Investigating the causal links among gut microbiome features, inflammation-related proteins, and diverticular disease: Insights from a mediation Mendelian randomization study

The pathophysiological mechanisms underlying diverticular disease (DD) remain incompletely understood, and there is considerable debate regarding the roles of gut microbiome features and inflammation-related proteins in the development of the disease. In this study, we employed mediation Mendelian randomization (MR) analysis to investigate the causal relationships among these 3 factors. In this study, we conducted a MR analysis on the genome-wide association studies data of 412 gut microbiome features (207 microbial taxa and 205 pathways), 91 inflammation-related proteins, and DD. We employed the inverse-variance weighted (IVW) method as our primary screening approach, followed by a mediation MR analysis to explore potential causal relationships among these 3 aspects. Our findings were further reinforced by comprehensive heterogeneity analyses, horizontal pleiotropy testing, outlier detection, and "leave-one-out" sensitivity analysis. Through our screening process, we identified potential causal relationships between DD and 18 gut microbiome features, as well as 6 inflammation-related proteins. These include s_Oscillibacter_unclassified (IVW odds ratio (OR): 1.139; 95% confidence interval (CI): 1.044-1.241, P = .003), g_Bilophila (IVW OR: 1.107, 95% CI: 1.016-1.206, P = .020), T-cell surface glycoprotein CD5 levels (IVW OR: 1.065, 95% CI: 1.011-1.123, P = .019), and inosine 5'-phosphate biosynthesis I (IVW OR: 0.882, 95% CI: 0.800-0.973, P = .012), etc. In the mediation MR analysis, we found that the genetic predictors of g_Bilophila and inosine 5'-phosphate biosynthesis I could explain 23.956% and 24.630% of the variation in T-cell surface glycoprotein CD5 levels, respectively. This study detailed analysis of the links between gut microbiome features, inflammation-related proteins, and DD offers key insights into DD pathogenesis and prevention.