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

  • Cell Host Microbe. 2025 Jun 11;33(6):957-972.e6. doi: 10.1016/j.chom.2025.05.003.
Yongqiang Yang  1 ,  Yi Duan  2 ,  Sonja Lang  3 ,  Marcos F Fondevila  1 ,  David Schöler  1 ,  Aenne Harberts  1 ,  Noemí Cabré  1 ,  Sainan Chen  1 ,  Yan Shao  4 ,  Kevin Vervier  4 ,  Yukiko Miyamoto  1 ,  Xinlian Zhang  5 ,  Huikuan Chu  6 ,  Ling Yang  6 ,  Chen Tan  7 ,  Lars Eckmann  1 ,  Francisco Bosques-Padilla  8 ,  Elizabeth C Verna  9 ,  Juan G Abraldes  10 ,  Robert S Brown Jr  11 ,  Victor Vargas  12 ,  Jose Altamirano  13 ,  Juan Caballería  14 ,  Debbie L Shawcross  15 ,  Alexandre Louvet  16 ,  Michael R Lucey  17 ,  Philippe Mathurin  16 ,  Guadalupe Garcia-Tsao  18 ,  Ramon Bataller  19 ,  Peter Stärkel  20 ,  Trevor D Lawley  4 ,  Bernd Schnabl  21
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: [email protected].
PMID: 40441146 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.
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