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Black, CJ, Staudacher, HM and Ford, AC orcid.org/0000-0001-6371-4359 (2022) Efficacy
of a low FODMAP diet in irritable bowel syndrome: systematic review and network meta-
analysis. Gut, 71 (6). pp. 1117-1126. ISSN 0017-5749

https://doi.org/10.1136/gutjnl-2021-325214

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Ford et al. 1 of 46

Accepted for publication 29th July 2021

TITLE PAGE

Title: Efficacy of a Low FODMAP Diet in Irritable Bowel Syndrome: Systematic Review

and Network Meta-analysis.

Short title: Network Meta-analysis of a Low FODMAP Diet for IBS.

Authors: Christopher J. Black MBBS1,2, Heidi M. Staudacher PhD3, Alexander C. Ford

MD1,2.

1
Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK.
2
Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, UK.
3
Deakin University, IMPACT (the Institute for Mental and Physical Health and Clinical

Translation), Food & Mood Centre, Geelong, Victoria, Australia.

Abbreviations: BDA British Dietetic Association

CI confidence interval

FDA Food and Drug Administration

FODMAP fermentable oligosaccharides, disaccharides, and

monosaccharides, and polyols

IBS irritable bowel syndrome

IBS-C IBS with constipation

IBS-D IBS with diarrhoea

NICE National Institute for Health and Care Excellence

Ford et al. 2 of 46

RCT randomised controlled trial

RR relative risk

Correspondence: Professor Alex Ford

Leeds Gastroenterology Institute

Room 125

4th Floor

Bexley Wing

St. James’s University Hospital

Beckett Street

Leeds

United Kingdom

LS9 7TF

Email: [email protected]

Telephone: +441132684963

ORCID ID: 0000-0001-6371-4359

Twitter: @alex_ford12399

Key words: irritable bowel syndrome

RCT comparison

efficacy

diet

Word count: 5333

Ford et al. 3 of 46

ABSTRACT

Objective: A low FODMAP diet is recommended for irritable bowel syndrome (IBS), if

general lifestyle and dietary advice fails. However, although the impact of a low FODMAP

diet on individual IBS symptoms has been examined in some randomised controlled trials

(RCTs), there has been no recent systematic assessment, and individual trials have studied

numerous alternative or control interventions, meaning the best comparator is unclear. We

performed a network meta-analysis addressing these uncertainties.

Design: We searched the medical literature through to 2nd April 2021 to identify RCTs of a

low FODMAP diet in IBS. Efficacy was judged using dichotomous assessment of

improvement in global IBS symptoms or improvement in individual IBS symptoms,

including abdominal pain, abdominal bloating or distension, and bowel habit. Data were

pooled using a random effects model, with efficacy reported as pooled relative risks (RRs)

with 95% confidence intervals (CIs), and interventions ranked according to their P-score.

Results: We identified 13 eligible RCTs (944 patients). Based on failure to achieve an

improvement in global IBS symptoms, a low FODMAP diet ranked first versus habitual diet

(RR of symptoms not improving = 0.67; 95% CI 0.48-0.91, P-score = 0.99), and was superior

to all other interventions. Low FODMAP diet ranked first for abdominal pain severity,

abdominal bloating or distension severity, and bowel habit, although for the latter it was not

superior to any other intervention. A low FODMAP diet was superior to British Dietetic

Association (BDA)/National Institute for Health and Care Excellence (NICE) dietary advice

for abdominal bloating or distension (RR = 0.72; 95% CI 0.55-0.94). BDA/NICE dietary

advice was not superior to any other intervention in any analysis.

Conclusion: In a network analysis, low FODMAP diet ranked first for all endpoints studied.

However, most trials were based in secondary or tertiary care and did not study effects of

FODMAP reintroduction and personalisation on symptoms.

Ford et al. 4 of 46

STUDY HIGHLIGHTS

What is already known about this subject

• Irritable bowel syndrome (IBS) is a common condition, and efficacy of most drug

treatments is modest.

• Many patients with IBS report food-induced symptoms and are interested in making

dietary modifications to manage symptoms.

• Management guidelines for IBS recommend a diet low in FODMAPs, if general

lifestyle and dietary advice have failed.

What are the new findings

• A low FODMAP diet was ranked first for efficacy across all endpoints studied,

compared with alternative interventions, including British Dietetic Association

(BDA)/National Institute for Health and Care Excellence (NICE) dietary advice for

people with IBS.

• A low FODMAP diet was significantly more efficacious than habitual diet for global

IBS symptoms, and significantly more efficacious than BDA/NICE dietary advice for

abdominal bloating or distension.

• BDA/NICE dietary advice was not superior to any of the other interventions in any of

our analyses.

How might it impact on clinical practice in the foreseeable future

• The low FODMAP diet ranked first for all endpoints studied, and was superior to all

alternative interventions, including BDA/NICE dietary advice, supporting

recommendations for its use in current management guidelines.

Ford et al. 5 of 46

• Although guidelines recommend the use a low FODMAP diet for IBS in primary care,

trials conducted in this setting, and which include the FODMAP reintroduction and

personalisation phases, are needed.

Ford et al. 6 of 46

INTRODUCTION

Irritable bowel syndrome (IBS), characterised by abdominal pain in association with

altered stool form or frequency,[1, 2] affects 4% to 10% of the general population at any

point in time.[3, 4] The condition is a disorder of gut-brain interaction,[5] and is chronic with

a relapsing and remitting natural history.[6] Costs to the health service and society are

substantial,[7, 8] and the impact of symptoms on quality of life is considerable,[9, 10] with

patients willing to accept a median 1% risk of sudden death with a hypothetical medication in

return for a 99% chance of symptom cure.[11] However, efficacy of most drugs is

modest,[12-15] and placebo response rates are high.[16] Even novel, more selectively

targeted, therapies developed over the last 20 years produce a therapeutic gain over placebo

of only 10% to 15% and are expensive.[17] As a result, many are not widely available, and

when adverse events arise during post-marketing surveillance,[18-20] they are often

withdrawn, or their use restricted.[21, 22]

