A novel gut microbial-dependent nutrient metabolite and atherosclerosis

Diet is a modifiable cardiovascular disease (CVD) risk factor and a core component of population-based approaches for CVD prevention, yet well-documented individual variability in diet effects may limit our ability to meet prevention goals solely through population-level interventions. Gut bacteria are intimately involved in nutrient absorption and metabolism, but until recently we lacked the tools to efficiently characterize the whole microbiome in large-scale studies. New work supports a mechanism for increased CVD risk through gut microbiome-dependent metabolism of dietary choline or L-carnitine to trimethylamine N-oxide (TMAO). These findings have received much attention as they may point to interventions through diet or targeted pro/prebiotics; they have also raised questions about the impact of TMAO precursors on CVD risk. However, the pathway from diet to CVD through microbial production of TMAO has not been studied in representative samples. We propose to study this pathway in a population-based prospective epidemiologic study: the biracial (black/white) Coronary Artery Risk Development in Young Adults (CARDIA) study. My goal is to build a research program dedicated to understanding individual variability in metabolic response to diet. To this end, I seek to integrate my expertise in epidemiology, diet, nutrition, and biostatistical analysis, with substantive training in gut microbiome, genetics, and metabolomics—key biologic sources of variability in dietary response—as well as bioinformatics and statistical approaches to high-dimensional data analysis. Under the expertise of my mentors and advisory team, the proposed career development plan will provide me with unique training to conduct CVD epidemiology at the intersection of several disciplines. My scientific aim is to determine the extent to which diet-related variability in CVD is explained by gut microbial functions on nutrient absorption and metabolism. My central hypothesis is that dietary risk factors for CVD are partially mediated by gut microbial community composition and gene expression. My long-term career goal is to build an externally-funded, collaborative research program that bridges epidemiology with new methodologic and technologic advances related to high-throughput technologies and translational science. My department chair, Dr. Elizabeth Mayer-Davis (Nutrition), supports this research plan and will insure protected time necessary for completion of this career development award. Drs. Mayer-Davis and Zeisel (primary mentor) will provide resources needed to complete grant aims. Career development and research activities will culminate in writing an R01 application related to studying pathways to individual-level variability in CVD response to diet through the gut microbiome in large-scale epidemiologic studies.