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Clinical & Systematic Reviews

The Effect of Dietary Intervention on Irritable Bowel Syndrome: A Systematic Review

Moayyedi, Paul1; Quigley, Eamonn M M2; Lacy, Brian E3; Lembo, Anthony J4; Saito, Yuri A5; Schiller, Lawrence R6; Soffer, Edy E7; Spiegel, Brennan M R8; Ford, Alexander C9,10

Author Information
Clinical and Translational Gastroenterology: August 2015 - Volume 6 - Issue 8 - p e107
doi: 10.1038/ctg.2015.21
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Abstract

INTRODUCTION

Dietary restriction has long been recommended for lower gastrointestinal symptoms,1 and many irritable bowel syndrome (IBS) patients feel that their symptoms relate to food sensitivity.2 Initial research suggested that dietary restriction might be effective,3 but further studies reported that diet did not have a major role in IBS. The previous American College of Gastroenterology (ACG) monograph on IBS concluded that there was insufficient evidence to recommend exclusion diets in IBS and their routine use outside of a clinical trial was not recommended.5 Since the publication of this monograph there has been a resurgence of interest in how gluten sensitivity may have a role in IBS6 and new exclusion diets have emerged, such as restricting fermentable carbohydrates including oligosaccharides, disaccharides, monosaccharides, and polyols (termed the FODMAPs (Fermentable Oligo-Di-Monosaccharides and Polyols) diet).7 There have been randomized controlled trials (RCTs) evaluating these approaches, but there has been no systematic review summarizing the evidence.

METHODS

Search strategy and study selection.

A search of the medical literature was conducted using MEDLINE (1946 to December 2013), EMBASE and EMBASE Classic (1947 to December 2013), and the Cochrane central register of controlled trials. RCTs examining the effect of excluding factors from the diet or supplementing the diet with fiber in adult patients (over the age of 16 years) with IBS were eligible for inclusion (Box 1). We contacted the authors of studies that evaluated functional gastrointestinal disorders that could have included IBS, but did not report this group of patients separately, for further information. Similarly, we contacted original investigators of studies who did not report dichotomous data, but were otherwise eligible for inclusion in the systematic review, to explore whether these data were available.

Box 1
Box 1:
Eligibility criteria

The literature search was performed as part of a broader exercise to inform an update of the ACG monograph on the management of IBS. Specifically, studies on IBS were identified with the terms irritable bowel syndrome and functional diseases, colon (both as medical subject heading (MeSH) and free-text terms), and IBS, spastic colon, irritable colon, or functional adj5 bowel (as free-text terms). These were combined using the set operator AND with diet, fat-restricted, diet, protein-restricted, diet, carbohydrate-restricted, diet, gluten-free diet, macrobiotic diet, vegetarian diet, macrobiotic diet, Mediterranean diet, fads, gluten, lactose intolerance, lactose, both as MeSH and free-text terms, or the free text terms FODMAP$, glutens, or food adj5 intolerance.

Articles in any language were eligible and were translated where appropriate. Abstracts were also eligible, and conference proceedings from United European Gastroenterology Week and Digestive Diseases Week between 2001 and 2013 were hand-searched to identify potentially eligible studies published only in abstract form. We also performed a recursive search of the literature from the bibliographies of all relevant studies retrieved from the electronic search. Two masked reviewers assessed potentially relevant articles using predesigned eligibility forms, according to the prospectively defined eligibility criteria (Box 1). We resolved any disagreement between investigators by consensus.

Outcome assessment.

The primary outcome was defined as global improvement in IBS symptoms. If this was not available, then improvement in abdominal pain was taken as the primary outcome. If neither of these outcomes were reported, then the trial was not eligible. Where more than one definition was provided for improvement in the primary outcome, the most stringent definition with the lowest placebo response rate was taken. Secondary outcomes included quality of life and adverse events.

Data extraction.