Patients may, therefore, turn to other approaches. Over 80% of people with IBS report

food-related symptoms,[23] and in one survey more than 60% of patients had made dietary

changes to manage their IBS.[24] Perhaps as a result, there has been renewed interest in

dietary therapies as a treatment. One of the most widely accepted approaches is a diet that is

low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols

(FODMAPs). FODMAPs are present in a range of dietary sources including certain fruit,

vegetables, legumes, and artificial sweeteners. Unabsorbed fructose, polyols, and lactose

increase small intestinal water content and indigestible fructans and galacto-oligosaccharides

undergo microbial fermentation in the colon, and contribute to symptoms in some

patients.[25, 26] The low FODMAP diet consists of three phases: a period of FODMAP

restriction, ideally lasting 4 to 6 weeks, reintroduction of individual food items to determine

tolerance to each, and personalisation to create a modified FODMAP-containing diet based

Ford et al. 7 of 46

on individual tolerance to FODMAPs identified in the second phase.[27] Several randomised

controlled trials (RCTs) and meta-analyses conducted over the last 10 years have shown that

the first phase of the diet is efficacious for global IBS symptoms.[28-33]

In the UK, the National Institute for Health and Care Excellence (NICE) guideline for

the management of IBS in primary care recommends that if symptoms persist following

general lifestyle and dietary advice further dietary management, including a low FODMAP

diet, is offered.[34] Limitations of the current evidence base for a low FODMAP diet in IBS,

to date, include the fact that although the impact on individual IBS symptoms has been

examined in some RCTs, there has been no recent systematic assessment, and the numerous

different types of alternative or control interventions studied. These have included inactive

controls such as habitual diet, sham dietary advice, or even a high FODMAP diet, as well as

alternative dietary advice for IBS, such as that from the British Dietetic Association (BDA),

[35] or NICE, [34] which are largely empirical in nature. Both BDA and NICE advice

include eating small, regular meals, keeping hydrated, reducing intake of tea, coffee, alcohol,

and carbonated fluids, and limiting fruit intake, and could be viewed as an active dietary

intervention. However, there have been no RCTs of this approach versus habitual diet or a

sham dietary intervention, and establishing its efficacy is crucial for addressing concerns

about design bias in dietary trials.[36]

We conducted a network meta-analysis to estimate the efficacy of a low FODMAP

diet in IBS, as well as the relative efficacy of the different comparators studied, for both

global and individual IBS symptoms. Network meta-analysis allows indirect, as well as

direct, comparisons to be made across different RCTs, increasing the number of participants’

data available for analysis, an advantage over published conventional pairwise meta-analyses.

Importantly, it also allows a credible ranking system of the efficacy of different comparators

to be developed, even in the absence of trials making direct comparisons. This may assist in
Ford et al. 8 of 46

developing a more robust design for future RCTs of a low FODMAP diet, in terms of which

comparator should be selected to prevent overestimating its efficacy. It also allows the

relative efficacy of alternative dietary advice to be examined versus “inactive” control

interventions.
Ford et al. 9 of 46

METHODS

Search Strategy and Selection Criteria

We searched MEDLINE (1946 to 2nd April 2021), EMBASE and EMBASE Classic

(1947 to 2nd April 2021), and the Cochrane central register of controlled trials. In addition, we

searched clinicaltrials.gov for unpublished trials or supplementary data for potentially eligible

RCTs. We hand-searched conference proceedings (Digestive Diseases Week, American

College of Gastroenterology, United European Gastroenterology Week, and the Asian Pacific

Digestive Week) between 2001 and 2021 to identify trials published only in abstract form.

Finally, we used bibliographies of all obtained articles to perform a recursive search.

RCTs examining the effect of a low FODMAP diet in adults (≥18 years) with IBS of

any subtype were eligible (Supplementary Table 1). Trials had to compare a low FODMAP

diet with an alternative intervention. This could consist of any of habitual diet, sham dietary

advice, a high FODMAP diet, or alternative dietary advice, such as that for people with IBS

from the BDA or NICE.[34, 35] Given the overlap between the latter two, we classed these as

a single intervention. The first period of cross-over RCTs were eligible if they provided

efficacy data prior to cross-over. We considered definitions of IBS that included either a

clinician’s opinion, or those that met specific symptom-based criteria, for example the Rome

criteria. We required a minimum treatment duration of 2 weeks.

Two investigators (CJB and ACF) conducted the literature search, independently from

each other. We identified studies on IBS with the terms: irritable bowel syndrome or

functional diseases, colon (both as medical subject heading and free text terms), or IBS,

spastic colon, irritable colon, or functional adj5 bowel (as free text terms). We combined

these using the set operator AND with studies identified with the terms: fructan$,

FODMAP$, or fructooligosaccharide (as free text terms). There were no language

Ford et al. 10 of 46

restrictions. Two investigators (CJB and ACF) evaluated all abstracts identified by the search

for eligibility, again independently from each other. We obtained all potentially relevant

papers and evaluated them in more detail, using pre-designed forms, to assess eligibility

independently and according to the pre-defined criteria. We translated foreign language

papers, where required. We resolved disagreements between investigators (CJB and ACF) by

discussion.

Outcome Assessment

We assessed the efficacy of a low FODMAP diet in IBS, compared with the various

alternative interventions, in terms of failure to respond to therapy, according to several

endpoints of interest reported below. Other outcomes assessed included adverse events (total

numbers of adverse events, as well as adverse events leading to study withdrawal, and

individual adverse events), if reported.

Data Extraction

Two investigators (CJB and ACF) extracted all data independently onto a Microsoft

Excel spreadsheet (XP professional edition; Microsoft Corp, Redmond, WA, USA) as

dichotomous outcomes (response or no response to therapy). We assessed efficacy according

to the proportion of patients failing to achieve an improvement in the following: a) global

symptoms of IBS; b) abdominal pain severity; c) abdominal bloating or distension severity;

and d) bowel habit. Where studies reported a dichotomous assessment of response to therapy

according to these endpoints, for example a 50-point decrease in the IBS-SSS or a 30%

improvement in abdominal pain severity on the IBS-SSS (approximating Food and Drug

Administration (FDA)-recommended endpoints in drug trials in IBS), we extracted data from

the article itself. Where studies reported mean individual symptom severity scores at baseline
Ford et al. 11 of 46

together with follow-up mean symptom severity scores and standard deviation for these

endpoints for each intervention arm, we imputed dichotomous responder and non-responder

data using methodology previously described by Furukawa et al.[37, 38] As an example, for

a 30% improvement in abdominal pain severity on the IBS-SSS, this would be derived from

the formula number of participants in each treatment arm at final follow-up x normal standard

distribution. The latter corresponds to (70% of the baseline mean score – follow-up mean

score) / follow-up standard deviation. We contacted first and senior authors of studies to

provide additional data for individual trials, where required.

