Prevalence and predictors of nonceliac wheat sensitivity in refractory irritable bowel syndrome and functional dyspepsia: results from a randomized double-blind placebo-controlled study

Background and aims Nonceliac wheat sensitivity (NCWS) is characterized by gastrointestinal and extraintestinal symptoms triggered by gluten ingestion. Its symptomatology overlaps substantially with irritable bowel syndrome (IBS) and functional dyspepsia (FD), leading to diagnostic challenges. Data on the prevalence and predictors of NCWS among patients with IBS or FD, especially those with refractory symptoms, are limited. We aimed to determine the prevalence, clinical predictors, and impact of a gluten-free diet (GFD) in this population using the Salerno Experts’ Criteria. Methods In this prospective, multicenter trial, adults (18–65 years) with Rome IV-defined IBS or FD, refractory to standard therapy, were enrolled. Participants underwent a 6-week GFD; gluten responders subsequently underwent a double-blind placebo-controlled gluten challenge (DBPCGC) with crossover. Symptom trajectories, health-related quality of life (HRQOL), anxiety, and depression were assessed. Multivariable logistic regression identified predictors of NCWS. Trial registration number- CTRI/2021/10/037323. Results Of 252 screened patients, 177 were enrolled for a 6-week GFD (step I), and 154 patients completed this phase (mean age 41.9 ± 14.2 years, 53.2% males). Eighty-two (52.3%) patients responded to GFD, of whom 77 entered step II (DBPCGC). Thirty-one (20.1%) patients had significant symptom worsening on blinded gluten ingestion, suggesting the presence of NCWS. Female sex, FD-IBS overlap, headache, fatigue, and anxiety independently predicted NCWS. GFD was associated with significant HRQOL improvement. Conclusion Approximately one-fifth of the patients with refractory IBS/FD fulfill the NCWS criteria. Therefore, screening for NCWS in patients with refractory IBS or FD is extremely important to limit unnecessary pharmacotherapy and enhance patient outcomes.