for many of these options should include identifying optimal protocols/dosages and treatment durations. As the armamentarium for IBS treatment expands with increasingly refined options, we can offer growing hope for both patients and providers.
Questions for future research
Research questions
How do we standardize delivery of non-pharmaceutical therapeutics to better assess efficacy and effectiveness?
What is the cross cultural applicability of culturally rooted therapies from the culture of origin to a global population?
What is the role of digital therapeutics in improving care delivery and access?
How can we optimize implementation of evidence based non-pharmaceutical modalities in real world settings?
Patient involvement
We utilized patient input from clinical practice to include complementary and alternative therapies that are frequently explored or utilized from a patient standpoint. After drafting the paper, we involved well known patient advocates within the IBS space to review the paper to ensure all relevant and evidence based therapies were covered within the review.
Patient advocates Johannah Ruddy, president of Gastro Consulting and Communications, director of patient advocacy for Ardelyx, co-founder of Tuesday Night IBS, author of multiple books on patient centered communication in IBS, former chief operating officer and executive director of the Rome Foundation, Ceciel Rooker, president and executive director of the International Foundation for Gastrointestinal Disorders, an IBS patient advocate group, and Jeffrey Roberts, founder of IBS Patient Support Group and cofounder of Tuesday Night IBS, reviewed the paper and gave feedback which was incorporated into the final manuscript.
Acknowledgments
We thank Ceciel Rooker, Jeffrey Roberts, Johannah Ruddy, and Michael Camilleri for their time and input to enhance the quality of this review.
Footnotes
State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors
Contributors: XJW, ET, and JS all contributed to initial planning, literature search, article review, article selection, and drafting of the manuscript. Authors all contributed to revisions and the final product was reviewed and approved by all authors before submission. XJW is the guarantor.
Competing interests: The authors have no relevant conflicts of interest for disclosure.
Provenance and peer review: Commissioned; externally peer reviewed.