# Project 2: Gut microbial choline metabolites in cardiometabolic disease

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $523,250

## Abstract

Abstract:
Recent evidence has emerged that microbes resident in the human intestine represent a
key transmissible environmental factor contributing to obesity-associated
cardiometabolic disease. However, mechanisms by which gut microbial-derived factors
signal to the host to promote obesity are largely unknown. We have recently discovered
a meta-organismal pathway where nutrients present in high fat foods
(phosphatidylcholine, choline, and L-carnitine) can be metabolized by the gut microbial
enzymes to generate trimethylamine (TMA), which is then further metabolized by the
host enzyme flavin-containing monooxygenase 3 (FMO3) to produce trimethylamine-N-
oxide (TMAO). With Dr. Hazen's group (Project 1) we discovered that pharmacologic
inhibition of gut microbial choline TMA lyase activity (CutC/D) protects mice against in
vivo thrombosis and high fat diet-driven obesity. Interestingly, dietary provision of TMA,
but not TMAO, reverses the anti-obesity effects of TMA lyase inhibitors. Whereas, the
prothrombotic effects of this pathway are initiated by TMAO. We have also found that gut
microbial TMAO is abundantly secreted into bile, and the hepatobiliary secretion of
TMAO is transcriptionally controlled by the bile acid receptor farnesoid X receptor (FXR).
Collectively, our data support the following central hypothesis: The gut microbial co-
metabolites TMA and TMAO are unique hormone-like contributors to developing obesity,
thrombosis, and atherosclerosis. Our specific aims are: Aim 1. Testing the hypothesis
that gut microbial choline TMA lyase activity enhances susceptibility for high fat diet-
driven obesity via a host TMA - Taar5 receptor signaling axis. and Aim 2. We will test
the hypothesis that FXR-driven hepatobiliary secretion of TMAO initiates an
enterohepatic signaling axis that regulates gut microbiome community structure and host
bile acid and sterol metabolism. We anticipate our studies to reveal new molecular
mechanisms linking gut microbe-derived metabolites TMA and TMAO to cardiometabolic
diseases, which will ultimately be leveraged into to the first ever gut microbe-targeted
therapeutics targeting the metaorganismal TMAO pathway.
!

## Key facts

- **NIH application ID:** 10206255
- **Project number:** 5P01HL147823-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jonathan Mark Brown
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $523,250
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206255

## Citation

> US National Institutes of Health, RePORTER application 10206255, Project 2: Gut microbial choline metabolites in cardiometabolic disease (5P01HL147823-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10206255. Licensed CC0.

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