Yang Yongqiang, Duan Yi, Lang Sonja, Fondevila Marcos F, Schöler David, Harberts Aenne, Cabré Noemí, Chen Sainan, Shao Yan, Vervier Kevin, Miyamoto Yukiko, Zhang Xinlian, Chu Huikuan, Yang Ling, Tan Chen, Eckmann Lars, Bosques-Padilla Francisco, Verna Elizabeth C, Abraldes Juan G, Brown Robert S, Vargas Victor, Altamirano Jose, Caballería Juan, Shawcross Debbie L, Louvet Alexandre, Lucey Michael R, Mathurin Philippe, Garcia-Tsao Guadalupe, Bataller Ramon, Stärkel Peter, Lawley Trevor D, Schnabl Bernd
Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA, USA; National Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM and Department of Infectious Diseases, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China.
Cell Host Microbe. 2025 Jun 11;33(6):957-972.e6. doi: 10.1016/j.chom.2025.05.003. Epub 2025 May 28.
Alcohol-associated liver disease poses a global health burden with high mortality. Imbalances in the gut microbiota are important for disease progression. Using metagenomic sequencing of fecal samples from a multicenter, international cohort of patients with alcohol-associated hepatitis, we found that the presence of virulence factor KpsM, encoded in the genome of Escherichia coli (E. coli), correlated with patient mortality. Functional studies using gnotobiotic mouse models and genetic manipulation of bacteria demonstrated that kpsM-positive E. coli exacerbate ethanol-induced liver disease. The kpsM gene mediates the translocation of capsular polysaccharides to the cell surface. This enables kpsM-positive E. coli to evade phagocytosis by the scavenger receptor Marco on Kupffer cells in the liver, leading to bacterial spread. Importantly, inhibiting kpsM-dependent capsules with the small molecule 2-(4-phenylphenyl)benzo[g]quinoline-4-carboxylic acid (C7) attenuated ethanol-induced liver disease in mice. We show that precision targeting of the virulence factor KpsM is a promising approach to improve outcomes of patients with alcohol-associated hepatitis.
酒精性肝病给全球健康带来沉重负担，死亡率很高。肠道微生物群失衡对疾病进展至关重要。通过对来自多中心国际酒精性肝炎患者队列的粪便样本进行宏基因组测序，我们发现大肠杆菌（E. coli）基因组中编码的毒力因子KpsM的存在与患者死亡率相关。使用无菌小鼠模型和细菌基因操作的功能研究表明，KpsM阳性大肠杆菌会加剧乙醇诱导的肝病。KpsM基因介导荚膜多糖向细胞表面的转运。这使得KpsM阳性大肠杆菌能够逃避肝脏库普弗细胞上清道夫受体Marco的吞噬作用，从而导致细菌扩散。重要的是，用小分子2-（4-苯基苯基）苯并[g]喹啉-4-羧酸（C7）抑制KpsM依赖性荚膜可减轻小鼠乙醇诱导的肝病。我们表明，精准靶向毒力因子KpsM是改善酒精性肝炎患者预后的一种有前景的方法。
