Impact of Acute and Sub-Acute Gluten Exposure on Gastrointestinal Symptoms and Psychological Responses in Non-Coeliac Gluten Sensitivity: A Randomised Crossover Study

Abstract

Background/Aims: Non-coeliac gluten sensitivity (NCGS) is a controversial entity, characterised by symptom improvement with gluten exclusion in the absence of coeliac disease. We primarily investigated the effects of acute and sub-acute gluten on psychological and mood profiles, with secondary outcomes examining gastrointestinal symptoms and biological markers in healthy controls (HC) and individuals with NCGS. Methods: A randomised, single-blind, crossover study used acute (16 g gluten or whey in yoghurt) and sub-acute (gluten-containing (16 g) or gluten-free muffins per day for 5 days) challenges. (Extra)intestinal symptoms, intestinal permeability, high-sensitive C-reactive protein and cortisol awakening response were assessed. Responses over time were analysed using generalised linear mixed models. Results: Twenty HCs (15% men, mean age 30 years) and 16 individuals with NCGS (31% men, mean age 33 years) participated. No significant group-by-nutrient interactions were observed. Negative affect scores were higher and positive affect scores were lower in NCGS compared to HC (p = 0.01 and p = 0.04, respectively). Participants experienced higher tension scores after gluten compared with placebo (p = 0.01 acute; p = 0.05 sub-acute) regardless of the group. After acute administration, fatigue scores increased in NCGS (p = 0.03) compared with HC regardless of nutrient intake. After sub-acute administration, abdominal pain scores (p < 0.001) and bloating (p = 0.001) increased in NCGS compared with HC regardless of nutrient intake. No differences were found for biological markers. Conclusions: These findings reveal that NCGS is characterised by baseline differences in affect, and higher acute fatigue and subacute gastrointestinal symptoms that are not gluten-specific. This may be explained by nocebo effects, warranting research into novel mechanisms and re-evaluating the NCGS definition. Trial Registration: ClinicalTrials.gov no: NCT03798262; NCT03798249.