# Aromatic Amino Acids, Microbiome-Generated Metabolites, and Incident Subclinical and Clinical CVD and Mortality

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2024 · $1,378,637

## Abstract

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.

## Key facts

- **NIH application ID:** 10802950
- **Project number:** 2R01HL135920-05
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Stanley L Hazen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,378,637
- **Award type:** 2
- **Project period:** 2017-07-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802950

## Citation

> US National Institutes of Health, RePORTER application 10802950, Aromatic Amino Acids, Microbiome-Generated Metabolites, and Incident Subclinical and Clinical CVD and Mortality (2R01HL135920-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10802950. Licensed CC0.

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