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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Nature Portfolio
2024-12-01
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| Online Access: | https://doi.org/10.1038/s41467-024-55084-2 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zhen Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-896bd5cca5f94b8f933bece32eaeb648 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-896bd5cca5f94b8f933bece32eaeb6482025-01-05T12:36:22ZengNature PortfolioNature Communications2041-17232024-12-0115112310.1038/s41467-024-55084-2Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular diseaseZhen Li0Min Gu1Aline Zaparte2Xiaoming Fu3Kala Mahen4Marko Mrdjen5Xinmin S. Li6Zhihong Yang7Jing Ma8Themis Thoudam9Kristina Chandler10Maggie Hesler11Laura Heathers12Kiersten Gorse13Thanh Trung Van14David Wong15Aaron M. Gibson16Zeneng Wang17Christopher M. Taylor18Pearl Quijada19Catherine A. Makarewich20Stanley L. Hazen21Suthat Liangpunsakul22J. Mark Brown23David J. Lefer24David A. Welsh25Thomas E. Sharp26Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical CenterSection of Pulmonary/Critical Care and Allergy/Immunology, Department of Medicine, Louisiana State University Health Science CenterSection of Pulmonary/Critical Care and Allergy/Immunology, Department of Medicine, Louisiana State University Health Science CenterDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland ClinicDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland ClinicDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland ClinicDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland ClinicDivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of MedicineDivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of MedicineDivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of MedicineDivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of MedicineDivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of MedicineDepartment of Medical and Molecular Genetics, Indiana University School of MedicineDepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South FloridaDepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South FloridaIntegrative Biology and Physiology, University of CaliforniaThe Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical CenterDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland ClinicComprehensive Alcohol Research Center, School of Medicine, Louisiana State University Health Science CenterIntegrative Biology and Physiology, University of CaliforniaThe Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical CenterDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland ClinicDivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of MedicineDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland ClinicDepartment of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical CenterSection of Pulmonary/Critical Care and Allergy/Immunology, Department of Medicine, Louisiana State University Health Science CenterDepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South FloridaAbstract 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.https://doi.org/10.1038/s41467-024-55084-2 |
| spellingShingle | 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 Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease Nature Communications |
| title | Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease |
| title_full | Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease |
| title_fullStr | Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease |
| title_full_unstemmed | Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease |
| title_short | Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease |
| title_sort | alcohol induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease |
| url | https://doi.org/10.1038/s41467-024-55084-2 |
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