# Project 1: Discovery of gut microbiota dependent pathways contributing to cardiovascular disease in type 2 diabetes

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $523,250

## Abstract

Abstract
 The role of gut microbiota in human health and disease processes is increasingly recognized. Moreover,
the gut microbiome is now recognized as a large endocrine organ that can generate biologically active
metabolites, which upon absorption into the host, often have dedicated receptors, and impact physiological
processes, and disease susceptibility. In this Project, we examine the role of specific gut microbiota pathways
in cardiovascular disease (CVD) pathogenesis. We have employed untargeted metabolomics as a discovery
platform, coupled with cellular and animal model studies, to identify additional/new potential gut microbiota-
dependent pathways enhanced in type 2 diabetes mellitus that are both associated with, and potentially a
contributor to CVD. Subjects with type 2 diabetes are at a disproportionately increased risk for development of
CVD, and yet, the overall level of glycemic control is not necessarily related to CVD risks. There thus are
metabolic pathways beyond the glucocentric view of diabetes that contribute to CVD in this at risk population.
Large-scale clinical investigations are used to focus research attention on candidate metabolites whose
circulating levels are reproducibly associated with incident development of adverse cardiovascular events like
heart attack, stroke and death in this at risk population. After validating the associations (and often typically
observing the candidate metabolite predicts risks in diabetic and non-diabetic subject alike), we move forward
with mechanistic studies aimed at defining whether observed associations are linked to CVD and metabolic
disease relevant phenotypes, through cellular and animal model studies. Preliminary cell, animal model and
microbial transplantation related studies using genetically engineered human commensals (gain and loss of
function mutants) are used to interrogate the role of specific microbiota derived metabolites, and the microbial
enzyme(s) responsible for their generation, in eliciting relevant phenotypes in the host like enhanced
thrombosis potential, or susceptibility to atherosclerosis. Our proposed studies promise to identify new
mechanisms through which gut microbiota may contribute to CVD. They also will help improve identification of
those at risk for CVD and its adverse events who otherwise might not be identified. They also will provide
enabling discoveries that will foster potential development of novel treatments for CVD.

## Key facts

- **NIH application ID:** 10004734
- **Project number:** 5P01HL147823-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Stanley L Hazen
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $523,250
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004734

## Citation

> US National Institutes of Health, RePORTER application 10004734, Project 1: Discovery of gut microbiota dependent pathways contributing to cardiovascular disease in type 2 diabetes (5P01HL147823-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10004734. Licensed CC0.

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