TABLE 1.
Outline of research findings from the main studies on the role of gluten, ATIs, FODMAPs, and gut microbiota in IBS and NCGS1
| Study (reference) | Subjects | Number of participants | Methods | Research findings |
|---|---|---|---|---|
| Human studies | ||||
| Biesiekierski et al., 2011 (29) | CD genetically predisposed subjects | 34 | Double-blind, randomized, controlled study | A GFD in IBS-D patients significantly improved their IBS-like symptoms |
| Fritscher-Ravens et al., 2014 (30) | IBS patients | 36 | Confocal laser endomicroscopy | Half of patients presented intestinal leakage and epithelial breaks after wheat challenge |
| Pedersen et al., 2017 (31) | IBS patients | 89 | Randomized controlled trial | FODMAP removal from the diet significantly decreased abdominal pain and bloating |
| Bennet et al., 2018 (32) | IBS patients | 67 | Randomized controlled trial | Low-FODMAP diet improved IBS symptoms and correlated with reduced Bifidobacterium and Actinobacteria fecal bacteria and with lactose consumption |
| Böhn et al., 2015 (33) | IBS patients | 75 | Multicenter, parallel, single-blind study | Low-FODMAP diet improved IBS symptoms |
| Frieling et al., 2019 (34) | IBS patients | 93 | Prospective study | Low-FODMAP diet improved IBS symptoms but patients lost weight and received insufficient nutrients |
| Staudacher et al., 2017 (15) | IBS patients | 104 | Randomized, controlled study | Low-FODMAP diet improved IBS symptoms and co-administration with multistrain probiotic increased Bifidobacterium fecal bacteria |
| Hustoft et al., 2017 (35) | IBS patients | 20 | Double-blind, randomized, controlled study | Low-FODMAP diet improved IBS symptoms and decreased serum IL-6, IL-8, fecal Actinobacteria, Bifidobacterium, and Faecalibacterium, SCFAs, and n-butyric acid |
| O'Keeffe et al., 2018 (36) | IBS patients | 103 | Long-term prospective study | Low-FODMAP education can be nutritionally adequate for 18 mo |
| Klem et al., 2017 (37) | IBS patients | 45 studies | Meta-analysis from 1994 | IBS onset is due to bacterial, viral, or parasitic infections in the microbiota |
| Kerckhoffs et al., 2009 (38) | IBS patients | 41 | FISH and PCR analysis of fecal and duodenal brush samples for microbiota composition | Decreased Bifidobacteria levels in IBS |
| Rajilić-Stojanović et al., 2011 (39) | IBS patients | 62 | Phylogenic microarray and PCR analysis of microbiota composition | Decreased Bifidobacterium, Faecalibacterium, and Bacteroidetes and increased ratio of Firmicutes to Bacteroidetes |
| Parkes et al., 2012 (40) | IBS patients | 47 | Hybridization of rectal biopsies for microbial quantification | Increased Bacteroides and Clostridia and reduced Bifidobacteria in mucosa-microbiota in IBS |
| Tana et al., 2010 (41) | IBS patients | 26 | Liquid chromatography and PCR analysis on fecal samples and abdominal X-ray films for gas quantification | Increased levels of Veillonella and Lactobacillus, acetic acid, propionic acid, and total organic acids |
| Rigsbee et al., 2012 (42) | IBS-D children | 20 | Phylogenetic microbiota array, FISH, PCR analysis on fecal samples | Different microbiota taxonomy in IBS with increased Clostridia levels |
| Labus et al., 2017 (43) | IBS patients | 29 | 16S rRNA sequencing on fecal samples and structural brain images | Microbial composition correlated with structural measures of brain regions |
| Vandeputte et al., 2016 (44) | IBS patients | 9 | 16S rRNA sequencing on fecal samples and lactulose breath testing | Increased levels of M. smithii methanogen in IBS-C and correlated with breath methane |
| Tap et al., 2017 (45) | IBS patients | 110 | Assessment of 16S rRNA sequencing on fecal samples and mucosal samples for microbiota, exhaled H2 and CH4, psychological and gastrointestinal symptoms, and fecal methanogens | IBS symptom severity associated with decreased microbial richness, exhaled CH4, methanogens, and enterotypes with Clostridiales or Prevotella species |