We also extracted the following data for each trial, where available: country of origin,

setting (primary, secondary, or tertiary care), proportion of female patients, diagnostic criteria

used to define IBS, and proportion of patients with IBS according to subtype. We also

recorded the duration of follow-up and mode of delivery of the low FODMAP diet and the

alternative intervention, in terms of the intervention itself and the length of the initial

consultation, where reported. We extracted data as intention-to-treat analyses, with dropouts

assumed to be treatment failures (i.e., no response to a low FODMAP diet or the comparator),

wherever trial reporting allowed. If this was not clear from the original article, we performed

an analysis on all patients with reported evaluable data.

Quality Assessment and Risk of Bias

We used the Cochrane risk of bias tool to assess this at the study level.[39] Two

investigators (CJB and ACF) performed this independently; we resolved disagreements by

discussion. We recorded the method used to generate the randomisation schedule and conceal

treatment allocation, as well as whether blinding was implemented for participants,

personnel, and outcomes assessment, whether there was evidence of incomplete outcomes

data, and whether there was evidence of selective reporting of outcomes.

Ford et al. 12 of 46

Data Synthesis and Statistical Analysis

We performed a network meta-analysis using the frequentist model, with the

statistical package “netmeta” (version 0.9-0, https://cran.r-

project.org/web/packages/netmeta/index.html) in R (version 4.0.2). We reported this

according to the PRISMA extension statement for network meta-analyses,[40] to explore

direct and indirect treatment comparisons of the efficacy and safety of each intervention.

Network meta-analysis results usually give a more precise estimate, compared with results

from standard, pairwise analyses,[41, 42] and can rank interventions to inform clinical

decisions.[43]

We examined the symmetry and geometry of the evidence by producing a network

plot with node size corresponding to number of study subjects, and connection size

corresponding to number of studies. We produced comparison adjusted funnel plots to

explore publication bias or other small study effects, for all available comparisons, using

Stata version 16 (Stata Corp., College Station, TX, USA). This is a scatterplot of effect size

versus precision, measured via the inverse of the standard error. Symmetry around the effect

estimate line indicates absence of publication bias, or small study effects.[44] We produced a

pooled relative risk (RR) with 95% confidence intervals (CIs) to summarise effect of each

comparison tested, using a random effects model as a conservative estimate. We used a RR of

failure to achieve each of the endpoints of interest, where if the RR was less than 1 and the

95% CI did not cross 1, there was a significant benefit of one intervention over another. This

approach is the most stable, compared with RR of improvement, or using the odds ratio, for

some meta-analyses.[45] In each RCT, direct comparisons were made between a low

FODMAP diet and a single comparator, but there were no direct comparisons made between

any of the alternative interventions themselves, meaning that there was insufficient direct
Ford et al. 13 of 46

evidence to perform consistency modelling to check the correlation between direct and

indirect evidence across the network.[46]

Many meta-analyses use the I2 statistic to measure heterogeneity, which ranges

between 0% and 100%.[47] This statistic is easy to interpret and does not vary with the

number of studies. However, the I2 value can increase with the number of patients included in

the meta-analysis.[48] We therefore assessed global statistical heterogeneity across all

comparisons using the τ2 measure from the “netmeta” statistical package. Estimates of τ2 of

approximately 0.04, 0.16, and 0.36 are considered to represent a low, moderate, and high

degree of heterogeneity, respectively.[49]

We ranked both the low FODMAP diet and all comparators studied according to their

P-score, which is a value between 0 and 1. P-scores are based solely on the point estimates

and standard errors of the network estimates, and measure the mean extent of certainty that

one intervention is better than another, averaged over all competing interventions.[50] Higher

scores indicate a greater probability of the intervention being ranked as best,[50] but the

magnitude of the P-score should be considered, as well as the treatment rank. As the mean

value of the P-score is always 0.5 if individual interventions cluster around this value they are

likely to be of similar efficacy. However, when interpreting the results, it is also important to

take the RR and corresponding 95% CI for each comparison into account, rather than relying

on rankings alone.[51] In our primary analyses, we pooled data for the risk of being

symptomatic at the final point of follow-up in each study for all included RCTs using an

intention-to-treat analysis, but we also performed a priori analyses restricted to trials that

used identical endpoints to judge efficacy, and trials that recruited patients with IBS with

diarrhoea (IBS-D), or excluded those with IBS with constipation (IBS-C).

Ford et al. 14 of 46

RESULTS

The search strategy generated 1231 citations, 79 of which appeared relevant and were

retrieved for further assessment (Supplementary Figure 1). Of these, we excluded 66 that did

not fulfil eligibility criteria, leaving 13 eligible articles,[28, 29, 33, 52-61] which included

944 patients, 472 of whom were allocated to a low FODMAP diet. Twelve RCTs evaluated

low FODMAP dietary advice,[28, 33, 52-61] and one RCT evaluated a low FODMAP diet in

which participants were provided with the majority of food to be consumed and advised

about fluid choices throughout the duration of the intervention.[29] In terms of the alternative

intervention, 237 patients received BDA/NICE dietary advice for IBS in five RCTs,[33, 52-

55] 106 were allocated to habitual diet in four RCTs,[28, 29, 56, 57] 76 were randomised to

sham dietary advice in two trials,[58, 59] 33 were allocated to alternative brief dietary advice

in one RCT,[60] and 20 received a high FODMAP diet in one trial (Supplementary Table

2).[61] Agreement between investigators for trial eligibility was excellent (kappa statistic =

0.82). Seven trials recruited only patients with IBS-D or excluded those with IBS-C

specifically.[28, 33, 53-55, 58, 59] Detailed characteristics of individual RCTs are provided

in Table 1.

