# Gut-microbial metabolism of aromatic amino acids and cardiovascular disease

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $546,944

## Abstract

A novel gut microbial pathway has been clinically and mechanistically linked to cardiovascular
disease (CVD) via generation of phenylacetylglutamine (PAGln), a compound we show to
modulate adrenergic receptor signaling. PAGln is the product of a meta-organismal pathway
that begins with gut microbial catabolism of dietary phenylalanine into phenylacetic acid
followed by conjugation of glutamine by the host liver enzymes. PAGln is just one of a dozen
possible microbial metabolites derived from aromatic amino acids. Using untargeted and
targeted metabolomics, we have identified multiple gut-microbe metabolites derived from
phenylalanine and tyrosine in clinical study samples that are associated (or not) with incident
CVD risk. The overall goals of this application are to define gut microbial pathways of aromatic
amino acid metabolism that impact host CVD. This is a critical initial step for improved
understanding of gut microbiota contributions to CVD, and in the development of therapeutic
strategies to leverage this information. In Aim 1 we will identify specific gut microbial metabolites
derived from aromatic amino acids that can impact CVD phenotypes. In Aim 2, by combining
microbial transplantation studies using genetically engineered human commensals (gain and
loss of function mutants), we will test causal contribution of defined microbial enzymes to
specific candidate metabolites linked to CVD.

## Key facts

- **NIH application ID:** 10748339
- **Project number:** 5R01HL160747-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Ina Nemet
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $546,944
- **Award type:** 5
- **Project period:** 2021-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10748339

## Citation

> US National Institutes of Health, RePORTER application 10748339, Gut-microbial metabolism of aromatic amino acids and cardiovascular disease (5R01HL160747-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10748339. Licensed CC0.

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