| Silk et al., 2009 (46) | IBS patients | 44 | Randomized, parallel, crossover, controlled clinical trial | Prebiotics increased fecal bifidobacteria |
| Hunter et al., 1999 (47) | IBS patients | 21 | Double-blind crossover study | Oligofructose prebiotics did not improve IBS symptoms |
| Olesen et al., 2000 (48) | IBS patients | 98 | Multicenter, prospective, randomized, double-blind, placebo-controlled parallel study | Oligofructose prebiotics did not affect IBS symptoms |
| Paineau et al., 2008 (49) | IBS patients | 105 | Comparative, randomized, double-blind study | Oligofructose prebiotics improved significantly the IBS symptoms |
| Didari et al., 2015 (50) | IBS patients | 24 studies | Meta-analysis on the efficacy of probiotics in IBS | Probiotics improve IBS symptoms |
| Min et al., 2012 (51) | IBS patients | 130 | Randomized controlled study | Yogurt with acacia fiber and B. lactis has significant therapeutic effects in IBS |
| Tsuchiya et al., 2004 (52) | IBS patients | 68 | Randomized, blind control study | Administration of symbiotic novel symbiotic Microflorana F (SCM-III) increased Lactobacilla, Eubacteria, and Bifidobacteria and improved IBS symptoms |
| Chey et al., 2015 (53) | IBS patients | 1074 | Phase 3, randomized, double-blind, controlled study | Repeated rifaximin treatment was efficacious in IBS-D patients with relapsing symptoms |
| Dieterich et al., 2019 (22) | NCGS patients | 19 | Clinical trial | Low-FODMAP diet improved clinical and psychological NCGS symptoms. NCGS patients present a microbiota dysbalance |
| Zanini et al., 2015 (54) | NCGS patients | 35 | Randomized, double-blind, clinical study | Symptom recurrence occurred in one-third of the patients after gluten challenge |
| Dale et al., 2018 (55) | NCGS patients | 20 | A randomized, double-blind controlled study | NCGS symptoms did not re-appear after gluten challenge in most patients |
| Skodje et al., 2018 (56) | NCGS patients | 59 | Randomized, double-blind crossover study | Fructans rather than gluten-induced NCGS symptoms in 24 patients |
| Molina-Infante et al., 2017 (57) | NCGS patients | 231 | Data analysis from 10 double-blind, controlled study | Heterogeneity and methodology flaws among studies of gluten challenge; the role of gluten in NCGS is questionable |
| Tovoli et al., 2017 (58) | NCGS patients | 44 | Questionnaire-based study | About 70% of patients continued to have NCGS symptoms after 1 y of a GFD |
| Garcia-Mazcorro et al., 2018 (59) | NCGS patients | 12 | 16S rRNA sequencing on fecal and duodenal samples | Significant changes in duodenal Pseudomonas levels after 4 wk of a GFD |
| Animal studies | ||||
| Verdu et al., 2007 (27) | CD genetically predisposed subjects | 15 | Gliadin-sensitized HLA-DQ8 mouse model | Gluten induced IBS-D like symptoms (increased acetylcholine production and colonic motility) that improved upon gluten removal from the diet |
| Junker et al., 2012 (60) | TLR-4–deficient subjects | 12 | Mouse model challenged with gliadin and ATIs | Mice with defective TLR-4 or TLR-4 pathways are protected from the intestinal and immune responses when they are challenged with ATIs |
| Zevallos et al., 2017 (61) | TLR-4–responsive mice | 38 | TLR-4–sensitized mouse and human cell line model | Gluten-containing cereals have the highest concentrations of ATIs that activate TLR-4 |
| Bellinghausen et al., 2018 (62) | Humanized mice | 10 | Mice were engrafted with the PBMCs from allergic donors and were challenged | ATIs are strong allergen activators |
1ATI, α-amylase/trypsin inhibitor; CD, celiac disease; FISH, fluorescent in situ hybridization; FODMAPs, fermentable oligo-, di-, monosaccharide, and polyols; GFD, gluten-free diet; IBS, irritable bowel syndrome; IBS-C, IBS with predominant constipation; IBS-D, IBS with predominant diarrhea; NCGS, non-celiac gluten sensitivity; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain reaction; rRNA, ribosomal RNA; TLR, Toll-like receptor.