Gluten-free Diet Reduces the Risk of Irritable Bowel Syndrome: A Mendelian Randomization Analysis

Background: Whether a gluten-free diet (GFD) is a cause of irritable bowel syndrome (IBS) remains controversial. We aim at exploring the causal relationship between gluten intake and IBS within Mendelian randomization (MR) design. Methods: We conducted a two-sample MR and selected single-nucleotide polymorphisms (SNPs) associated with GFD as instrumental variables (IVs). SNPs and genetic associations with GFD and IBS were obtained from the latest genome-wide association studies (GWAS) in Europeans (GFD: cases: 1,376; controls: 63,573; IBS: cases:1,121; controls: 360,073). We performed inverse variance weighting (IVW) as the primary method with several sensitivity analyses like MR-Egger and MR-PRESSO for quality control. The above analyses were re-run using another large dataset of IBS, as well as changing the p-value threshold when screening IVs, to verify the stability of the results. Results: The final estimate indicated significant causal association [per one copy of effect allele predicted log odds ratio (OR) change in GFD intake: OR = 0.97, 95% confidence interval (CI) 0.96 to 0.99, p < 0.01] without heterogeneity statistically (Q = 2.48, p = 0.78) nor horizontal pleiotropy biasing the causality (p = 0.92). Consistent results were found in validation analyses. Results of MR Steiger directionality test indicated the accuracy of our estimate of the causal direction (Steiger p < 0.001). Conclusion: GFD might be a protective factor of IBS. Therefore, we suggest taking a diet of lower gluten intake into account in IBS prevention and clinical practice.