Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease
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.
Authors
- Catherine A. Makarewich (ORCID: https://orcid.org/0000-0001-6907-4401)
- Thanh Trung Van
- K. Mahen (ORCID: https://orcid.org/0000-0002-3739-6972)
- David J. Lefer (ORCID: https://orcid.org/0000-0003-2293-7278)
- Themis Thoudam (ORCID: https://orcid.org/0000-0002-3845-2964)
- David A. Welsh (ORCID: https://orcid.org/0000-0002-0008-6161)
- Aaron M. Gibson
- Pearl Quijada (ORCID: https://orcid.org/0000-0003-2477-2374)
- Zeneng Wang (ORCID: https://orcid.org/0000-0002-6455-8228)
- Stanley L. Hazen (ORCID: https://orcid.org/0000-0001-7124-6639)
- Xinmin S. Li (ORCID: https://orcid.org/0000-0003-4946-4271)
- J. Mark Brown (ORCID: https://orcid.org/0000-0003-2708-7487)
- Kristina Chandler
- Xiaoming Fu (ORCID: https://orcid.org/0000-0003-4073-9822)
- Suthat Liangpunsakul (ORCID: https://orcid.org/0000-0002-6504-8123)
- Marko Mrdjen (ORCID: https://orcid.org/0000-0003-3000-0266)
- Kiersten Gorse
- Min Gu (ORCID: https://orcid.org/0000-0002-7780-7051)
- Thomas E. Sharp (ORCID: https://orcid.org/0000-0001-8706-9825)
- Zhen Li (ORCID: https://orcid.org/0000-0002-0729-2910)
- Aline Zaparte (ORCID: https://orcid.org/0000-0003-4069-3676)
- Christopher M. Taylor (ORCID: https://orcid.org/0000-0002-7983-5275)
- Laura Heathers (ORCID: https://orcid.org/0009-0008-1097-2678)
- Maggie Hesler
- Jing Ma (ORCID: https://orcid.org/0000-0002-2671-3792)
- Zhihong Yang (ORCID: https://orcid.org/0000-0001-6199-3956)
- David Wong (ORCID: https://orcid.org/0000-0002-0712-153X)
Institutions
- Louisiana State University (US)
- Cedars-Sinai Medical Center (US)
- Cincinnati Children's Hospital Medical Center (US)
- Cleveland Clinic (US)
- University of California, Los Angeles (US)
- University of South Florida (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Integra (United States) (US)
- Richard L. Roudebush VA Medical Center (US)
- International Flavors & Fragrances (United States) (US)
- USF Health Byrd Alzheimer's Institute (US)
- Cedars-Sinai Smidt Heart Institute (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Louisiana State University Health Sciences Center New Orleans (US)
- International Flavors & Fragrances (France) (FR)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1038/s41467-024-55084-2
- Citations
- 10
- Primary Topic
- Alcohol Consumption and Health Effects
- Type
- article
- Field-Weighted Citation Impact
- 4.25
Funders
- National Science Foundation
- U.S. Department of Defense
- U.S. Department of Veterans Affairs
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Arthritis and Musculoskeletal and Skin Diseases