All trials were published in full. We obtained extra data from the investigators of

seven RCTs.[53, 55-60] Risk of bias for all included trials is reported in Supplementary Table

3. No RCT was at low risk of bias across all domains, although nine trials were low risk of

bias across all domains other than double blinding.[28, 52, 54-59, 61] Dietary trials are

inherently difficult to blind, but two trials stated that investigators were blinded to treatment

allocation,[33, 55] and eight that patients were blinded.[29, 52-54, 58-61] Endpoints used, or

imputed, in each trial are provided in Supplementary Table 4. Adverse events were not

reported in sufficient detail in most trials to allow any meaningful pooling of data.
Ford et al. 15 of 46

Table 1. Characteristics of Randomised Controlled Trials of a Low FODMAP Diet for IBS.

Study Country and Duration Details of low FODMAP diet and Details of comparator and number of Number Diagnostic criteria

setting number of patients patients (%) used for IBS, and

female number (%) with

each subtype

Bohn 2015 [52] Sweden, 4 weeks 38 patients assigned to a low FODMAP 37 patients assigned to BDA/NICE diet, 61 Rome III, 22

secondary and diet, with dietary advice from a with dietary advice from a dietitian and (81.3%) (29.3%) IBS-C, 18

tertiary care dietitian and provision of written provision of written information (24.0%) IBS-D, 35

information (46.7%) IBS-M

Eswaran 2016 USA, tertiary 4 weeks 50 patients assigned to a low FODMAP 42 patients assigned to NICE diet, with 65 Rome III, 92

[33] care diet, with dietary advice from a dietary advice from a dietitian and (70.7%) (100%) IBS-D

dietitian and provision of teaching provision of teaching materials

materials

Zahedi 2018 Iran, secondary 6 weeks 55 patients assigned to a low FODMAP 55 patients assigned to BDA diet, with 51 Rome III, 110

[53] care diet, with dietary advice from a dietary advice from a dietitian during a (50.5%) (100%) IBS-D

dietitian during a 45-minute 45-minute appointment

appointment and provision of written

information
Ford et al. 16 of 46

Goyal 2021 [54] India, 4 weeks 52 patients assigned to a low FODMAP 49 patients assigned to BDA/NICE diet, 42 Rome IV, 101

secondary care diet, with dietary advice from a with dietary advice from a dietitian and (41.6%) (100%) IBS-D

dietitian and provision of written provision of written information

information

Zhang 2021 [55] China, tertiary 3 weeks 54 patients assigned to a low FODMAP 54 patients assigned to BDA/NICE diet, 51 Rome III, 108

care diet, with dietary advice from a with dietary advice from a dietitian (47.2%) (100%) IBS-D

dietitian during a 20-minute during a 20-minute appointment and a

appointment and a menu plan to follow menu plan to follow

Staudacher UK, tertiary 4 weeks 19 patients assigned to a low FODMAP 22 patients advised to continue with 27 Rome III, subtype

2012 [28] care diet, with dietary advice from a their habitual diet by a dietitian during a (65.9%) not stated but

dietitian during a 45-minute 45-minute appointment excluded patients

appointment with IBS-C

Halmos 2014 Australia, 3 weeks 13 patients assigned to a low FODMAP 17 patients assigned to a typical 21 Rome III, 13

[29] unclear diet, with almost all food provided as Australian diet, with almost all food (70.0%) (43.3%) IBS-C, 10

frozen complete meals, but additional provided as frozen complete meals, but (33.3%) IBS-D, 5

food lists provided to enable purchase additional food lists provided to enable (16.7%) IBS-M

of additional low FODMAP foods purchase of additional FODMAP-

containing foods
Ford et al. 17 of 46

Pedersen 2014 Denmark, 6 weeks 42 patients assigned to a low FODMAP 40 patients continued with their habitual 63 Rome III, 12

[56] tertiary care diet, with dietary advice from a diet (76.8%) (14.6%) IBS-C, 37

dietitian during a 1-hour appointment (45.1%) IBS-D, 28

and additional food lists provided (34.1%) IBS-M

Harvie 2017 New Zealand, 3 months 23 patients assigned to a low FODMAP 27 patients continued with their habitual 43 Rome III, 5 (10.0%)

[57] primary, diet, with dietary advice from a diet (86.0%) IBS-C, 32 (64.0%)

secondary, and dietitian during a 1-hour appointment IBS-D, 14 (28.0%)

tertiary care IBS-M

Staudacher UK, tertiary 4 weeks 51 patients assigned to a low FODMAP 53 patients assigned to a sham dietary 70 Rome III, 69

2017 [58] care diet, with dietary advice from a intervention, with dietary advice from a (67.3%) (66.3%) IBS-D, 24

dietitian of 10 minutes duration, based dietitian of 10 minutes duration, based (23.1%) IBS-M, 11

on provided food lists on provided food lists (10.6%) IBS-U

Wilson 2020 UK, tertiary 4 weeks 22 patients assigned to a low FODMAP 23 patients assigned to a sham dietary 25 Rome III, 45

[59] care diet, with dietary advice from a intervention, with dietary advice from a (55.6%) (66.7%) IBS-D,

dietitian during a 1-hour appointment dietitian during a 15 to 25-minute patients with IBS-C

and provision of written information appointment and provision of written were excluded

information
Ford et al. 18 of 46

Patcharatrakul Thailand, 4 weeks 33 patients assigned to a low FODMAP 33 patients assigned to dietary advice 47 Rome III, subtype

2019 [60] secondary care diet, with dietary advice from a from a gastroenterologist during a 5- (75.8%) not stated

gastroenterologist during a 30-minute minute appointment

appointment, an example food menu,

and provision of written information

McIntosh 2016 Canada, tertiary 3 weeks 20 patients assigned to a low FODMAP 20 patients assigned to a high FODMAP 32 Rome III, 2 (5.0%)

[61] care diet, with dietary advice from a diet, with dietary advice from a dietitian (86.5%) IBS-C, 10 (25.0%)

dietitian during a 30 to 60-minute during a 30 to 60-minute appointment, IBS-D, 23 (57.5%)

appointment, sample food menus, and sample food menus, and provision of IBS-M, 1 (2.5%)

provision of written information written information IBS-U

Ford et al. 19 of 46

Global IBS Symptoms

Twelve RCTs provided extractable dichotomous data,[28, 29, 33, 52-59, 61] and data

were imputed for another study,[60] meaning that all 13 trials contributed to this analysis.

