# The Obese Microbiota as a Novel Regulator of Vascular Function: A Translational Approach

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2020 · $336,540

## Abstract

PROJECT SUMMARY
Vascular dysfunction represents a critical link between obesity and cardiovascular disease (CVD). The two most
clinically relevant manifestations of vascular dysfunction are endothelial dysfunction and arterial stiffness.
Despite focused efforts, the underlying cause of these vascular impairments in obese individuals is unclear.
The gut microbiota has emerged as an important regulator of human physiology. Deleterious changes to the
number or composition of the microbiota, broadly termed dysbiosis, have been implicated in the development of
CVD, and more recently, to endothelial dysfunction. However, four fundamental questions regarding the link
between dysbiosis and vascular dysfunction remain unstudied: 1) what specific bacterial alterations initiate the
development of vascular dysfunction? 2) what circulating factor(s), downstream of dysbiosis, mediates intestinal-
vascular crosstalk and hastens the development of vascular dysfunction? 3) in addition to endothelial
dysfunction, does dysbiosis also mediate arterial stiffness? 4) are the existing animal data relevant to human
vascular dysfunction?
The overall goal of the current proposal is to address these four questions and comprehensively examine the
link between the gut microbiota and vascular dysfunction. Building upon our recent data, we hypothesize a
sequence of events whereby diet-induced obesity causes gut dysbiosis, characterized by reductions in
Bifidobacterium, that lead to compromised intestinal barrier function and elevations in circulating
lipopolysaccharide (LPS). Once in circulation, LPS activates toll-like receptor 4 (TLR4) on the vasculature, and
elicits an inflammatory signaling cascade that ultimately lead to arterial stiffness and endothelial dysfunction.
The translational studies proposed herein will test this hypothesis using three innovative, complementary
approaches: 1) microbiota transplants 2) selective microbiota enrichment; and 3) colonization of germ free mice
with human microbiota samples. In aim 1, microbiota transplants will be performed in control mice (C57); mice
with impaired LPS signaling (TLR4-/-); and mice with enhanced LPS signaling (acyloxyacyl hydrolase knockout
mice, AOAH-/-) fed either a standard (SD) or western (WD) diet. In aim 2, specific Bifidobacterium populations
that are reduced by WD and correlate with vascular dysfunction will be isolated from the microbiota of healthy
animals, cultured, then administered to WD-fed mice to examine their vascular protective effects. In aim 3,
relations between the gut microbiota and vascular function will be determined in lean and obese individuals; and
microbiota samples from these individuals will be used to colonize the intestines of germ free mice. Collectively,
these studies will help identify a novel cause of, and therapeutic target for, obesity-related vascular dysfunction
with broad and immediate clinical potential.

## Key facts

- **NIH application ID:** 9894846
- **Project number:** 5R01HL144611-02
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Christopher L Gentile
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,540
- **Award type:** 5
- **Project period:** 2019-03-20 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894846

## Citation

> US National Institutes of Health, RePORTER application 9894846, The Obese Microbiota as a Novel Regulator of Vascular Function: A Translational Approach (5R01HL144611-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9894846. Licensed CC0.

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