Activation of intestinal endogenous retroviruses by alcohol exacerbates liver disease
Noemí Cabré, … , Peter Stärkel, Bernd Schnabl
Noemí Cabré, … , Peter Stärkel, Bernd Schnabl
Published May 13, 2025
Citation Information: J Clin Invest. 2025;135(13):e188541. https://doi.org/10.1172/JCI188541.
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Research Article Gastroenterology Hepatology

Activation of intestinal endogenous retroviruses by alcohol exacerbates liver disease

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.

Authors

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

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Figure 5

Antiretroviral treatment reduces ethanol-induced intestinal necroptosis and liver disease.

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Antiretroviral treatment reduces ethanol-induced intestinal necroptosis ...
(A) Germ-free C57BL/6 mice were colonized with fecal microbiota from patients with alcohol-associated hepatitis (AH) and treated with a combination of antiretrovirals (660 μM emtricitabine, 314 μM tenofovir, and 375 μM nevirapine) in the drinking water after second colonization and then in liquid diet. Gnotobiotic mice were fed oral isocaloric (control) or chronic-binge ethanol diets. (B) Levels of mouse mammary tumor virus (MMTV) env and gag mRNA in the ileum. (C) Levels of MMTV env and gag mRNA in intestinal epithelial cells (IECs) isolated from the small intestine. (D) Levels of Zbp1 mRNA in the ileum and in intestinal epithelial cells isolated from the small intestine. (E and F) Intestinal epithelial cells were isolated from ethanol-fed mice, and immunoblots were performed for phospho-Mlkl, Mlkl, Zbp1, and Gapdh; protein amounts of Zbp1 relative to Gapdh and protein amounts of phospho-Mlkl relative to Mlkl are shown (n = 8 in each group). (G) Serum levels of ALT. (H) Hepatic triglyceride content. (I) Representative images of liver sections stained with Oil Red O (scale bars: 200 μm) and quantification of Oil Red O-stained area. (J) Hepatic levels of Cxcl1 and Cxcl2 mRNA. (K) Colony-forming units on MacConkey agar plates from the liver. (L) Hepatic E. coli abundance normalized to bacterial 16S, as measured by qPCR. (B–L) Results were generated from 2 technical replicates. P values among groups were determined by 1-way ANOVA with Tukey’s post hoc test (B; D, left; G–I; and L) or Mann-Whitney U test (C, D, right, F, J, and K). Results are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001. AU, arbitrary units.