The network plot is provided in Supplementary Figure 2. When data were pooled, there was

no heterogeneity (τ2 = 0), and the funnel plot appeared symmetrical (Supplementary Figure

3). However, there was evidence of funnel plot asymmetry when pooling pairwise data,

suggesting publication bias or other small study effects (Egger test, P = 0.043)

(Supplementary Figure 4). Compared with habitual diet, a low FODMAP diet was ranked

first (RR of global IBS symptoms not improving = 0.67; 95% CI 0.48 to 0.91, P-score 0.99)

(Figure 1). This means that the probability of a low FODMAP diet being the most efficacious

when all interventions were compared with each other was 99%. Among alternative

interventions, compared with habitual diet, BDA/NICE dietary advice was ranked second

(RR = 0.82; 95% CI 0.57-1.18, P-score 0.71) and high FODMAP diet last (P-score 0.10).

Low FODMAP diet was superior to all other interventions, including BDA/NICE dietary

advice (Table 2). None of the alternative interventions was superior to habitual diet, or any of

the other alternative interventions.

There were seven RCTs that used a 50-point decrease in the IBS-SSS to define

response.[52-57, 61] When we restricted the analysis to these studies, low FODMAP diet was

still ranked first, although it was no more efficacious than habitual diet (RR = 0.76; 95% CI

0.53 to 1.11, P-score 0.97) (Supplementary Figure 5). However, it was more efficacious than

both BDA/NICE dietary advice and a high FODMAP diet (Supplementary Table 5). There

were no other significant differences. When we restricted the analysis to seven trials that

recruited only patients with IBS-D, or excluded those with IBS-C specifically,[28, 33, 53-55,

58, 59] low FODMAP diet again ranked first for global IBS symptoms (RR = 0.41; 95% CI

0.20 to 0.82, P-score 0.99) (Supplementary Figure 6) and was superior to all alternative
Ford et al. 20 of 46

Table 2. Summary Treatment Effects from the Network Meta-analysis for Failure to Achieve an Improvement in Global IBS Symptoms.

Low FODMAP diet

0.81 (0.67; 0.97) BDA/NICE dietary advice

0.70 (0.52; 0.95) 0.87 (0.61; 1.23) Sham dietary advice

0.67 (0.48; 0.91) 0.82 (0.57; 1.18) 0.95 (0.61; 1.47) Habitual diet

0.58 (0.38; 0.87) 0.71 (0.45; 1.12) 0.82 (0.49; 1.37) 0.87 (0.52; 1.46) Alternative dietary advice

0.44 (0.23; 0.83) 0.54 (0.28; 1.05) 0.62 (0.31; 1.26) 0.66 (0.32; 1.34) 0.76 (0.36; 1.62) High FODMAP diet

Relative risk with 95% confidence intervals in parentheses. Comparisons, column versus row, should be read from left to right, and are ordered

relative to their overall efficacy. The intervention in the top left position is ranked as best after the network meta-analysis of direct and indirect

effects. Boxes shaded green denote a statistically significant difference.

BDA/NICE; British Dietetic Association/National Institute for Health and Care Excellence, FODMAP; fermentable oligosaccharides,

disaccharides, monosaccharides, and polyols.

Ford et al. 21 of 46

interventions (Supplementary Table 6). There were no significant differences between

alternative interventions.

Abdominal Pain Severity

There were 12 trials reporting data on effect on abdominal pain severity,[28, 33, 52-

61] recruiting 914 patients, 459 of whom received a low FODMAP diet. Five trials compared

a low FODMAP diet with BDA/NICE dietary advice for IBS,[33, 52-55] three habitual

diet,[28, 56, 57] two sham dietary advice,[58, 59] one alternative brief dietary advice,[60]

and one high FODMAP diet.[61] The network plot is provided in Supplementary Figure 7.

When data were pooled, there was moderate heterogeneity (τ2 = 0.068), and the funnel plot

appeared symmetrical (Supplementary Figure 8), but again there was funnel plot asymmetry

when pooling pairwise data (Egger test, P = 0.025) (Supplementary Figure 9). Compared

with habitual diet, a low FODMAP diet ranked first, but it was not superior in terms of

efficacy (RR of abdominal pain severity not improving = 0.72; 95% CI 0.47 to 1.10, P-score

0.92) (Figure 2). A low FODMAP diet was superior to sham dietary advice (Table 3), but

there were no other significant differences.

There were nine RCTs that used an endpoint of a 30% improvement in abdominal

pain severity on the IBS-SSS.[33, 52-54, 56-59, 61] Restricting the analysis to these studies,

low FODMAP diet still ranked first, although again it was no more efficacious than habitual

diet (RR = 0.74; 95% CI 0.43 to 1.28, P-score 0.94) (Supplementary Figure 10). However, it

was more efficacious than sham dietary advice, although there were no other significant

differences (Supplementary Table 7). When we restricted the analysis to seven trials that

recruited only patients with IBS-D, or excluded those with IBS-C specifically,[28, 33, 53-55,

58, 59] low FODMAP diet again ranked first but was not superior to habitual diet (RR =

0.63; 95% CI 0.22 to 1.81, P-score 0.91) (Supplementary Figure 11). However, low
Ford et al. 22 of 46

Table 3. Summary Treatment Effects from the Network Meta-analysis for Failure to Achieve an Improvement in Abdominal Pain

Severity.

Low FODMAP diet

0.79 (0.39; 1.59) Alternative dietary advice

0.78 (0.57; 1.06) 0.98 (0.46; 2.11) BDA/NICE dietary advice

0.72 (0.47; 1.10) 0.91 (0.40; 2.06) 0.92 (0.54; 1.57) Habitual diet

0.51 (0.30; 0.87) 0.65 (0.27; 1.56) 0.66 (0.35; 1.22) 0.71 (0.36; 1.41) Sham dietary advice

0.47 (0.20; 1.07) 0.59 (0.20; 1.74) 0.60 (0.25; 1.45) 0.65 (0.26; 1.65) 0.91 (0.34; 2.44) High FODMAP diet

Relative risk with 95% confidence intervals in parentheses. Comparisons, column versus row, should be read from left to right, and are ordered

relative to their overall efficacy. The intervention in the top left position is ranked as best after the network meta-analysis of direct and indirect

effects. Boxes shaded green denote a statistically significant difference.

