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

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

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...

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Main Authors: Zhen Li, Min Gu, Aline Zaparte, Xiaoming Fu, Kala Mahen, Marko Mrdjen, Xinmin S. Li, Zhihong Yang, Jing Ma, Themis Thoudam, Kristina Chandler, Maggie Hesler, Laura Heathers, Kiersten Gorse, Thanh Trung Van, David Wong, Aaron M. Gibson, Zeneng Wang, Christopher M. Taylor, Pearl Quijada, Catherine A. Makarewich, Stanley L. Hazen, Suthat Liangpunsakul, J. Mark Brown, David J. Lefer, David A. Welsh, Thomas E. Sharp
Format: Article
Language:English
Published: Nature Portfolio 2024-12-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-024-55084-2
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Summary: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.
ISSN:2041-1723

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