# Nexus between miR-204, gut microbiome, and aortic aneurysmal disease

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Aortic aneurysms are often silent and deadly, and there is no medical therapy for them. Veterans,
especially those who smoke (nicotine), are highly vulnerable to aortic aneurysms and their sequelae such as
ruptures and dissections. Thus, understanding the fundamental basis for the disease is central to developing
cures that can have a positive impact on health of veterans.
 Studies in human cohorts show that the non-coding microRNA-204 (miR-204) is downregulated in aortic
aneurysmal tissue compared to non-affected tissue. In addition, human population-based studies have shown
increased prevalence of aortic aneurysms and risk of their rupture with use of broad-spectrum antibiotics. These
antibiotics are widely (and often inappropriately) prescribed in the VA Health System. Antibiotics change the
composition of the healthy gut microbiome (dysbiosis). This application will test the hypothesis that gut dysbiosis
caused by antibiotics promotes aortic aneurysms via its effect on aortic miR-204 expression.
 Dedifferentiation of smooth muscle cells from a normal contractile phenotype to a dysfunctional
synthetic one, is a core feature in diseases of arterial remodeling, including aortic aneurysms. Synthetic smooth
muscle cells preferentially utilize fat over glucose. This application will also explore the hypothesis that
downregulation of miR-204 causes switching of aortic smooth muscle cells from a contractile to a dysfunctional
synthetic phenotype by stimulating fatty acid utilization.
 The hypotheses underlying this application are grounded in exciting data showing that aortic miR-204
expression is governed by the gut microbiome – dysbiosis caused by broad-spectrum antibiotics leads to
profound decrease in aortic miR-204 expression. In addition, absence of miR-204 in mice makes them
susceptible to Angiotensin II-induced aortic aneurysmal dilatation and upregulates metabolites in the fatty acid
oxidation pathway.
 This application will leverage state-of-the-art molecular tools and genetically modified mice to examine
the role of smooth muscle miR-204 in Angiotensin II-induced and nicotine-induced aortic aneurysms. It will
determine if antibiotic-induced dysbiosis down-regulates aortic smooth muscle miR-204 and promotes aortic
aneurysmal disease, and whether this disease can be rescued by gain-of-function of miR-204. It will explore the
role of miR-204 in regulating the plasticity of smooth muscle cells and investigate whether loss of function of
miR-204 promotes dedifferentiation of aortic smooth muscle cells in aneurysmal disease. Additionally, using
metabolomics and bioenergetic tools, it will uncover the role of miR-204 in regulating smooth muscle cell
preference for fuel utilization, and investigate if deficiency of miR-204 in aortic aneurysmal disease increases
smooth muscle fatty acid oxidation.
 Aortic aneurysms are common and represent a significant health burden in veterans. This application
offers a unique opportunity to explore how a vascula...

## Key facts

- **NIH application ID:** 10476286
- **Project number:** 5I01BX002940-07
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Kaikobad J. Irani
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476286

## Citation

> US National Institutes of Health, RePORTER application 10476286, Nexus between miR-204, gut microbiome, and aortic aneurysmal disease (5I01BX002940-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10476286. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*