# Targeting the Meta-organismal Butyrate Pathway to Prevent Arterial Restenosis after Vascular Surgery

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $503,170

## Abstract

PROJECT SUMMARY/ABSTRACT
Cardiovascular disease is a leading cause of death globally. Despite advancements in surgical approaches for
cardiovascular disease, up to 50% of vascular procedures such as balloon angioplasty, stenting, and surgical
bypass fail due to restenosis from neointimal hyperplasia in the treated artery, a cell proliferative process
potentiated by inflammation. New therapies for prevention and treatment of neointimal hyperplasia are urgently
needed. However, there are major knowledge gaps in understanding the complex contribution of environmental
effectors in this process. Compelling preliminary work by the PI using germ-free (GF) and antibiotic-treated
mouse models has demonstrated a novel meta-organismal pathway for neointimal hyperplasia susceptibility. We
have shown that GF mice have attenuated neointimal hyperplasia compared to conventionally-raised mice,
which is restored by fecal transplantation. Furthermore, antibiotic treatment to deplete gut microbiota results in
reduced levels of butyrate, a short chain fatty acid produced exclusively by microbial fermentation of dietary fiber,
which is accompanied by exacerbated neointimal hyperplasia susceptibility; these effects are reversed by
butyrate supplementation. Arterial expression of the butyrate receptor, free fatty acid receptor 3 (FFAR3), is
increased by injury, and stimulation of FFAR3 modulates endothelial (EC), vascular smooth muscle cell (VSMC),
and inflammatory responses. Taken together, we now hypothesize that a meta-organismal microbe-host
interaction impacts neointimal hyperplasia following vascular surgery: prebiotic fiber augments gut microbial
production of butyrate; and butyrate, in turn, attenuates arterial injury-induced neointimal hyperplasia by direct
effects on EC and inflammation that are mediated by FFAR3. We will test this innovative hypothesis in a
comprehensive series of studies employing GF and transgenic mice, butyrogenic bacteria, and spatial and
dynamic profiling of the inflammatory response. We will also test the translational application of this pathway
using a novel formulation of encapsulated tributyrin, a butyrate precursor, in a pig model of arterial injury.
Collectively, these studies will test phenomenological, mechanistic, and translational facets of this pathway, thus
having a potentially transformative impact on patients undergoing vascular surgery.

## Key facts

- **NIH application ID:** 10591598
- **Project number:** 5R01HL153306-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** KAREN J. HO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $503,170
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10591598

## Citation

> US National Institutes of Health, RePORTER application 10591598, Targeting the Meta-organismal Butyrate Pathway to Prevent Arterial Restenosis after Vascular Surgery (5R01HL153306-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10591598. Licensed CC0.

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