Two reviewers (PM and ACF) independently recorded data from eligible studies on to a Microsoft Excel spreadsheet (XP professional edition; Microsoft Corp, Redmond, WA). In addition to the primary outcome (Box 2), the following clinical data were extracted for each trial: setting (primary, secondary, or tertiary care-based), number of centers, country of origin, type of dietary restriction or fiber supplementation, duration of therapy, total number of adverse events reported, criteria used to define IBS, primary outcome measure used to define symptom improvement or cure following therapy, duration of follow-up, proportion of female patients, and proportion of patients according to predominant stool pattern. Data were extracted as intention-to-treat analyses, with all dropouts assumed to be treatment failures, wherever trial reporting allowed this.

Box 2
Box 2:
Data extraction methodology

Assessment of risk of bias.

Two independent reviewers (PM and ACF) assessed risk of bias using the Cochrane handbook risk of bias tool.8 This evaluates the method of randomization, whether allocation was concealed, method of blinding, the completeness of follow-up, whether there was evidence of selective outcome reporting, and other biases.

Data synthesis and statistical analysis.

If data permitted, we intended to summarize global IBS symptoms or abdominal pain persisting with intervention compared with control as a relative risk with 95% confidence intervals. If enough data were provided, these summary statistics would be pooled using a random-effects model,9 to allow for any heterogeneity between studies. Adverse events data was also summarized with relative risks if this information was provided.

RESULTS

Efficacy of dietary intervention in the treatment of IBS.

The search strategy provided 360 papers on dietary intervention to review. We identified 17 papers evaluating 1,568 IBS patients who were potential RCTs that evaluated dietary intervention in IBS.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 Only three papers10, 11, 12 evaluating 230 patients were eligible, and agreement between reviewers regarding eligibility was perfect (κ-statistic=1.0) (Figure 1). The remaining 14 papers13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 were excluded for a variety of reasons outlined in Table 1. The eligible studies are summarized in Table 2, but each evaluated a different dietary intervention, thus precluding meta-analysis (Table 3).

Figure 1
Figure 1:
Flow chart of papers evaluated for the systematic review of food elimination diets in irritable bowel syndrome (IBS). IgG, immunoglobulin G.
Table 1
Table 1:
Reasons for exclusion of potentially eligible papers that were considered for the dietary intervention in IBS systematic review
Table 2
Table 2:
RCTs eligible for inclusion in the dietary intervention in IBS systematic review
Table 3
Table 3:
RCTs of specific diets excluded from the dietary intervention in IBS systematic review
Table 3
Table 3:
Continued

Gluten-free diet.

There were four trials11, 18, 20, 23 in 400 IBS patients evaluating the impact of a gluten-free diet (GFD) on symptoms or a gluten challenge in patients who were sensitive to gluten (or in one case20 had a positive response to a low FODMAPs diet). Three trials11, 18, 23 reported that a GFD was effective in reducing IBS symptoms, or that a gluten challenge in those already on a GFD significantly increased symptoms. However, only one study11 met our eligibility criteria and the others were excluded because of a variety of reasons, including not assessing IBS symptoms,18 not treating for at least 7 days,20 or not being a randomized study.23 The eligible trial recruited 39 IBS patients who had normal duodenal biopsies and negative tissue transglutaminase and endomysial antibodies, but with symptom improvement on a GFD. Patients were instructed to continue on this diet and in addition each took a gluten-free muffin and two slices of gluten-free bread for 6 weeks. Patients were randomized to have this supplement spiked with gluten, so they would receive 16 g of gluten per day, or for the supplement to remain gluten free. The trial design was at low risk of bias. IBS symptoms were measured by visual analog scale. Thirty-four patients completed the study, and global symptoms, pain, bloating, and tiredness statistically significantly increased in the gluten group from every week after the first week in the gluten group. Furthermore, 13 (68%) of 19 patients in the gluten group reported that symptoms were not adequately controlled compared with 6 (40%) of 15 in the placebo group. The paper reported this difference as highly statistically significant using a generalizing estimating equation that controls for baseline variables (P=0.0001). This is a legitimate statistical approach, but if the authors had used another legitimate approach of using a Fisher's exact test, the results would not have been statistically significant (P=0.16), although this was not reported in the paper. The relative risk of symptoms occurring in the group challenged with gluten was 1.71 (95% confidence interval =0.91–3.62) according to these proportions.

