Abstract 589: Host-Genotype Shaped Microbiome Modulates Development of Atherosclerosis

Abstract

Genetic variation drives phenotypic diversity and determines predisposition to cardiovascular disease. Previous work revealed a large degree of variation on atherosclerosis susceptibility among 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). Additionally, each HMDP inbred strain shows a distinct microbiota composition. Here, we assessed the contributions of the gut microbiome to the development of atherosclerosis. Cecal samples from four HMDP strains showing disparate atherosclerosis phenotypes were transplanted into groups of ApoE -/- germ-free mice. Transplanted ApoE -/- mice were maintained on a high-plant polysaccharide diet containing 0.2% cholesterol for 8 weeks and analyzed for atherosclerotic lesions, microbiome, and metabolome. We found that mice colonized with cecal microbes from two HMDP donors prone to atherosclerosis development exhibited larger lesions compared to recipient mice colonized with samples from donors that show little signs of atherosclerosis. Metabolomic analyses of plasma from transplanted mice and metagenomic analyses of cecal contents from the transplanted and 24 HMDP donor mice identified microbial functions that are associated with the severity of disease. Altogether, our work provides novel insights into how microbes contribute to the development of cardiovascular disease and suggest that host genotype may select for microbial communities that modulate progression of atherosclerosis.