Targeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease

Yongqiang Yang¹, Yi Duan², Sonja Lang³, Marcos F Fondevila¹, David Schöler¹, Aenne Harberts¹, Noemí Cabré¹, Sainan Chen¹, Yan Shao⁴, Kevin Vervier⁴, Yukiko Miyamoto¹, Xinlian Zhang⁵, Huikuan Chu⁶, Ling Yang⁶, Chen Tan⁷, Lars Eckmann¹, Francisco Bosques-Padilla⁸, Elizabeth C Verna⁹, Juan G Abraldes¹⁰, Robert S Brown Jr¹¹, Victor Vargas¹², Jose Altamirano¹³, Juan Caballería¹⁴, Debbie L Shawcross¹⁵, Alexandre Louvet¹⁶, Michael R Lucey¹⁷, Philippe Mathurin¹⁶, Guadalupe Garcia-Tsao¹⁸, Ramon Bataller¹⁹, Peter Stärkel²⁰, Trevor D Lawley⁴, Bernd Schnabl²¹

Affiliations

¹ Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
² 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.
³ Department of Medicine, University of California, San Diego, La Jolla, CA, USA; University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany.
⁴ Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
⁵ Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA.
⁶ Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁷ State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China.
⁸ Hospital Universitario, Departamento de Gastroenterología, Universidad Autonoma de Nuevo Leon, Monterrey, México.
⁹ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
¹⁰ Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, AB, Canada.
¹¹ Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA.
¹² Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
¹³ Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹⁴ Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clinic, Barcelona Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Centro de investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
¹⁵ Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, London, UK.
¹⁶ Service des Maladies de L'appareil Digestif et Unité INFINITE 1286, Hôpital Huriez, Lille, France.
¹⁷ Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
¹⁸ Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA; Section of Digestive Diseases, VA-CT Healthcare System, West Haven, CT, USA.
¹⁹ Liver Unit, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
²⁰ St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
²¹ Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. Electronic address: beschnabl@ucsd.edu.

PMID: 40441146
PMCID: PMC12162233 (available on 2026-06-11)
DOI: 10.1016/j.chom.2025.05.003

Targeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease

Yongqiang Yang et al. Cell Host Microbe. 2025.

. 2025 Jun 11;33(6):957-972.e6.

doi: 10.1016/j.chom.2025.05.003. Epub 2025 May 28.

Authors

Affiliations

¹ Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
² 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.
³ Department of Medicine, University of California, San Diego, La Jolla, CA, USA; University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany.
⁴ Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
⁵ Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA.
⁶ Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁷ State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China.
⁸ Hospital Universitario, Departamento de Gastroenterología, Universidad Autonoma de Nuevo Leon, Monterrey, México.
⁹ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
¹⁰ Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, AB, Canada.
¹¹ Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA.
¹² Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
¹³ Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹⁴ Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clinic, Barcelona Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Centro de investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
¹⁵ Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, London, UK.
¹⁶ Service des Maladies de L'appareil Digestif et Unité INFINITE 1286, Hôpital Huriez, Lille, France.
¹⁷ Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
¹⁸ Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA; Section of Digestive Diseases, VA-CT Healthcare System, West Haven, CT, USA.
¹⁹ Liver Unit, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
²⁰ St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
²¹ Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. Electronic address: beschnabl@ucsd.edu.

PMID: 40441146
PMCID: PMC12162233 (available on 2026-06-11)
DOI: 10.1016/j.chom.2025.05.003

Abstract

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.

Keywords: alcoholic liver disease; gut-liver axis; metagenomics; microbiome; microbiota; virulence factor.

Published by Elsevier Inc.

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Conflict of interest statement

Declaration of interests K.V. is currently an employee of the company Novartis. V.V. is on the advisory board for Ipsen and receives speaker fees from Orphalan. B.S. has been consulting for Ambys Medicines, Boehringer Ingelheim, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen, and Takeda. B.S.’s institution, UC San Diego, has received research support from Axial Biotherapeutics, BiomX, ChromoLogic, CymaBay Therapeutics, Intercept, NGM Biopharmaceuticals, Prodigy Biotech, and Synlogic Operating Company. B.S. is the founder of Nterica Bio. UC San Diego has filed several patents with Y.D., S.L., and B.S. as inventors related to this work.

References

1. Collaborators, G.B.D.C. (2020). The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol. 5, 245–266. 10.1016/S2468-1253(19)30349-8. - DOI - PMC - PubMed
1. Singal AK, and Mathurin P (2021). Diagnosis and Treatment of Alcohol-Associated Liver Disease: A Review. JAMA 326, 165–176. 10.1001/jama.2021.7683. - DOI - PubMed
1. Rehm J, Samokhvalov AV, and Shield KD (2013). Global burden of alcoholic liver diseases. J. Hepatol. 59, 160–168. 10.1016/j.jhep.2013.03.007. - DOI - PubMed
1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al. (2012). Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2095–2128. 10.1016/S0140-6736(12)61728-0. - DOI - PMC - PubMed
1. Lee BP, Vittinghoff E, Dodge JL, Cullaro G, and Terrault NA (2019). National Trends and Long-term Outcomes of Liver Transplant for Alcohol-Associated Liver Disease in the United States. JAMA Intern. Med. 179, 340–348. 10.1001/jamainternmed.2018.6536. - DOI - PMC - PubMed

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Targeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease

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Targeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease

Authors

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Conflict of interest statement

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