Aromatic Amino Acids, Microbiome-Generated Metabolites, and Incident Subclinical and Clinical CVD and Mortality - The host diet and gut microbiome combine to produce a range of microbiome-generated plasma metabolites that influence human health. Characterizing these metabolites and their relationships with major disease endpoints is critical to elucidate new pathways of risk and corresponding novel preventive and pharmacologic treatments. Phenylalanine, tyrosine, and tryptophan are the three aromatic amino acids (AAA), centrally involved in protein synthesis and metabolized to a range of bioactive compounds. Gut microbial enzymes ferment AAA into a plethora of small molecules via deamination, oxidation, and/or reduction. The gut microbe-derived metabolites can be further metabolized by host liver enzymes before they reach systemic circulation. Several AAA-derived microbial metabolites have been previously identified as of potential interest in human health, such as indole-3-propionic acid (I3PA), derived from microbial metabolism of tryptophan and implicated in diet induced obesity, advanced atherosclerosis, gut permeability, and brain health. However, the health effects of this and other AAA-derived microbial metabolites remain understudied. This project resubmission will leverage the power of serial biomarkers measures to investigate the interrelationships of novel microbiome-generated AAA metabolites with initiation, extent, and clinical onset of subclinical CVD, clinical CHD, and total mortality. Primary aims include: (1) To investigate the independent relationships of serial measures of plasma aromatic amino acid (AAA)-derived microbial metabolites with longitudinal onset and progression of subclinical CVD. (2) To investigate the independent relationships of serial measures of plasma AAA-derived microbial metabolites with incident CVD events. (3) To investigate the independent relationships of serial measures of plasma AAA-derived microbial metabolites with total mortality. Secondary Aims include focuses to investigate (a) the independent dietary, lifestyle, and demographic predictors of plasma AAA-derived microbial metabolites and change in these metabolites over time in two diverse community-based populations; and (b) potential effect modification of metabolite-outcome associations by age, sex, race/ethnicity, socioeconomic status, background diet, lipid-lowering medication use, renal function, and prevalent CVD. This project will provide novel, impactful evidence on how AAA-derived microbial metabolites, measured serially over time, relate to subclinical CVD, clinical CVD, and mortality in the Multi-Ethnic Study of Atherosclerosis (MESA; 6,800 middle-aged white, Black, Hispanic, and Chinese adults) and the Cardiovascular Health Study (CHS; 5,148 older white and Black adults). In pilot work, we have evaluated the long-term reproducibility of these AAA analytes using serial blood samples collected at baseline (year 2) and 9 years later (year 11) in a random subset of 100 CHS participants.
