Background & Aims: Coeliac disease (CD) is the most common immune-mediated enteropathy, and a lifelong gluten-free diet (GFD) remains the only accepted treatment. However, adherence to a strict GFD is highly variable, and many patients report occasional gluten ingestion without evidence of disease activity. Whether a subset of patients can develop gluten tolerance remains controversial. We performed a systematic review and meta-analysis to estimate the prevalence of gluten tolerance among patients with CD and documented gluten exposure.
Methods: MEDLINE, Web of Science, Cochrane Library, and EMBASE were searched through March 2025 for studies assessing GFD adherence and follow-up duodenal histology. Gluten exposure was defined by self-reported dietary transgressions and/or positive gluten immunogenic peptide (GIP) testing. The primary outcome was the proportion of patients without villous atrophy (Marsh 0–2) despite documented gluten exposure. Pooled proportions were calculated using a random-effects model.
Results: Seventeen studies comprising 735 patients with CD and documented gluten exposure were included. The pooled prevalence of patients meeting criteria for gluten tolerance was 38% (95% CI, 26%–50%). Histological reassessment was performed at least one year after diagnosis, with follow-up ranging from 12 months to 20 years. Subgroup analyses according to age and method of gluten exposure assessment showed no significant differences.
Conclusions: More than one-third of patients with documented gluten exposure did not exhibit villous atrophy at follow-up, supporting the existence of a gluten-tolerant phenotype in a subgroup of patients with CD. These findings suggest heterogeneity in mucosal responsiveness to gluten and warrant prospective studies to define the mechanisms, predictors, and clinical implications of gluten tolerance.