FODMAPs diet.

There were four RCTs12, 14, 17, 19 evaluating a low FODMAP diet in 112 IBS patients. Three RCTs14, 17, 19 were excluded, two as the data were not extractable for a meta-analysis17, 19 and one as they studied patients for <1 week.14 All these trials reported that a low FODMAP diet was effective in reducing IBS symptoms. The eligible trial12 evaluated 41 IBS patients and randomized them to 4 weeks of a low FODMAP diet or to continue on with their normal diet. There was a trend for all symptoms, except constipation or diarrhea, to improve, and this was statistically significant for bloating, borborygmi, and urgency. This study measured fecal microbiota using fluorescent in situ hybridization and found those on a low FODMAP diet had a significant reduction in bifidobacteria compared with controls. Overall, 13 (68%) of 19 patients randomized to the low FODMAP diet reported adequate control of their symptoms compared with 5 (23%) of 22 in the control group. This difference was statistically significant (P=0.005), but it is important to emphasize that this trial had a high risk of bias, as participants and researchers were not blinded and were aware who was on a low FODMAP diet.

Other exclusion diets.

Nine RCTs10, 13, 15, 16, 21, 22, 24, 25, 26 evaluated other exclusion diets in 1,056 IBS patients. Most gave empirical exclusion diets that omitted a broad range of foods (e.g., one trial16 excluded cow's milk, eggs, wheat, tomato, or chocolate from the diet) but two10, 15 constructed the diet based on an individual's food sensitivity testing. Three of these trials were excluded because they evaluated sodium cromoglycate24 or compared an elimination diet with cromoglycate.25, 26 Five further13, 15, 16, 21, 22 trials were excluded as they did not have data that was extractable for a meta-analysis, usually because of a crossover design. Three of these trials16, 21, 22 were positive and two13, 15 were negative. One RCT10 was eligible and this evaluated 150 patients with Rome II IBS recruited from a single gastroenterology outpatient center in the United Kingdom. Celiac disease and lactose intolerance was excluded and patients underwent immunoglobulin G antibody testing to a panel of 29 food antigens. Food sensitivity was defined as an immunoglobulin G titer that was three times the level of normal. Patients were then randomized to a true diet in which they omitted all foods that they were intolerant of, according to their sensitivity testing, for 12 weeks, or a sham diet where patients were asked to avoid the same number of foods, but these were not related to their sensitivity testing. Subjects were most commonly intolerant of milk, yeast, egg, and wheat in sensitivity testing. The trial had an unclear risk of bias. Nineteen patients were lost to follow-up and 18/65 (28%) in the active intervention arm reported an improvement in symptoms compared with 11/66 (17%) in the control group, which was not statistically significant (P=0.14). Interestingly, 11 patients withdrew in the intervention arm because the diet was too restrictive compared with only three in the control arm. If only those who strictly followed their diet (24 (32%) of 75 of those allocated to the intervention group) were analyzed, then the mean IBS severity score was statistically significantly lower in the intervention group.

DISCUSSION

Concerns regarding the quality of the underlying studies are particularly true for data relating to exclusion diets in IBS. There are a number of RCTs that have, in total, enrolled more than 1,500 IBS patients, but few provide data that can be synthesized using meta-analysis. The reasons for this are numerous, but one of the key factors relates to the use of the crossover design. This design is not, in itself, a problem for meta-analytic techniques, but data are rarely reported in a way that can be used to synthesize results.

