UC Davis

Trimethylamine n-oxide (TMAO) is a plasma metabolite derived from the meta-organismal pathway involving diet and the gut microbiome and is associated with adverse cardiometabolic phenotypes. Despite robust evidence demonstrating TMAO's clinical significance in populations with cardiometabolic disease, characterizations of plasma TMAO concentrations in healthy adults are few. Further, despite understanding that TMAO generation is due to diet, the gut microbiome, and enzymatic hepatic oxidation, the interplay of these factors by sex, age, and genetics have not been thoroughly studied. Characterizing these relationships will refine our understanding of the factors that influence TMAO concentration and therefore cardiometabolic diseases. Thus, to address these gaps, we first utilized a cohort of healthy adults equally represented by sex, age, and BMI to clarify the relationships among diet, gut microbiome composition, CVD biomarkers, and fasting plasma TMAO in the absence of disease. Next, we used multiple systems-genetics mouse models to perform genome-wide association studies to identify loci regulating fasting plasma TMAO concentrations in different diet environments. Finally, we returned to the healthy human cohort to perform a proof-of-concept precision nutrition study evaluating the postprandial dynamics of plasma TMAO concentration following the consumption of a high-fat mixed macronutrient tolerance test. In all, these studies illuminate the regulation of plasma TMAO in healthy states, which can be leveraged to design preventative and reactive strategies to reduce the metabolite's pathogenicity.