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

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 and Thomas E. Sharp ()
Additional contact information
Zhen Li: Cedars-Sinai Medical Center
Min Gu: Louisiana State University Health Science Center
Aline Zaparte: Louisiana State University Health Science Center
Xiaoming Fu: Cleveland Clinic
Kala Mahen: Cleveland Clinic
Marko Mrdjen: Cleveland Clinic
Xinmin S. Li: Cleveland Clinic
Zhihong Yang: Indiana University School of Medicine
Jing Ma: Indiana University School of Medicine
Themis Thoudam: Indiana University School of Medicine
Kristina Chandler: Indiana University School of Medicine
Maggie Hesler: Indiana University School of Medicine
Laura Heathers: Indiana University School of Medicine
Kiersten Gorse: University of South Florida
Thanh Trung Van: University of South Florida
David Wong: University of California
Aaron M. Gibson: Cincinnati Children’s Hospital Medical Center
Zeneng Wang: Cleveland Clinic
Christopher M. Taylor: Louisiana State University Health Science Center
Pearl Quijada: University of California
Catherine A. Makarewich: Cincinnati Children’s Hospital Medical Center
Stanley L. Hazen: Cleveland Clinic
Suthat Liangpunsakul: Indiana University School of Medicine
J. Mark Brown: Cleveland Clinic
David J. Lefer: Cedars-Sinai Medical Center
David A. Welsh: Louisiana State University Health Science Center
Thomas E. Sharp: University of South Florida

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-55084-2

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