Most published RCTs report positive results, but this should be interpreted with caution as the three trials that were eligible for this review all have their limitations. The only trial in this review that had a low risk of bias11 suggested that gluten exacerbates IBS symptoms in non-celiac IBS patients whose symptoms are already controlled with a GFD. This is the strongest evidence we have that a GFD may help some IBS patients, but the numbers recruited in this trial were modest and more data are needed so we can be confident of the estimate of effect. A low FODMAP diet has emerged as a new and interesting approach to the management of IBS. Four RCTs have evaluated this, but only one trial12 met the eligibility criteria and this was small and at high risk of bias as it was an open study. Although there is a great deal of interest in this approach,27 more data are needed before we can be confident this is effective in IBS patients. There are a large number of trials evaluating other elimination diets, but the only trial that was eligible for this review was negative.10

Some trials eliminate foods based on food allergy testing,10, 15 but this focuses the approach on the presumption that allergy is the underlying mechanism of action, which may or may not be true even if certain foods are the cause of IBS symptoms. There are a number of mechanisms whereby ingested food may cause gastrointestinal symptoms.28 The osmotic activity of the ingested food may encourage the influx of water, which may cause distention of the lumen.29 Distention may also be caused by gas produced from the fermentation of ingested food by the gut flora.30 Fermentation of food results in the release of many soluble molecules, such as short-chain fatty acids described above, which can have both pro- and anti-inflammatory properties. Ingested food also acts a substrate for the gut microbiome, and change in diet can lead to a change in the microbiome composition.31 This in turn could lead to an alteration in gut function, which, in turn, can lead to IBS symptoms.32 Support for this hypothesis comes from one study that did evaluate changes in the microbiome with a low FODMAP diet and reported a decrease in Bifidobacterium counts associated with this dietary intervention.12

The discussion of mechanisms through which diet can cause IBS symptoms is important as this directly affects the future design of food elimination trials. If the cause of symptoms relates to a direct effect of the food in the gut lumen, then the impact will be closely related to meals and should resolve within a relatively short time, if the offending food is removed from the diet. In this scenario, a crossover trial may be an appropriate design. However, if the mechanism relates to subtle manifestations of inflammation and/or changes in the gut microbiome, then this may take some time to return to baseline and a crossover design would not be appropriate. As the mechanism of dietary intervention in IBS is not known at this stage, it would be better if trials maintained a parallel group design to avoid problems with delayed or carry-over effects. Crossover designs should be relegated to treatment trials for rare disorders when subject accrual may be difficult. IBS is a common disorder affecting 10 to 20% of the population,33 and subject accrual should not be a problem

Despite promising data on the efficacy of dietary restriction in IBS, we suggest that this approach cannot be recommended strongly until more evidence is accumulated. These interventions are generally considered cheap and harmless, but a GFD is difficult to implement and is far from inexpensive; in fact, the food industry is projected to make US$16 billion annually in 2016 as it capitalizes on our concerns regarding gluten.34 Elimination diets can also be very restrictive for patients,35 highlighting the need for further data before such approaches are used widely in IBS.36

Acknowledgments.

This study was performed to inform the American College of Gastroenterology Monograph on irritable bowel syndrome. We are grateful to Professor Camilleri and colleagues for providing additional data on their trial.

CONFLICT OF INTEREST

Guarantor of the article: Paul Moayyedi, MBChB, PhD, MPH, FACG.

Specific author contributions: ACF, EMMQ, BEL, AJL, YAS, LRS, EES, BMRS, and PM conceived the study. ACF and PM collected all data. ACF and PM analyzed and interpreted the data. PM drafted the manuscript. All authors commented on drafts of the paper. All authors have approved the final draft of the manuscript.

Financial support: American College of Gastroenterology.

Potential competing interests: Alexander C. Ford, Eamonn M.M. Quigley, Brian E. Lacy, Anthony J. Lembo, Yuri A. Saito, Lawrence R. Schiller, Edy E. Soffer, Brennan M.R. Spiegel, and Paul Moayyedi: none.

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© 2015 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology