The Role of a Low Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyol Diet in Nonceliac Gluten Sensitivity

Table 1

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 [10]	RDBPCC fructan challenge (2.1 g), gluten (5.7 g), and placebo given as a muesli bar	self-reported NCGS	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; Overall GSRS-IBS borderline significant for fructan (38.6) versus gluten (33.1) and placebo (34.3); Significant difference in GSRS-IBS for bloating after fructan	Daily GI symptoms by VAS for overall GI symptoms higher with fructan; Health-related quality of life by SF-36 lowest for fructan for vitality Depression and anxiety by Hospital Anxiety and Depression Scale and fatigue by VAS and GSCL highest after fructan
Dieterich et al., 2018, Germany [14]	Open low FODMAP diet adherence for 2 wk	self-reported NCGS,; healthy controls	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; Further improvement on GFD for abdominal pain, diarrhea, and constipation	Psychological well-being by PGWB improved on low FODMAP diet and further on GFD; Reduced IELs on GFD; Stool microbiota showed differences in NCGS and controls with reduced Bifidobacteriae on low FODMAP diet.; Near normalization of gut flora on GFD
Zanini et al., 2015, Italy [11]	RDBPCC GCF had fructans 0.8 g/100 g. GFF had 0.16 g/100 g fructans present in both study arm materials.	self-reported NCGS	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 (34%); Inaccurate, (49%); Unable to distinguish (17%)	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 [12]	RDBCC fructans present in both study arm materials and low FODMAP diet for 8 weeks	self-reported NCGS	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; Inaccurate,; Unable to distinguish,	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 [13]	RDPBPCC, low FODMAP diet adherence for 2 wk	IBS patients fulfilling NCGS criteria	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 β-defensin-2, calprotectin, and ammonia levels
Peters et al., 2014, Australia [15]	RDBPCC low FODMAP diet adherence for the entire duration of study	IBS with improvement on GFD	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.