Gluten avoidance has become a popular health trend with nearly 30% of adults avoiding gluten or limiting their intake. Despite conflicting evidence regarding the existence of nonceliac gluten sensitivity (NCGS) as an entity amongst clinicians, it has found prompt and easy acceptance in the general public [
Although the etiology of NCGS remains unknown, the role of FODMAPs is being increasingly investigated. FODMAPs have been postulated to precipitate functional gastrointestinal (GI) symptoms by inducing distention of GI lumen through their osmotic effects and production of gas in the small bowel and proximal colon related to rapid fermentation by gut bacteria in subjects with visceral hypersensitivity or GI motility disorders [
This review includes studies on patients with NCGS in whom FODMAPs either directly precipitated symptoms or adherence to low FODMAP diet improved symptoms. In addition, we sought to determine if NCGS is a heterogeneous entity that consists of patients who may improve on low FODMAP diet with or without following a GFD.
Relevant articles were identified by systematically searching the Cochrane Library, EMBASE, and PubMed for English language articles published by April 30, 2018. Manual search for relevant publications from the references of extracted articles was also performed. No publication date or publication status restrictions were applied. Preferred reporting items for systemic reviews and meta-analyses (PRISMA) guidelines were followed to develop a protocol including eligibility criteria, search strategies, criteria for study selection, methods for data extraction, and assessing study quality and statistics [
Full text of these citations was retrieved and examined in more detail. Six studies were finally included for this review, as shown in Table
Studies for FODMAPs role in NCGS.
Authors, year, country | Design/method of studying FODMAP effect | Number of subjects ( |
CD exclusion method | Protocol | Primary outcome/results | Secondary outcomes/results |
---|---|---|---|---|---|---|
Skodje et al., 2018, Norway [ |
RDBPCC fructan challenge (2.1 g), gluten (5.7 g), and placebo given as a muesli bar | Negative HLA DQ2/DQ8 or normal duodenal biopsy (marsh 0) on GFD if positive for above haplotypes | GFD for 6 m, 7 d on first diet challenge, 7 d washout, then crossover to next arm | GSRS-IBS, recorded for pain, bloating, constipation, diarrhea, satiety |
Daily GI symptoms by VAS for overall GI symptoms higher with fructan | |
Dieterich et al., 2018, Germany [ |
Open low FODMAP diet adherence for 2 wk | IgA/G to TTG and deamidated gliadin peptides, EGD, and duodenal biopsy in NCGS patients | GCD with 10 g gluten for 4 wk, 2 wk low FODMAP diet, then 5 d transition, GFD 2 wk follow up EGD in 17 patients (with persisting symptoms) | Improvement of GI symptoms by GSRS on low FODMAP diet for NCGS pts. for reflux, abdominal pain, and indigestion |
Psychological well-being by PGWB improved on low FODMAP diet and further on GFD | |
Zanini et al., 2015, Italy [ |
RDBPCC GCF had fructans 0.8 g/100 g. GFF had 0.16 g/100 g fructans present in both study arm materials. | Negative t-TG and/or endomysial antibodies and normal villous structure on duodenal biopsies (marshes 0, 1, 2) | GCF or GFF for 10 days, then 2 wk washout period, then crossed over to another group | GFD for 6 m, ability to identify gluten-containing flour |
GSRS score for pain, reflux, indigestion, diarrhea, and constipation and VAFS for fatigue increased with GCF in NCGS and GFF in GFF-sensitive. No changes in t-TG IgA and antigliadin IgA and IgG | |
Zanini et al., 2014, Italy [ |
RDBCC fructans present in both study arm materials and low FODMAP diet for 8 weeks | Negative t-TG and/or endomysial antibodies and normal villous structure on duodenal biopsies (marshes 0, 1, 2) | GFD, 10 g gluten versus 10 g gluten-free flour for 10 d, then 2 wk washout, then low FODMAP diet for 8 wk | Able to identify gluten-containing flour |
GSRS score for pain, reflux, indigestion, diarrhea, and constipation improved on low FODMAP diet with worsening on GFF. VAS for fatigue unchanged with GCF. No changes in t-TG IgA and antigliadin IgA and IgG | |
Biesiekierski et al., 2013, Australia [ |
RDPBPCC, low FODMAP diet adherence for 2 wk | Negative HLA DQ2/DQ8 or normal duodenal biopsy (marsh 0) on GFD if positive for the above haplotypes | GFD and 2-week low FODMAP diet, then one of the arms—high gluten (16 g), low gluten (2 g gluten and 14 g whey protein), control for 3 d, washout 2 weeks, crossover 3 d | VAS for overall abdominal symptoms, pain, bloating, wind, stool consistency satisfaction, and tiredness nausea improved in low FODMAP run-in period. 6 (16%) pts. had worsening of overall symptoms in high-gluten arm; only 3 pts. had worsening in placebo arm. | Fatigue with D-FIS was the lowest with low FODMAP diet and worse with all the 3 challenges. No effects on physical activity or sleep by accelerometry in any arm; only 1 subject elicited positive gliadin-specific T-cell response. No significant difference across the arms for ECF protein, RAST, serological markers, fecal wet and dry weight, pH, human | |
Peters et al., 2014, Australia [ |
RDBPCC low FODMAP diet adherence for the entire duration of study | Negative HLA DQ2/DQ8 or normal duodenal biopsy (marsh 0) on GFD if positive for above haplotypes | GFD and low FODMAP diet for the duration of study followed by 1 of the 3 dietary challenges —gluten, whey, and placebo 3 d, then 3 d crossover to next diet | Depression by STPI worse with gluten versus placebo but similar to whey | GI symptoms by VAS, cortisol levels similar across all the treatment arms |
RDBPCC: randomized double-blind placebo-controlled crossover challenge; G: Gram; GSRS-IBS: gastrointestinal symptom rating scale irritable bowel syndrome; VAS: visual analogue scale; VAFS: visual analogue fatigue score; GSRS: gastrointestinal symptom rating scale; GSCL: Giessen Subjective Complaint List; STPI: Spielberger State-Trait Personality Inventory; PGWB: Psychological General Well-Being Index; GCF: gluten-containing flour; GFF: gluten-free flour; GCD: gluten-containing diet; t-TG: tissue transglutaminase; EGD: esophagogastroduodenoscopy; wk: week; IEL: intraepithelial lymphocyte; pt: patient; D-FIS: daily-fatigue impact scale; ECF: eosinophil cationic protein; RAST: radioallergosorbent test; d: days.
