Gastrointestinal and Extraintestinal Symptoms among Celiac Disease Patients Undergoing a Dose Specified Gluten Challenge: a Systematic Review and Meta-Analysis

Objectives: 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. Methods: Pubmed, Embase, CINAHL, and Cochrane Central were searched through December 2024 for studies reporting symptoms in adult CeD patients 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 was pooled using random-effects meta-analysis, and heterogeneity was assessed. Results: We identified 48 eligible studies with a total of 1409 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% 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 to 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 ≥6g gluten/day. Conclusions: GC commonly induces gastrointestinal symptoms in CeD patients, with abdominal pain, bloating and nausea being most frequent. Standardized challenge protocols are needed to advance therapeutic research while minimizing symptom burden.