BDA/NICE; British Dietetic Association/National Institute for Health and Care Excellence, FODMAP; fermentable oligosaccharides,

disaccharides, monosaccharides, and polyols.

Ford et al. 23 of 46

FODMAP diet was again superior to sham dietary advice (Supplementary Table 8). There

were no significant differences between alternative interventions.

Abdominal Bloating or Distension Severity

The same 12 RCTs, recruiting 914 patients, provided data for effect on abdominal

bloating or distension severity.[28, 33, 52-61] The network plot is provided in Supplementary

Figure 12. There was moderate heterogeneity (τ2 = 0.058), and the funnel plot appeared

symmetrical (Supplementary Figure 13), with no evidence of funnel plot asymmetry when

pooling pairwise data (Egger test, P = 0.31). Compared with habitual diet, low FODMAP diet

ranked first, but it was not superior in terms of efficacy (RR of abdominal bloating or

distension severity not improving = 0.71; 95% CI 0.47 to 1.06, P-score 0.82) (Figure 3).

However, a low FODMAP diet was superior to BDA/NICE dietary advice (Table 4). There

were no other significant differences.

There were nine RCTs that used an endpoint of a 30% improvement in abdominal distension

severity on the IBS-SSS.[33, 52-54, 56-59, 61] When we restricted the analysis to these

studies, low FODMAP diet still ranked first, although again it was no more efficacious than

habitual diet (RR = 0.80; 95% CI 0.49 to 1.30, P-score 0.84) (Supplementary Figure 14).

However, it was more efficacious than BDA/NICE dietary advice, which ranked last

(Supplementary Table 9). There were no other significant differences. When we restricted the

analysis to seven trials that recruited only patients with IBS-D or excluded those with IBS-

C,[28, 33, 53-55, 58, 59] low FODMAP diet again ranked first but was not superior to

habitual diet (RR = 0.46; 95% CI 0.18 to 1.20, P-score 0.86) (Supplementary Figure 15).

However, low FODMAP diet was superior to BDA/NICE dietary advice (Supplementary

Table 10). There were no significant differences between alternative interventions.

Ford et al. 24 of 46

Table 4. Summary Treatment Effects from the Network Meta-analysis for Failure to Achieve an Improvement in Abdominal Bloating

or Distension Severity.

Low FODMAP diet

0.95 (0.50; 1.79) Alternative dietary advice

0.85 (0.51; 1.43) 0.90 (0.40; 2.05) Sham dietary advice

0.69 (0.36; 1.32) 0.73 (0.29; 1.81) 0.81 (0.35; 1.86) High FODMAP diet

0.72 (0.55; 0.94) 0.76 (0.38; 1.52) 0.84 (0.47; 1.52) 1.05 (0.51; 2.13) BDA/NICE dietary advice

0.71 (0.47; 1.06) 0.75 (0.35; 1.59) 0.83 (0.43; 1.60) 1.03 (0.48; 2.22) 0.98 (0.61; 1.60) Habitual diet

Relative risk with 95% confidence intervals in parentheses. Comparisons, column versus row, should be read from left to right, and are ordered

relative to their overall efficacy. The intervention in the top left position is ranked as best after the network meta-analysis of direct and indirect

effects. Boxes shaded green denote a statistically significant difference.

BDA/NICE; British Dietetic Association/National Institute for Health and Care Excellence, FODMAP; fermentable oligosaccharides,

disaccharides, monosaccharides, and polyols.

Ford et al. 25 of 46

Improvement in Bowel Habit

Ten trials provided data on effect on improvement in bowel habit,[33, 52-59, 61]

randomising 807 patients. Of these, 407 received a low FODMAP diet. Five trials compared

a low FODMAP diet with BDA/NICE dietary advice for IBS,[33, 52-55] two habitual

diet,[56, 57] two sham dietary advice,[58, 59] and one high FODMAP diet.[61] The network

plot is provided in Supplementary Figure 16. When data were pooled, there was moderate

heterogeneity (τ2 = 0.071), and the funnel plot appeared symmetrical (Supplementary Figure

17). However, there was funnel plot asymmetry when pooling pairwise data (Egger test, P =

0.0034) (Supplementary Figure 18). Compared with habitual diet, a low FODMAP diet

ranked first, but again it was not superior in terms of efficacy (RR of bowel habit not

improving = 0.62; 95% CI 0.37 to 1.04, P-score 0.88) (Figure 4). There were no significant

differences between low FODMAP diet and any of the comparators (Table 5).

There were eight RCTs that used an endpoint of a 30% improvement in bowel habit

on the IBS-SSS.[52-54, 56-59, 61] When we restricted the analysis to these studies, low

FODMAP diet ranked first, although it was no more efficacious than habitual diet (RR =

0.60; 95% CI 0.31 to 1.18, P-score 0.84) (Supplementary Figure 19), or to any other

alternative intervention (Supplementary Table 11). When restricting the analysis to the six

trials that recruited only patients with IBS-D or excluded those with IBS-C specifically,[33,

53-55, 58, 59] a low FODMAP diet again ranked first but was not superior to sham dietary

advice (RR = 0.82; 95% CI 0.51 to 1.32, P-score 0.87) (Supplementary Figure 20), and there

were no significant differences between any of the other interventions (Supplementary Table

12).
Ford et al. 26 of 46

Table 5. Summary Treatment Effects from the Network Meta-analysis for Failure to Achieve an Improvement in Bowel Habit.

Low FODMAP diet

0.83 (0.55; 1.25) Sham dietary advice

0.81 (0.61; 1.07) 0.97 (0.59; 1.60) BDA/NICE dietary advice

0.73 (0.36; 1.48) 0.88 (0.39; 1.99) 0.90 (0.42; 1.93) High FODMAP diet

0.62 (0.37; 1.04) 0.75 (0.39; 1.44) 0.77 (0.43; 1.38) 0.85 (0.36; 2.03) Habitual diet

Relative risk with 95% confidence intervals in parentheses. Comparisons, column versus row, should be read from left to right, and are ordered

relative to their overall efficacy. The intervention in the top left position is ranked as best after the network meta-analysis of direct and indirect

effects. Boxes shaded green denote a statistically significant difference.

