# Gut Microbiota and Cardiometabolic Diseases

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $2,423,889

## Abstract

Gut Microbiota and Cardiometabolic Diseases. Abstract:
 The overarching mission of our Program is to generate critical scientific discoveries in the field of gut
microbiome and cardiometabolic diseases that lead to potential improvements in human health, wellbeing, and
patient care. Substantial evidence has accrued demonstrating a critical role for gut microbiota in both human
health and disease. Our Program will advance the concept of metaorganismal endocrinology – specifically –
that gut microbes organize to form a key endocrine organ that converts nutritional cues from the environment
into hormone-like signals that impact cardiovascular and metabolic phenotypes in the human host. Our
Program is comprised of 3 Projects and 4 Cores. Project 1, seeks to discover and functionally interrogate
novel gut microbial pathways linked to the development of CVD and its adverse events, with initial focus on the
metaorganismal PhenylAcetyGlutamine (PAGln) pathway. Preliminary studies show PAGln is gut microbiota
generated metabolite whose levels are strikingly linked to CVD that through numerous preliminary cellular,
microbiota and animal model studies, contributes to CVD pathogenesis. Analytical, biochemical and disease
model studies in mice and humans explore the functional impact of PAGln on in vivo thrombosis and
atherosclerosis. Project 2 is thematically linked to Projects 1 and 3, and tests the hypothesis that the gut
microbial co-metabolites TMA and TMAO are unique hormone-like drivers of high fat diet induced obesity and
atherosclerosis. Through use of tools generated with Project 1 and 3, the role of microbial choline TMA lyase
activity in enhancing susceptibility for high fat diet-driven obesity via a host TMA - Taar5 receptor signaling axis
will be tested. The hypothesis that FXR-driven hepatobiliary secretion of TMAO initiates a newly discovered
enterohepatic TMAO signaling axis that regulates gut microbiome community structure and host bile acid/sterol
metabolism will also be explored. Project 3 is similarly interrelated to Projects 1 and 2, and leverages both
human untargeted metabolomics data collaboratively discovered with Project 1, animal cardiometabolic
disease phenotyping expertise of Project 2 investigators, and metabolic pathway discovery and microbiome
gene editing expertise of Project 3 investigators to enabled studies of causality and mechanism for structurally
specific members of two key classes of gut microbe-derived molecules, aryl sulfates and secondary bile acids.
The role of specific microbial genes responsible for forming candidate CVD- and diabetes-associated
metabolites will be examined for their involvement in enhanced thrombosis, atherosclerosis, obesity and other
metabolic phenotypes. Four cores (Analytical/Clinical/Bioinformatics; Analytical and Chemical Synthesis;
Microbial Engineering and Transplantation; and Cardiometabolic Disease Phenotyping) provide multi-project
support, significantly strengthening the research Pr...

## Key facts

- **NIH application ID:** 10447064
- **Project number:** 5P01HL147823-04
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Stanley L Hazen
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,423,889
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447064

## Citation

> US National Institutes of Health, RePORTER application 10447064, Gut Microbiota and Cardiometabolic Diseases (5P01HL147823-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10447064. Licensed CC0.

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