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

Author

Listed:
  • Zhen Li

    (Cedars-Sinai Medical Center)

  • Min Gu

    (Louisiana State University Health Science Center
    International Flavors and Fragrances Health and Bioscience)

  • Aline Zaparte

    (Louisiana State University Health Science Center
    Louisiana State University Health Science Center)

  • Xiaoming Fu

    (Cleveland Clinic
    Cleveland Clinic)

  • Kala Mahen

    (Cleveland Clinic
    Cleveland Clinic
    Cleveland Clinic
    Cleveland Clinic)

  • Marko Mrdjen

    (Cleveland Clinic
    Cleveland Clinic
    Cleveland Clinic
    Cleveland Clinic)

  • Xinmin S. Li

    (Cleveland Clinic
    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
    Cleveland Clinic)

  • Christopher M. Taylor

    (Louisiana State University Health Science Center
    Louisiana State University Health Science Center)

  • Pearl Quijada

    (University of California)

  • Catherine A. Makarewich

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Stanley L. Hazen

    (Cleveland Clinic
    Cleveland Clinic
    Cleveland Clinic)

  • Suthat Liangpunsakul

    (Indiana University School of Medicine
    Indiana University School of Medicine
    Roudebush Veterans Administration Medical Center)

  • J. Mark Brown

    (Cleveland Clinic
    Cleveland Clinic
    Cleveland Clinic
    Cleveland Clinic)

  • David J. Lefer

    (Cedars-Sinai Medical Center)

  • David A. Welsh

    (Louisiana State University Health Science Center
    Louisiana State University Health Science Center)

  • Thomas E. Sharp

    (University of South Florida
    University South Florida)

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.

Suggested Citation

  • 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 Gors, 2024. "Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-55084-2
    DOI: 10.1038/s41467-024-55084-2
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    References listed on IDEAS

    as
    1. Ohad Manor & Chengzhen L. Dai & Sergey A. Kornilov & Brett Smith & Nathan D. Price & Jennifer C. Lovejoy & Sean M. Gibbons & Andrew T. Magis, 2020. "Health and disease markers correlate with gut microbiome composition across thousands of people," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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