Role of metabolites in mediating the effect of gut microbiota on Crohn disease: A two-step Mendelian randomization (MR) study

This study aims to investigate the causal relationship between gut microbiota and Crohn disease (CD) and identify and quantify the role of metabolites as potential mediators. Using summary-level data from a genome-wide association study (GWAS), a two-sample Mendelian randomization (MR) analysis of genetically predicted gut microbiota and CD was performed. Furthermore, we used two-step MR to quantify the proportion of the effect of metabolites-mediated gut microbiota on CD. We identified 15 metabolites (carnitine levels, isovalerate (i5:0) levels, hydroxyoctanoate levels, 6-hydroxyindole sulfate levels, heptenedioate, 4-methylhexanoylglutamine levels, uridine levels, X-13866 levels, X-17354 levels, X-18345 levels, X-22834 levels, X-25519 levels, serine to pyruvate ratio, URIDINE to 2’-deoxyuridine ratio, and histidine to glutamine ratio) with mediating effects in the impact of genus Ruminococcaceae UCG013 on CD. Our study identified a causal relationship between gut microbiota and CD, with a small proportion of the effect mediated by fifteen metabolites.