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ResearchIn-Press PreviewGastroenterologyHepatology Open Access | 10.1172/JCI188541

Activation of intestinal endogenous retroviruses by alcohol exacerbates liver disease

Noemí Cabré,1 Marcos F. Fondevila,1 Wenchao Wei,1 Tomoo Yamazaki,1 Fernanda Raya Tonetti,1 Alvaro Eguileor,1 Ricard Garcia-Carbonell,2 Abraham S. Meijnikman,1 Yukiko Miyamoto,1 Susan Mayo,1 Yanhan Wang,1 Xinlian Zhang,3 Thorsten Trimbuch,4 Seija Lehnardt,5 Lars Eckmann,1 Derrick E. Fouts,6 Cristina Llorente,1 Hidekazu Tsukamoto,7 Peter Stärkel,8 and Bernd Schnabl1

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Cabré, N. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Fondevila, M. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Wei, W. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Yamazaki, T. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Raya Tonetti, F. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Eguileor, A. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Garcia-Carbonell, R. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Meijnikman, A. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Miyamoto, Y. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Mayo, S. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Wang, Y. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Zhang, X. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Trimbuch, T. in: PubMed | Google Scholar |

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Lehnardt, S. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Eckmann, L. in: PubMed | Google Scholar |

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Fouts, D. in: PubMed | Google Scholar |

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Llorente, C. in: PubMed | Google Scholar |

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Tsukamoto, H. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Stärkel, P. in: PubMed | Google Scholar

1Department of Medicine, UCSD, La Jolla, United States of America

2Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, United States of America

3Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Pu, UCSD, La Jolla, United States of America

4Cluster of Excellence, NeuroCure, Charité – Universitätsmedizin Berlin, Berlin, Germany

5Charité – Universitätsmedizin Berlin, Berlin, Germany

6J. Craig Venter Institute, Rockville, United States of America

7Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, United States of America

8Laboratory of Gastroenterology, St. Luc University Hospital, Brussels, Belgium

Find articles by Schnabl, B. in: PubMed | Google Scholar

Published May 13, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI188541.
Copyright © 2025, Cabré et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 13, 2025 - Version history
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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 controls. Chronic-binge ethanol feeding markedly induced ERV abundance in intestinal epithelial cells, but not the liver 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.

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  • Version 1 (May 13, 2025): In-Press Preview
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