BDA/NICE; British Dietetic Association/National Institute for Health and Care Excellence, FODMAP; fermentable oligosaccharides,

disaccharides, monosaccharides, and polyols.

Ford et al. 27 of 46

DISCUSSION

This is the first systematic review and network meta-analysis of a low FODMAP diet

for IBS, comparing its efficacy against alternative dietary advice for IBS, such as that

provided by the BDA and NICE, as well as inactive control interventions. A low FODMAP

diet ranked first for global IBS symptoms, and was superior to all alternative interventions

studied, including BDA/NICE dietary advice. In terms of its effects on individual symptoms

a low FODMAP diet was superior to sham dietary advice for abdominal pain severity, and it

was superior to BDA/NICE dietary advice for abdominal bloating or distension severity. We

did not detect any significant effect of a low FODMAP diet on bowel habit when data from

these trials were pooled. When we restricted the analysis to trials that used identical

dichotomous endpoints to assess response to treatment, or trials excluding patients with IBS-

C, results were broadly similar. Most trials did not report adverse events in detail, precluding

any relevant meaningful analysis.

We undertook the literature search, eligibility assessment, and data extraction in

duplicate and independently, with any discrepancies resolved by consensus. We used an

intention-to-treat analysis, assuming all dropouts failed therapy, and pooled data with a

random effects model, to reduce the likelihood that any beneficial effect of a low FODMAP

diet in IBS, or the alternative or control interventions studied, has been overestimated. We

also contacted authors of seven studies to obtain supplementary data to maximise the number

of eligible RCTs in the network,[53, 55-60] and imputed dichotomous responder data using

means and standard deviations according to validated methods.[37, 38] This allowed us to

include global IBS symptom data from three trials, and 242 patients, that would otherwise

have been excluded altogether,[53, 56, 57] as well as to study the effect of a low FODMAP

diet on individual symptoms of abdominal pain severity, abdominal bloating or distension

severity, and improvement in bowel habit, using endpoints that were relatively standardised
Ford et al. 28 of 46

between trials, and which are closely aligned to those recommended by the FDA. This

network meta-analysis, therefore, represents a considerable advance over previous pairwise

meta-analyses.

There are some limitations. No trials were at low risk of bias, due to a lack of double

blinding, although this is almost impossible in dietary trials, and 10 trials blinded either

investigators or patients to treatment allocation. Based on quality assessment criteria intended

for pharmacotherapy trials, it would be recommended the results of the network meta-

analysis are interpreted with caution, as trials that do not employ double blinding tend to

overestimate efficacy of the intervention studied.[62] However, it could be argued that this is

not possible in dietary and other non-pharmacotherapy trials (e.g. psychological therapies).

Four of the RCTs restricted recruitment to patients with IBS-D,[33, 53-55] and a further three

did not recruit patients with IBS-C,[28, 58, 59] meaning the efficacy of a low FODMAP diet

in those with IBS-C or IBS with a mixed stool pattern is less clear. Even though a low

FODMAP diet is recommended as a dietary intervention in primary care,[34] all but one of

the trials was conducted in secondary or tertiary care.[57] There was no heterogeneity in our

analysis for global IBS symptoms, but moderate heterogeneity in our other analyses, which

may relate to mode of delivery and nature of the interventions studied. There was also

evidence of funnel plot asymmetry for all analyses, except abdominal bloating or distension

severity. Despite these limitations, the results of our study are still useful for informing

treatment decisions for patients and can be used in future updates of evidence-based IBS

management guidelines.[17, 32, 34]

Restriction of FODMAPs is not recommended long-term, to minimise risk of

nutritional inadequacy. Further, short-term alterations in the gastrointestinal microbiota have

been reported, including a consistent finding of reduced abundance of Bifidobacteria.[28, 59,

63] Although the long-term consequences of these changes are unknown, reintroduction of
Ford et al. 29 of 46

high FODMAP foods to tolerance is a critical phase of the low FODMAP diet in clinical

practice and may curb the impacts on dietary intake and the microbiota. However, very few

of the included RCTs incorporated this phase of the diet into their design, meaning that the

effect of FODMAP reintroduction on IBS symptoms remains unclear. One 4-week trial

comparing a low FODMAP diet with BDA/NICE dietary advice reported data at 12 weeks,

after FODMAP reintroduction, and still demonstrated a significant difference in responder

rates favouring a low FODMAP diet at 16 weeks.[54] Uncontrolled studies support the long-

term efficacy of the diet after FODMAP reintroduction.[64, 65] However, RCTs are needed

to confirm this, although it is acknowledged these are difficult to carry out, particularly with

regard to blinding over longer periods of time and minimising attrition.[66] Outside of a

clinical trial setting individual patients may struggle with the FODMAP restriction phase of

the diet, although a real-world study demonstrated less than 10% of patients were non-

adherent during this part of the intervention.[67]

Our results confirm that a low FODMAP diet is an efficacious treatment for global

IBS symptoms in secondary and tertiary care. Importantly, a dietitian delivered counselling in

all but one of the 12 low FODMAP dietary advice RCTs.[60] These findings support the use

of a low FODMAP diet under dietetic supervision, although it is important to point out that

RCTs in primary care are lacking, which is in contrast with its placement in current NICE

guidance for the management of IBS.[34] The recent British Society of Gastroenterology

guidelines for the management of IBS also recommend the use of a low FODMAP diet as a

second-line dietary approach in those individuals who have not responded to first-line

advice.[32] These guidelines stated that it was likely to be beneficial for both global IBS

symptoms, and abdominal pain, based on an update of a prior systematic review and pairwise

meta-analysis.[30] However, our analysis suggests that any effect on abdominal pain severity,

versus alternative dietary advice or a habitual diet, is less certain.

Ford et al. 30 of 46

Of note, BDA/NICE dietary advice was not superior to any of the alternative or

control interventions in our analyses, and a low FODMAP diet was significantly more

efficacious for both global IBS symptoms and abdominal bloating or distension severity. This

contrasts with the results of individual trials themselves,[33, 52-55] and likely relates to the

increased power of the meta-analysis to detect smaller, but still potentially clinically relevant,

differences. Nevertheless, there were fewer patients assigned to BDA/NICE dietary advice

than a low FODMAP diet and it is, perhaps, premature to dismiss this approach based on the

findings of this network meta-analysis, particularly as it usually less intensive to follow than

the whole-diet approach of a low FODMAP diet. Indeed, there are also safety,

microbiological, and clinical capacity implications of a low FODMAP diet, which were

unable to be examined as part of this meta-analysis, and which mean BDA/NICE dietary

advice is still a reasonable first-line dietary approach. We believe there is still, therefore, a

need for head-to-head trials of BDA/NICE dietary advice versus sham dietary advice, to

assess whether the dietary modifications recommended are beneficial for patients with IBS.

