Cell host & microbe · 2025
Targeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease.
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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
Аннотация
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.