Low-FODMAP Diet Improves Irritable Bowel Syndrome Symptoms: A Meta-Analysis

Irritable bowel syndrome (IBS) affects 7–15% of the general population. A recently devised dietary approach consists of restricting foods with highly fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs), which can trigger and/or exacerbate IBS symptoms. The aim of this study is to use meta-analysis to provide an update on the randomised control trials (RCTs) and cohort studies, and examine them separately in relation to diet type. Papers were selected using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. Cohen’s d and odds ratios were used as a measure of effect size for RCTs. A random effects model was used to account for different sources of variation among studies. Heterogeneity was assessed using Q statistics, I2, Tau, and Tau2. Publication bias was analysed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger’s test. The results showed that in the RCTs, the patients receiving a low-FODMAP diet experienced a statistically significant pain and bloating reduction compared with those receiving a traditional diet; as regards to stool consistency, there was no significant difference between treatments. A significant reduction in abdominal pain and bloating were described by patients receiving a low-FODMAP diet compared with those receiving a high-FODMAP diet. In cohort studies, pain and bloating were significantly reduced after treatment compared with the baseline diet. We conclude that there is evidence that a low-FODMAP diet could have a favourable impact on IBS symptoms, especially abdominal pain and bloating. However, it remains to be demonstrated whether a low-FODMAP diet is superior to conventional IBS diets, especially in the long term.


Introduction
Irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and colorectal cancer (CRC) are chronic intestinal conditions whose high incidence and prevalence make them major healthcare problems [1][2][3][4][5]. IBS affects 7-15% of the general population [4,5]. It is twice as frequent in women [6] and is diagnosed more often in patients less than 50 years of age [7]. It is characterised by recurrent episodes of functional gastrointestinal symptoms whose pathophysiological mechanisms are not completely clear [8]. The most common symptoms include abdominal pain, bloating, constipation, and/or diarrhoea [8]. IBS negatively impacts quality of life and causes a substantial burden on healthcare resources [9,10]. Like the clinical phenotypes, the pathophysiological mechanisms underlying the syndrome are heterogeneous and not fully understood [11]. However, there is evidence that IBS may result from a combination of gastrointestinal motility changes, visceral hypersensitivity, low-grade inflammation, altered microbiota, and food components [12][13][14][15]. Due to the diversity of IBS symptoms and their considerable variability over time, a wide range of pharmacological treatments A manual search of possible references of interest was also performed. Only studies published in English over the previous 10 years were considered. The papers were selected by three independent reviewers (P.M.A., V.D.N., and G.L.); a methodologist (E.A.) resolved any disagreements. The study included clinical investigations involving the effect of a FODMAP diet on IBS patients. In particular, we assessed RCTs comparing a low-FODMAP diet with a traditional IBS diet, and a low-FODMAP diet with a high-FODMAP diet; cohort studies examining the effect of a low-FODMAP diet, comparing baseline with the follow-up, were also included. Outcomes evaluated were abdominal pain and bloating, which were assessed in all three study types. Since stool consistency and frequency were evaluated in all RCTs comparing FODMAP and traditional diets, these outcomes were also included.
Bias was assessed using the Cochrane Collaboration tool for assessing risk of bias [42] and the Newcastle-Ottawa scale for cohort studies (Tables S2 and S3) [43].

Statistical Analysis
Cohen's d, with 95% confidence interval (CI) and p-value, was used as a measure of effect size. Odds ratios (ORs), with 95% CI and p-value, were used as a measure of effect size for the RCTs. A manual search of possible references of interest was also performed. Only studies published in English over the previous 10 years were considered. The papers were selected by three independent reviewers (P.M.A., V.D.N., and G.L.); a methodologist (E.A.) resolved any disagreements. The study included clinical investigations involving the effect of a FODMAP diet on IBS patients. In particular, we assessed RCTs comparing a low-FODMAP diet with a traditional IBS diet, and a low-FODMAP diet with a high-FODMAP diet; cohort studies examining the effect of a low-FODMAP diet, comparing baseline with the follow-up, were also included. Outcomes evaluated were abdominal pain and bloating, which were assessed in all three study types. Since stool consistency and frequency were evaluated in all RCTs comparing FODMAP and traditional diets, these outcomes were also included.
Bias was assessed using the Cochrane Collaboration tool for assessing risk of bias [42] and the Newcastle-Ottawa scale for cohort studies (Tables S2 and S3) [43].

