Dissecting the Gut Microbiota-MetaboliteCoronary Atherosclerosis Axis: Evidence from Two-Sample Mendelian...

Coronary Atherosclerosis (CAS) is a complex disease influenced by host genes, the gut microbiota, and circulating metabolites. Causal relationships and mediating effects among these factors have not yet been clarified.

A two-sample Mendelian Randomization (MR) study was conducted using genomewide association study data from FinnGen, OpenGWAS, and Canadian Longitudinal Study on Aging. A total of 473 genetic instruments for gut microbial traits and 1,400 for plasma metabolites were selected. We applied bidirectional Mendelian randomization, sensitivity tests, and two-step mediation analysis to assess causal effects and identify metabolic mediators.

18 gut microbiota taxa and 36 metabolites that are associated with coronary atherosclerosis. Protective taxa included Genus Roseibacillus and Genus Negativibacillus; Genus Geobacter C and Species Lawsonibacter sp000492175 were identified as risk. Inversely, bile acid derivatives, such as deoxycholic acid 12-sulfate, were negatively correlated, whereas guanidinoacetate was positively correlated. Mediation analysis found glutamine degradant, sphingomyelin, and 3β-hydroxy-5-cholestenoate as partially mediated by the microbial effect, with mediation proportions ranging from -30.1% to 15.8%.

These findings provide genetic evidence for the involvement of the gut microbiota in the development of coronary atherosclerosis, which may occur through metabolic pathways. Beneficial microbial taxa may be preferentially sustained by amino acid metabolism and anti-inflammatory mediators, whereas pathogenic taxa tend to proliferate under conditions characterized by lipid and sterol metabolic dysregulation.

This study emphasizes the potential central axis of gut microbiota-plasma metabolites-CAS and identifies microbial and plasma metabolite candidates that may serve as targets for early prevention and intervention of CAS. These findings provide new insights into the molecular mechanisms underlying the interactions between gut microbiota and plasma metabolites in the development and progression of C.