Gastrointestinal and Extraintestinal Symptoms Among Subjects With Celiac Disease Undergoing a Dose-Specified Gluten Challenge: A Systematic Review and Meta-Analysis.

Abstract

Celiac disease (CeD) is an immune-mediated enteropathy driven by gluten ingestion. Gluten challenges (GC) are commonly used to evaluate novel therapeutics and CeD mechanisms, but their associated symptom burden has not been well characterized. We aim to evaluate the proportion of subjects with gastrointestinal and extraintestinal symptoms during an experimental GC. Pubmed, Embase, CINAHL, and Cochrane Central were searched through December 2024 for studies reporting symptoms in adult patients with CeD in remission on a gluten-free diet undergoing a GC. Studies of GC for clinical diagnosis were excluded. Eligible studies included randomized (RCT) and non-randomized trials (non-RCT) that reported symptoms. Data were pooled using random-effects meta-analysis, and heterogeneity was assessed. We identified 48 eligible studies with a total of 1,409 participants of which 35 were included in the meta-analysis (6 RCTs, 29 non-RCTs). The most common symptoms were abdominal pain (RCT 0.56, 95% confidence interval [CI] 0.45-0.65; non-RCT 0.40, 95% CI 0.32-0.49), bloating (RCT 0.55, 95% CI 0.38 to 0.71; non-RCT 0.37, 95% CI 0.28-0.47), and nausea (0.41, 95% CI 0.24-0.59; non-RCT 0.34, 95% CI 0.24-0.46). There was significant heterogeneity across studies, with variable GC doses and durations, no systematic reporting of all symptom categories, and missing individual data for some studies. Bloating, fatigue, flatulence, and nausea were significantly more reported in studies administering ≥6 g gluten/d. GC commonly induces gastrointestinal symptoms in patients with CeD, with abdominal pain, bloating, and nausea being most frequent. Standardized challenge protocols are needed to advance therapeutic research while minimizing symptom burden.