Genetic evidence elucidates the effect of gut microbiota on diverticular disease: A bidirectional Mendelian randomization study

Background: Observational studies have implicated the association between gut microbiota and diverticular disease. However, the causality remains unclear. We aim to evaluate the causal association of gut microbiota alterations and circulating metabolite level with the risk of diverticular disease. Methods: A bidirectional two-sample Mendelian randomization (MR) was conducted by using GWAS summary-level data of gut microbiota, circulating metabolites, and diverticular disease. The inverse-variance weighted (IVW) MR approach was applied as the primary analysis. The MR-Egger, weighted-median, and MR-PRESSO methods were supplemented as sensitivity analyses if applicable. The false discovery rate was adopted for multiple testing corrections. Results: In the forward MR analysis, a genetically determined higher abundance of Ruminococcus torques group was found to be causally associated with decreased risk of diverticular disease. With each one-unit increase in log-transformed relative abundance values of the Ruminococcus torques group, there was a significant decrease in the odds ratio (OR) and 95% confidence interval (CI) for diverticular disease risk, with an OR of 0.68 (95% CI: 0.56-0.82, P=4.72ⅹ10-5). A genetically determined increased abundance of Oxalobacter (OR=0.88, 95%CI: 0.80-0.97, P=0.011) was suggestively associated with a lower risk of diverticular disease. We did not find any significant association between circulating metabolites level and diverticular disease risk. Additionally, no association between genetic liability to diverticular disease and the relative abundance of microbiota was observed in reverse MR analysis. Conclusions: This study provides evidence for a causal association between genetically determined higher abundance of the Ruminococcus torques group and decreased risk of diverticular disease. We also suggest a potential protective role of Oxalobacter on diverticular disease.