These trials should ideally include specific IBS subtypes as the nature of dietary changes

based on BDA/NICE dietary advice are dependent on symptom profile. In terms of

alternative interventions studied, a high FOMDAP diet ranked last for global IBS symptoms

and abdominal pain severity, suggesting its use as a comparator is likely to overestimate

efficacy of a low FODMAP diet. This is expected, given previous research showing acute

challenge with individual FODMAPs provokes symptoms in IBS.[25] Habitual diet ranked

last in several analyses. This is, perhaps, not surprising as this is similar to an “attention”

control used in trials of psychological therapies,[68] where patients receive no treatment.

There is the possibility that, in a trial designed to assess an active dietary intervention, being

randomised to continue usual diet is associated with anticipation that symptoms will not

improve, leading to overestimation of the efficacy of a low FODMAP diet. Both sham dietary
Ford et al. 31 of 46

advice and BDA/NICE dietary advice ranked higher and should be preferred as a comparator

in future RCTs. They should be made as comparable as possible with the low FODMAP diet

in terms of complexity of the intervention and time spent with the dietitian.

In summary, this systematic review and network meta-analysis has demonstrated that

a low FODMAP diet ranked first in all analyses, compared with five alternative interventions,

in IBS in terms of efficacy. Although BDA/dietary advice ranked second for global

symptoms, it was not superior to a low FODMAP diet for any of the endpoints studied, and it

performed no better than the other alternative or control interventions questioning its place in

IBS primary care guidelines. Of note, almost all low FODMAP dietary advice RCTs

implemented a dietitian-delivered intervention, emphasising the importance of dietetic

supervision. This may limit availability in a clinical practice setting. Seven trials excluded

patients with IBS-C, meaning the benefit of these dietary approaches in this patient group is

less clear, and only one trial examined the effect of FODMAP reintroduction on IBS

symptoms. The inherent challenges of study design in trials of dietary intervention meant that

the quality of the evidence, according to GRADE criteria, [69] was low for a low FODMAP

diet due to risk of bias of included RCTs, as well as imprecision due to uncertainty around

effects and possible publication bias, and very low for all other interventions studied.

However, endpoints we used to judge efficacy approximated those recommended by the

FDA. Adverse event reporting was suboptimal in most trials. In addition, even though a low

FODMAP diet or BDA/NICE dietary advice are recommended for patients with IBS in

primary care, and before referral to a gastroenterologist, most trials were conducted in

referral populations. Further RCTs of both a low FODMAP diet and BDA/NICE dietary

advice against each other, or against sham dietary advice, in primary care that are powered

adequately, used FDA-recommended endpoints, examine efficacy during the FODMAP

Ford et al. 32 of 46

reintroduction and personalisation phase, and report adverse events data more thoroughly are

required.

ACKNOWLEDGEMENTS
We are grateful to Vahideh Behrouz, Sutep Gonlachanvit, Ruth Harvie, Chung Owyang,

Natalia Pedersen, and Bridgette Wilson for providing extra information and data from their

studies.

CONTRIBUTOR AND GUARANTOR INFORMATION

Guarantor: ACF is guarantor. He accepts full responsibility for the work and the conduct of

the study, had access to the data, and controlled the decision to publish. The corresponding

author attests that all listed authors meet authorship criteria and that no others meeting the

criteria have been omitted.

Specific author contributions: Study concept and design: ACF, HMS, and CJB conceived

and drafted the study. CJB and ACF analysed and interpreted the data. ACF and HMS drafted

the manuscript. All authors have approved the final draft of the manuscript. The

corresponding author attests that all listed authors meet authorship criteria and that no others

meeting the criteria have been omitted.

COPYRIGHT/LICENSE FOR PUBLICATION

The Corresponding Author has the right to grant on behalf of all authors and does grant on

behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in

all forms, formats and media (whether known now or created in the future), to i) publish,
Ford et al. 33 of 46

reproduce, distribute, display and store the Contribution, ii) translate the Contribution into

other languages, create adaptations, reprints, include within collections and create summaries,

extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on

the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of

electronic links from the Contribution to third party material where-ever it may be located;

and, vi) licence any third party to do any or all of the above.

COMPETING INTERESTS DECLARATION

All authors have completed the ICMJE uniform disclosure form

at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the

submitted work; no financial relationships with any organisations that might have an interest

in the submitted work in the previous three years; no other relationships or activities that

could appear to have influenced the submitted work.

TRANSPARENCY STATEMENT

The lead author (ACF, the manuscript's guarantor) affirms that the manuscript is an honest,

accurate, and transparent account of the study being reported; that no important aspects of the

study have been omitted; and that any discrepancies from the study as originally planned

(and, if relevant, registered) have been explained.

ROLE OF THE FUNDING SOURCE

None.
Ford et al. 34 of 46

PATIENT AND PUBLIC INVOLVEMENT STATEMENT

We did not involve patients or the public in this work. We will disseminate our findings in

lay terms via the national charity for people living with digestive diseases, “Guts UK”, and

the national charity for people living with IBS, the IBS Network.

DATA SHARING

No additional data available.

Ford et al. 35 of 46

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FIGURES

Figure 1. Forest Plot for Failure to Achieve an Improvement in Global IBS Symptoms.

Note: The P-score is the probability of each intervention being ranked as best in the network.

Figure 2. Forest Plot for Failure to Achieve an Improvement in Abdominal Pain

Severity.

Note: The P-score is the probability of each intervention being ranked as best in the network.

Figure 3. Forest Plot for Failure to Achieve an Improvement in Abdominal Bloating or

Distension Severity.

Note: The P-score is the probability of each intervention being ranked as best in the network.

Figure 4. Forest Plot for Failure to Achieve an Improvement in Bowel Habit.

Note: The P-score is the probability of each intervention being ranked as best in the network.