Statistical Analysis
Cohen's d, with 95% confidence interval (CI) and p-value, was used as a measure of effect size. Odds ratios (ORs), with 95% CI and p-value, were used as a measure of effect size for the RCTs.
Effect sizes were pooled across studies to obtain an overall effect size. A random effects model was used to account for different sources of variation among studies. Heterogeneity was assessed using Q statistics, I 2 , Tau, and Tau 2 . The stability of study findings was checked with moderator analysis.
Publication bias was analyzed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger's test [44]. Finally, publication bias was checked using the trim and fill procedure; we used Rosenthal's estimator and fail-safe number to analyze publication bias [45]. PROMETA 3 software (IDo Statistics-Internovi, Cesena, Italy) was used.

Results
The search found 362 records in the databases and eight records through the manual search. After the removal of 132 duplicates there remained 238 papers; of these, 215 were excluded for different reasons ( Figure 1). In the second phase of the PRISMA flow-chart, full-text articles were identified for eligibility; of these, 11 were excluded for the following reasons: three compared the FODMAP to a placebo [35], lactobacillus [46], or hypnotherapy [47], one considered healthy controls versus IBD patients [48]; one involved a paediatric population [39]; one administered the FODMAP to non-celiac gluten-sensitive patients [49]; one included interventions that only regarded two different types of rye bread (normal versus low-FODMAP rye bread) [31]; one study reviewed two different types of educational training [50]; one was a retrospective study [51]; one regarded fructose restriction [27]; and finally one did not include any outcomes of interest for our study [52]. This left six RCTs, of which three compared the traditional IBS diet to the low-FODMAP diet [29,30,36] and three compared the low-and high-FODMAP diets [25,26,53] (Table 1). Six cohort studies [54][55][56][57][58] compared patients' conditions at baseline and after administration of the low-FODMAP diet ( Table 2). In each meta-analysis, sensitivity analysis indicated that the meta-analytical findings were stable.

Low-FODMAP Diet Versus Traditional IBS Diet
The primary studies (k = 3 RCTs) by Bohn [29], Eswaran [30], and Staudacher [36] compared groups of IBS patients receiving a low-FODMAP diet to those receiving a traditional diet. These studies examined four outcomes: reduction of abdominal pain, reduction of abdominal bloating, increase of stool consistency, and reduction of stool frequency. Their main features are reported in Table 1.

Abdominal Pain
The present meta-analysis demonstrates that the patients receiving a low-FODMAP diet experienced a statistically significant pain reduction compared to those receiving a traditional diet. The overall effect size was odds ratio (OR) = 0.44 (Table 3); there was no statistical heterogeneity (Table 3, Figure 2A). Publication bias analysis did not highlight any differences between observed and estimated values (zero trimmed studies) ( Figure 2B). Egger's test was not statistically significant (Table 3).

Bloating
Patients managed with a low-FODMAP diet experienced significant bloating reduction compared with those receiving a traditional diet, OR = 0.32 (Table 3), and there was no significant heterogeneity (Table 3, Figure 2C). Analysis of publication bias by the trim and fill method did not lead to the exclusion of any paper ( Figure 2D). Egger's test was not significant (Table 3).

Stool Consistency
There was no significant difference between treatments (effect size (ES) = 0.24, Table 3); statistical heterogeneity was moderate but not significant ( Figure 3A). Analysis of publication bias with the trim and fill method failed to exclude any paper ( Figure 3B). Egger's test was not significant (Table 3).

