2. Academic Validation
  3. Activation of intestinal endogenous retroviruses by alcohol exacerbates liver disease

Activation of intestinal endogenous retroviruses by alcohol exacerbates liver disease

  • J Clin Invest. 2025 May 13;135(13):e188541. doi: 10.1172/JCI188541.
Noemí Cabré 1,  Marcos F Fondevila 1,  Wenchao Wei 1,  Tomoo Yamazaki 1 2,  Fernanda Raya Tonetti 1,  Alvaro Eguileor 1,  Ricard Garcia-Carbonell 3,  Abraham S Meijnikman 1,  Yukiko Miyamoto 1,  Susan Mayo 1,  Yanhan Wang 1,  Xinlian Zhang 4,  Thorsten Trimbuch 5,  Seija Lehnardt 6,  Lars Eckmann 1,  Derrick E Fouts 7,  Cristina Llorente 1,  Hidekazu Tsukamoto 8 9,  Peter Stärkel 10,  Bernd Schnabl 1 11
Affiliations

Affiliations

  • 1 Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • 2 Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.
  • 3 Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, California, USA.
  • 4 Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, California, USA.
  • 5 Institute of Neurophysiology, Charité Viral Core Facility, and.
  • 6 Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • 7 J. Craig Venter Institute, Rockville, Maryland, USA.
  • 8 Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
  • 9 Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA.
  • 10 Department of Hepatology and Gastroenterology, St. Luc University Hospital, Catholic University of Louvain, Brussels, Belgium.
  • 11 Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA.
PMID: 40359032 DOI: 10.1172/JCI188541
Abstract

Alcohol-associated liver disease represents a significant global health challenge, with gut microbial dysbiosis and Bacterial translocation playing a critical role in its pathogenesis. Patients with alcohol-associated hepatitis had increased fecal abundance of mammalian viruses, including retroviruses. This study investigated the role of endogenous retroviruses (ERVs) in the development of alcohol-associated liver disease. Transcriptomic analysis of duodenal and liver biopsies revealed increased expression of several human ERVs, including HERV-K and HERV-H, in patients with alcohol-associated liver disease compared with individuals acting as controls. Chronic-binge ethanol feeding markedly induced ERV abundance in intestinal epithelial cells but not the livers of mice. Ethanol increased ERV expression and activated the Z-DNA binding protein 1 (Zbp1)-mixed lineage kinase domain-like pseudokinase (Mlkl) signaling pathways to induce Necroptosis in intestinal epithelial cells. Antiretroviral treatment reduced ethanol-induced intestinal ERV expression, stabilized the gut barrier, and decreased liver disease in microbiota-humanized mice. Furthermore, mice with an intestine-specific deletion of Zbp1 were protected against Bacterial translocation and ethanol-induced steatohepatitis. These findings indicate that ethanol exploits this pathway by inducing ERVs and promoting innate immune responses, which results in the death of intestinal epithelial cells, gut barrier dysfunction, and liver disease. Targeting the ERV/Zbp1 pathway may offer new therapies for patients with alcohol-associated liver disease.

Keywords

Gastroenterology; Hepatology; Microbiome; Molecular biology.

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