Cabré Noemí, Fondevila Marcos F, Wei Wenchao, Yamazaki Tomoo, Tonetti Fernanda Raya, Eguileor Alvaro, Garcia-Carbonell Ricard, Meijnikman Abraham S, Miyamoto Yukiko, Mayo Susan, Wang Yanhan, Zhang Xinlian, Trimbuch Thorsten, Lehnardt Seija, Eckmann Lars, Fouts Derrick E, Llorente Cristina, Tsukamoto Hidekazu, Stärkel Peter, Schnabl Bernd
Department of Medicine, University of California, San Diego, La Jolla, California, USA.
Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.
J Clin Invest. 2025 May 13;135(13). doi: 10.1172/JCI188541. eCollection 2025 Jul 1.
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.
酒精性肝病是一项重大的全球健康挑战，肠道微生物群失调和细菌易位在其发病机制中起着关键作用。酒精性肝炎患者粪便中包括逆转录病毒在内的哺乳动物病毒丰度增加。本研究调查了内源性逆转录病毒（ERV）在酒精性肝病发展中的作用。十二指肠和肝脏活检的转录组分析显示，与对照组个体相比，酒精性肝病患者中几种人类ERV的表达增加，包括HERV-K和HERV-H。慢性暴饮乙醇喂养显著诱导肠道上皮细胞中ERV的丰度，但不诱导小鼠肝脏中ERV的丰度。乙醇增加ERV表达并激活Z-DNA结合蛋白1（Zbp1）-混合谱系激酶结构域样假激酶（Mlkl）信号通路，以诱导肠道上皮细胞坏死性凋亡。抗逆转录病毒治疗可降低乙醇诱导的肠道ERV表达，稳定肠道屏障，并减少微生物群人源化小鼠的肝病。此外，肠道特异性缺失Zbp1的小鼠可免受细菌易位和乙醇诱导的脂肪性肝炎的影响。这些发现表明，乙醇通过诱导ERV和促进先天免疫反应来利用这一途径，从而导致肠道上皮细胞死亡、肠道屏障功能障碍和肝病。靶向ERV/Zbp1途径可能为酒精性肝病患者提供新的治疗方法。