Stool Frequency
There was a significant difference between treatments for this outcome (ES = −0.54; p < 0.001). There was no statistical heterogeneity (Table 3, Figure 3C). Analysis of publication bias with the trim and fill method failed to exclude any paper ( Figure 3D). Egger's test was not significant (Table 3).

Low-FODMAP Diet vs. Medium/High-FODMAP Diet
The primary studies (k = 3 RCTs) compared patients managed with a low-FODMAP diet and patients receiving a high/medium-FODMAP diet [25,26,53]. Their main characteristics are listed in Table 1. This set of studies examined two outcomes: reduction of abdominal pain and of bloating.

Abdominal Pain
Significantly reduced abdominal pain was described by patients receiving a low-FODMAP diet compared with those receiving a high-FODMAP diet (OR = 0.17). There was no statistical heterogeneity ( Table 3). Analysis of publication bias with the trim and fill method failed to exclude any paper ( Figure 4B). Finally, Egger's test was not significant (Table 3).

Bloating
The patients receiving a low-FODMAP diet reported a significant reduction of bloating compared with those given a high-FODMAP diet (OR = 0.13); statistical heterogeneity was moderate but not significant (Table 3, Figure 4C). Analysis of publication bias by the trim and fill method did not lead to the exclusion of any paper ( Figure 4D). Egger's test was not significant (Table 3).

Cohort Studies
The primary studies (k = 6) compared baseline versus post-treatment data in patients treated with a low-FODMAP diet [34,[54][55][56][57][58] (Table 2). Two outcomes were assessed in this set: reduction of abdominal pain and reduction of bloating. Meta-regressions were performed for both outcomes using gender, age, and year of publication.

Abdominal Pain
Pain after treatment was significantly reduced compared with baseline in these patients (ES = −0.59). There was no statistical heterogeneity (Table 3, Figure 5A). Analysis of publication bias by the trim and fill method did not result in the exclusion of any paper ( Figure 5B). Egger's test was not significant ( Table 3). The meta-regression lines for age (p = 0.652), gender (p = 0.817), and year of publication (p = 0.543) were not significant ( Figure 5C-E).

Bloating
Significantly reduced bloating was reported by patients after treatment (ES = −0.64). There was no statistical heterogeneity (Table 3, Figure 6A). Analysis of publication bias by the trim and fill method did not lead to the exclusion of any paper ( Figure 6B). Finally, Egger's test was not significant ( Table 3). The meta-regression lines for age (p = 0.808), gender (p = 0.747), and year of publication (p = 0.804) were not significant ( Figure 6C-E).

