# Project 1 Title: Gut microbial metabolites as drivers of ethanol-induced liver injury

> **NIH NIH P50** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $274,230

## Abstract

ABSTRACT
Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible
environmental factor contributing to a number of human diseases. However, mechanisms by which gut
microbial-derived factors signal to the host to promote these diseases are largely unknown. We have recently
discovered a metaorganismal 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). Here we show that pharmacologic inhibition of the gut microbial choline TMA
lyase enzyme CutC/D protects mice against alcoholic liver disease. Unexpectedly, this protection is associated
with reorganization of the host circadian clock. Our specific aims are: Aim 1. Testing the hypothesis that
alcohol-induced circadian disruption depends on gut microbial TMA production, and that TMA lyase inhibitors
represent a gut microbe-targeted chronotherapy; and Aim 2. Testing the hypothesis that the microbe-derived
metabolite TMA activates the host G protein-coupled receptor trace amine-associated receptor 5 (TAAR5) to
Promote Ethanol-Driven Sarcopenia. These studies will be significant because they have the potential to
uncover the first ever described diet-microbe-derived zeitgeber. Successful completion of this project will be
transformative by providing proof of concept that a non- antibiotic drug targeting a specific microbial enzyme
can serve as a therapeutic strategy for alcohol-induced tissue injury.

## Key facts

- **NIH application ID:** 10056022
- **Project number:** 2P50AA024333-06
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jonathan Mark Brown
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $274,230
- **Award type:** 2
- **Project period:** 2016-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056022

## Citation

> US National Institutes of Health, RePORTER application 10056022, Project 1 Title: Gut microbial metabolites as drivers of ethanol-induced liver injury (2P50AA024333-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10056022. Licensed CC0.

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