Tufts TMAO and AAA investigation

We and others have shown that 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 in human populations is critical to elucidate new pathways of risk and corresponding novel preventive and pharmacologic treatments. Our prior work on gut microbial trimethylamine N-oxide (TMAO) pathway has demonstrated high impact findings regarding the associations of TMAO metabolites with incident subclinical CVD, clinical cardiovascular events, mortality, and other health outcomes. The new grant focuses on another novel set of gut microbial metabolites, namely metabolites of aromatic amino acids (AAA). Gut microbial fermentation of AAAs, including phenylalanine, tryptophan, and tyrosine, is an understudied and, based on our preliminary studies, exciting new area of CVD research. Dietary sources of AAAs include beef, pork, chicken, fish, dairy, eggs, and less so, plant proteins. After ingestion, these AAAs can be metabolized by the gut microbiota into a plethora of small circulating molecules. A limited number of AAA-derived metabolites were previously identified as of potential interest in health, with some (e.g., phenylalanine-derived metabolites PAGln and PAGly, tyrosine-derived metabolite pCS, and tryptophan-derived metabolite IS) showing pro-CVD effects on platelet function and thrombosis in mechanistic studies and associated with risk of CVD events in a clinical cohort of patients referred for cardiac evaluation. These preliminary studies suggest potential high relevance of AAA-derived microbial metabolites for CVD. However, the health effects of these metabolites remain largely understudied, and confirmation of previous findings in large, prospective cohorts of the general population is in urgent need to complement mechanistic research, address limitations of clinical studies (e.g., reverse causation, confounding by socioeconomic factors and lifestyles, limited generalizability), and guide the design of future mechanistic and intervention studies.

This project will evaluate long-term relationships of plasma AAA-derived microbial metabolites, measured serially over time, with subclinical CVD, clinical CVD, and mortality in two well-established, community-based, prospective cohorts: the Multi-Ethnic Study of Atherosclerosis (MESA), comprising 6,800 middle-aged White, Black, Hispanic, and Chinese adults; and the Cardiovascular Health Study (CHS), comprising 5,148 older White and Black adults.

Aim One

To investigate the independent relationships of serial measures of plasma AAA-derived microbial metabolites with longitudinal onset and progression of subclinical CVD.

Aim Two

To investigate the independent relationships of serial measures of plasma AAA-derived microbial metabolites with incident CVD events.

Aim Three

To investigate the independent relationships of serial measures of plasma AAA-derived microbial metabolites with total mortality.