Discussion
Several clinical trials have reported that reducing high-FODMAP foods achieves adequate symptom relief in approximately 70% of IBS patients [32,59,60]. In a recent meta-analysis, Marsh et al. [40] reported the efficacy of a low-FODMAP diet on the functional gastrointestinal symptoms associated with IBS and IBD, and found a significant improvement in symptom severity and quality of life scores compared to patients receiving a normal Western diet.
The meta-analysis in this study provides an update on the RCTs and cohort studies that have been published since then, and examines them separately in relation to diet type. Our results showed that a low-FODMAP diet versus a traditional IBS diet created a statistically significant reduction in abdominal pain, bloating, and stool frequency.
Significant reductions in abdominal pain and bloating were also found in patients administered a low-FODMAP compared to those receiving a medium or a high-FODMAP diet. Similarly, analysis of the six cohort studies demonstrated a significant reduction in abdominal pain and bloating, from baseline to follow-up, in patients treated with a low-FODMAP diet. The meta-regression lines for age and gender were not significant. Overall, the results of this meta-analysis confirm those reported in the meta-analysis by Marsh et al. [40]. The first limitation of this study lies in the relatively small number of primary studies. Moreover, given the low number of primary studies, to be able to provide quality evidence, we used random effect's model as suggested by Liberati et al. [61]. A second limitation is the lack of blinding. However, if IBS patients have a good knowledge of food and its FODMAP content, the food in their dietary treatment, or the food choices taught to them, cannot be blinded. A third limitation is the inadequate treatment duration, which does not allow for a long-term assessment. In fact, studies involving long-term follow-ups are few. In a recent retrospective study, only one third of IBS patients receiving a low-FODMAP diet were still adherent to their treatment after a median follow-up of 18 months, even though they reported reasonable symptom relief [51]. Nevertheless, a recent prospective study in the UK [62] showed that a low-FODMAP diet can be effective and nutritionally adequate up to 18 months after initial dietitian-led education. In this study, 82% of patients who concluded the short-term FODMAP restriction phase (six weeks), continued to follow an adapted FODMAP diet in which FODMAPs were gradually reintroduced, and 70% of them maintained adequate long-term symptom relief. However, it should also be highlighted that the results of the present study were not affected by statistically significant heterogeneity and publication bias is not present. A fourth limitation is the fact that, in the studies analysed in this meta-analysis, the FODMAP diet is never compared with the current standard dietary advice for IBS, as reported by the British National Institute for Health and Care Excellence (NICE) [63].
It should be emphasised that even though a low-FODMAP diet improves IBS symptoms compared with a normal diet, this does not in fact demonstrate that the low-FODMAP treatment is superior to the conventional IBS dietary intervention. Studies comparing the efficacy of a low-FODMAP diet versus proper dietary advice for IBS (NICE diet) did not show a clear-cut advantage over the low-FODMAP diet [30,50]. Furthermore, a high-FODMAP comparator diet has the potential to exaggerate symptoms in the control [32].
A recent placebo-controlled clinical trial conducted by Staudacher et al. [64] confirmed that the low-FODMAP diet reduces the relative abundance of bifidobacterial, but the co-administration of a probiotic (VLS#3) reduces the loss of the bacterial stain. The effects of IBD treatment with a low-FODMAP diet combined with probiotics need to be clarified by further clinical trials [64].
It has also been hypothesized that patients who follow this diet may be at risk of reduced intake of fiber and some micronutrients, such as calcium, iron, zinc, folate B, D vitamins, and natural antioxidants, especially in subjects with limited access to the expensive alternative items for this diet [65]. However, a prospective study [62] showed that a dietitian-led low-FODMAP diet can be nutritionally adequate for up to 18 months. Excluding the first restriction phase of six weeks, following an adapted FODMAP diet was nutritionally adequate in macronutrients, micronutrients, and energy intake, despite having a lower FODMAP content (20.6 ± 14.9 g/day) when compared to the habitual diet (29.4 ± 22.9 g/day). Another study showed that this diet does not seem to cause vitamin D and folic acid deficiencies, even in the restriction phase [66]. Although there are few studies that evaluated the nutritional adequacy of the low-FODMAP diet, it is reasonable to think that, where properly supported by an experienced dietitian, this diet can be nutritionally adequate in the long term.

Conclusions
There is evidence that a low-FODMAP diet can have a favorable impact on IBS symptoms, especially abdominal pain, bloating, and diarrhoea. However, it remains to be demonstrated whether a low-FODMAP diet is superior to conventional IBS diets, especially in the long term. In addition, further studies are needed to demonstrate whether the low-FODMAP diet is superior to the traditional IBS diet following the NICE guidelines in the long term. Long-term FODMAP depletion may entail physiological consequences on the intestinal microbiome, colonocyte metabolism, and nutritional status that should not be underestimated, and needs further investigation.
Finally, the purpose of this meta-analysis was to provide propositions to help drive future research on this topic of growing interest among researchers, and assist with designing the epidemiological studies with comparability features in order to achieve better outcomes in clinical practice.