Common forms of cardiovascular diseases are exceptionally complex, where several genetic and lifestyle/environmental factors are involved. The discovery of different risk factors will be crucial for prevention of these high mortality diseases. Metabolomic studies have broaden our understanding of cardiovascular phenotypes and have created possibility to find new biomarkers for disease risk prediction. Recently a targeted metabolomic study indentified a novel mechanism through which gut-flora and hepatic-mediated metabolism of dietary choline contributes to the development of cardiovascular disease. This study demonstrated that higher plasma levels of choline and two of its metabolites, trimethylamine N-oxide (TMAO) and betaine, are associated with atherosclerosis in humans and mice. The current proposal aims to study the role of choline metabolites in cardiovascular and metabolic traits and to examine microbial role in this process. The possible role of choline-derived metabolites in perturbation of cardiometabolic phenotypes will be determined using well-characterized metabolic and cardiovascular-targeted samples. The second part of the project aims to study the role of gut flora in choline metabolic pathway. We will use different approaches in order to identify specific group(s) of intestinal bacteria responsible for the formation of TMA(O) from dietary choline. In summary, the results of the study will provide important insights into the mechanism by which novel metabolite-gut flora interplay contributes to the regulation of cardiovascular system.