All included studies were original articles. Only one study was open in design, and the remaining studies were randomized, double-blind controlled trials; four were placebo controlled, and five had a crossover design. The primary inclusion criteria were adult patients with self-reported NCGS. In all, a total of 197 patients across all studies were included. The sample size of the studies included varied from 22 to 59 patients.
The abdominal symptoms and bloating were associated with fructan challenge in a recent randomized, double-blind, placebo-controlled, crossover challenge (DBPCC) study involving 59 subjects with self-reported NCGS, as measured by gastrointestinal symptom rating scale-irritable bowel syndrome (GSRS-IBS) and GSRS bloating score. Also, visual analogue scale (VAS) for pain, bloating, flatus, nausea, and stool dissatisfaction was higher in the fructan challenge cohort [
In an Australian DBPCC involving 37 patients, after a two-week run in period of low FODMAP diet and GFD, NCGS patients had significant and consistent improvement in abdominal pain, bloating, and satisfaction with stool consistency, flatus, and fatigue. Similar findings were noted in the rechallenge stage of the trial [
Health-related quality of life indicated the lowest score for the “vitality” subdimension during fructan challenge in a Norwegian study [
Fatigue and weakness were significantly higher after fructan challenge and not different between gluten and placebo arms [
Higher depression scores were noted in subjects challenged with gluten following a low FODMAP diet and GFD [
A strong nocebo response was seen in all the included studies [
About one-fifth of participants in an Italian study did not report worsening of symptoms after a challenge with either gluten-rich or gluten-free flour [
The strong nocebo effect raises the concern of feasibility or even the usefulness of a DBPCC in clinical practice for the diagnosis of NCGS.
In an emerging area of study, the use of biomarkers in monitoring response in NCGS is uncommon [
Only one trial examined changes in the gut microbiota [
Our review presents the evidence that NCGS patients could potentially benefit from FODMAP restriction with or without gluten restriction. The results suggest that a subset of NCGS patients actually has FODMAP intolerance. This raises the question of NCGS as an entity specifically used in the context of gluten sensitivity as well as its distinction from FODMAP intolerance. FODMAPs may be a causative factor in GI symptoms and to some extent in extraintestinal symptoms such as fatigue and loss of vitality in some NCGS patients. NCGS may be a heterogeneous entity with multiple factors such as FODMAPs in addition to gluten contributing to symptom generation.
In a landmark study that established the current existence of NCGS as a separate entity, gluten was shown to induce both GI and extraintestinal symptoms in patients without CD [
Extraintestinal manifestations of NCGS, such as fatigue, depression, and anxiety, were mostly evaluated as secondary outcomes. Fatigue and vitality were significantly worse after a fructan challenge in some studies [
Similar synergic effects of a low FODMAP diet and GFD were noted in other studies [
Increasing evidence indicates that only a very small percentage (16–30%) of patients were actually found to have NCGS in rechallenge studies. Two separate meta-analyses of double-blind placebo-controlled gluten challenge trials in NCGS explore the possibility of gluten not being responsible for symptoms in self-reported NCGS [
Despite the success of these diets in study conditions, or even clinically, adherence to a restrictive diet like low FODMAP should always be initiated and monitored by a registered dietician trained in this area. As a concept, low FODMAP diet is complex, and it has always been meant to be a dietician-delivered diet [
First, due to a high nocebo response, the role of a DBPCC, the current gold standard for the diagnosis of NCGS, may be questionable [
Second, the symptomatic effect of gluten with fructans and other components of wheat may be additive or even synergistic. The fructans in the food matrix may give a different clinical response than the study materials (supplements of pure fructans added to muesli bars derived from chicory roots versus real-world wheat sources) [
This review suggests a multifactorial etiology of NCGS. FODMAPs may be responsible for gastrointestinal and extraintestinal symptoms in a subset of patients with NCGS [
The authors declare that they have no conflicts of interest.
P. Priyanka is assigned in topic selection, study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, literature search, and writing, editing, and submitting the manuscript. S. Gayam and J. T. Kupec are assigned in the critical revision of the manuscript for important intellectual content and editing.