Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease

Authors

Zhen Li, Cedars-Sinai Medical Center, Los Angeles, CA
Min Gu, LSU Health Sciences Center - New Orleans
Aline Zaparte, LSU Health Sciences Center - New OrleansFollow
Xiaoming Fu, Cleveland Clinic, Cleveland, OH
Kala Mahen, Cleveland Clinic, Cleveland, OH
Marko Mrdjen, Cleveland Clinic, Cleveland, OH
Xinmin S. Li, Cleveland Clinic, Cleveland, OH
Zhihong Yang, Indiana University School of Medicine, Indianapolis, IN
Jing Ma, Indiana University School of Medicine, Indianapolis, IN
Themis Thoudam, Indiana University School of Medicine, Indianapolis, IN
Kristina Chandler, Indiana University School of Medicine, Indianapolis, IN
Maggie Hesler, Indiana University School of Medicine, Indianapolis, IN
Laura Heathers, Indiana University School of Medicine, Indianapolis, IN
Kiersten Gorse, University of South Florida, Tampa, FL
Thanh Trung Van, University of South Florida, Tampa, FL
David Wong, University of California, Los Angeles, CA
Aaron M. Gibson, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Zeneng Wang, Cleveland Clinic, Cleveland, OH
Christopher M. Taylor, LSU Health Sciences Center - New OrleansFollow
Pearl Quijada, University of California, Los Angeles, CA
Catherine A. Makarewich, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Stanley L. Hazen, Cleveland Clinic, Cleveland, OH
Suthat Liangpunsakul, Indiana University School of Medicine, Indianapolis, IN
J Mark Brown, Cleveland Clinic, Cleveland, OH
David J. Lefer, Cedars-Sinai Medical Center, Los Angeles, CA
David A. Welsh, LSU Health Sciences Center - New OrleansFollow
Thomas E. Sharp, University of South Florida, Tampa, FL

Document Type

Article

Publication Date

12-30-2024

Publication Title

Nature Communications

Abstract

The mechanism(s) underlying gut microbial metabolite (GMM) contribution towards alcohol-mediated cardiovascular disease (CVD) is unknown. Herein we observe elevation in circulating phenylacetylglutamine (PAGln), a known CVD-associated GMM, in individuals living with alcohol use disorder. In a male murine binge-on-chronic alcohol model, we confirm gut microbial reorganization, elevation in PAGln levels, and the presence of cardiovascular pathophysiology. Fecal microbiota transplantation from pair-/alcohol-fed mice into naïve male mice demonstrates the transmissibility of PAGln production and the CVD phenotype. Independent of alcohol exposure, pharmacological-mediated increases in PAGln elicits direct cardiac and vascular dysfunction. PAGln induced hypercontractility and altered calcium cycling in isolated cardiomyocytes providing evidence of improper relaxation which corresponds to elevated filling pressures observed in vivo. Furthermore, PAGln directly induces vascular endothelial cell activation through induction of oxidative stress leading to endothelial cell dysfunction. We thus reveal that the alcohol-induced microbial reorganization and resultant GMM elevation, specifically PAGln, directly contributes to CVD.

First Page

10788

PubMed ID

39738016

Volume

15

Issue

1

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Li, Zhen; Gu, Min; Zaparte, Aline; Fu, Xiaoming; Mahen, Kala; Mrdjen, Marko; Li, Xinmin S.; Yang, Zhihong; Ma, Jing; Thoudam, Themis; Chandler, Kristina; Hesler, Maggie; Heathers, Laura; Gorse, Kiersten; Van, Thanh Trung; Wong, David; Gibson, Aaron M.; Wang, Zeneng; Taylor, Christopher M.; Quijada, Pearl; Makarewich, Catherine A.; Hazen, Stanley L.; Liangpunsakul, Suthat; Brown, J Mark; Lefer, David J.; Welsh, David A.; and Sharp, Thomas E., "Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease" (2024). School of Medicine Faculty Publications. 3370.
https://digitalscholar.lsuhsc.edu/som_facpubs/3370
10.1038/s41467-024-55084-2