mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity

Cristina Llorente^#¹, Fernanda Raya Tonetti^#², Ryan Bruellman², Rocío Brea², Nuria Pell², Phillipp Hartmann^{3

4}, Luca Maccioni⁵, Hui Han², Noemí Cabré², Junlai Liu⁶, Alvaro Eguileor², Marcos F Fondevila², Abraham S Meijnikman^{2

7}, Cynthia L Hsu², Ameera Alghafri², Rongrong Zhou^{2

8}, Bei Gao², Yi Duan², Peng Zhang⁶, Mark A Febbraio⁹, Koji Taniguchi^{6

10

11}, Rodney D Newberry¹², Derrick E Fouts¹³, David A Brenner^{2

14}, Peter Stärkel^{5

15}, Michael Karin¹⁶, Bernd Schnabl^{17

18}

Affiliations

¹ Department of Medicine, University of California San Diego, La Jolla, CA, USA. allorenteizquierdo@health.ucsd.edu.
² Department of Medicine, University of California San Diego, La Jolla, CA, USA.
³ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
⁴ Division of Gastroenterology, Hepatology & Nutrition, Rady Children's Hospital San Diego, San Diego, CA, USA.
⁵ Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UC Louvain, Université Catholique de Louvain, Brussels, Belgium.
⁶ Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, USA.
⁷ Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
⁸ Department of Infectious Diseases, Xiangya Hospital, Central South University and Key Laboratory of Viral Hepatitis, Changsha, China.
⁹ Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
¹⁰ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
¹¹ Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹² Department of Internal Medicine, Washington University School of Medicine, St Louis, MI, USA.
¹³ J. Craig Venter Institute, Rockville, MD, USA.
¹⁴ Cancer Genome and Epigenetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹⁵ Department of Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
¹⁶ Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, USA. karinoffice@ucsd.edu.
¹⁷ Department of Medicine, University of California San Diego, La Jolla, CA, USA. beschnabl@ucsd.edu.
¹⁸ Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. beschnabl@ucsd.edu.

^# Contributed equally.

PMID: 40836099
DOI: 10.1038/s41586-025-09395-z

mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity

Cristina Llorente et al. Nature. 2025.

. 2025 Aug 20.

doi: 10.1038/s41586-025-09395-z. Online ahead of print.

Authors

Affiliations

¹ Department of Medicine, University of California San Diego, La Jolla, CA, USA. allorenteizquierdo@health.ucsd.edu.
² Department of Medicine, University of California San Diego, La Jolla, CA, USA.
³ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
⁴ Division of Gastroenterology, Hepatology & Nutrition, Rady Children's Hospital San Diego, San Diego, CA, USA.
⁵ Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UC Louvain, Université Catholique de Louvain, Brussels, Belgium.
⁶ Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, USA.
⁷ Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
⁸ Department of Infectious Diseases, Xiangya Hospital, Central South University and Key Laboratory of Viral Hepatitis, Changsha, China.
⁹ Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
¹⁰ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
¹¹ Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹² Department of Internal Medicine, Washington University School of Medicine, St Louis, MI, USA.
¹³ J. Craig Venter Institute, Rockville, MD, USA.
¹⁴ Cancer Genome and Epigenetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹⁵ Department of Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
¹⁶ Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, USA. karinoffice@ucsd.edu.
¹⁷ Department of Medicine, University of California San Diego, La Jolla, CA, USA. beschnabl@ucsd.edu.
¹⁸ Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. beschnabl@ucsd.edu.

^# Contributed equally.

PMID: 40836099
DOI: 10.1038/s41586-025-09395-z

Abstract

Alcohol-use disorder and alcohol-associated liver disease (ALD) are major causes of death and liver transplantation¹. The gut-liver axis has a crucial yet poorly understood role in ALD pathogenesis, which depends on microbial translocation. Intestinal goblet cells (GCs) educate the immune system by forming GC-associated antigen passages (GAPs) on activation of muscarinic acetylcholine receptor M4 (mAChR4, also known as M₄), enabling sampling of luminal antigens by lamina propria antigen-presenting cells. Here we show that chronic alcohol use in humans and mice downregulates small intestinal mAChR4 and reduces GAP formation, disrupting antimicrobial immunity. This is reversed on activation of intestinal IL-6 signal transducer (IL6ST, also known as glycoprotein 130; gp130), which restores mAChR4 expression and GAP formation, enabling induction of downstream type-3 innate lymphoid cell-derived IL-22 and antimicrobial REG3 proteins. This blunts translocation of enteric bacteria to the liver, thereby conferring ALD resistance. GAP induction by GC-specific mAChR4 activation was essential and sufficient for prevention of ethanol-induced steatohepatitis. These results lay the foundation for a therapeutic approach using mAChR4 or IL6ST agonists to promote GAP formation and prevent ALD by inhibiting microbial translocation.

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Conflict of interest statement

Competing interests: B.S. has consulted for Ferring Research Institute, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen and Takeda. P.H.’s institution, UC San Diego, has received research support from Nterica Bio. B.S.’s institution, UC San Diego, has received research support from Axial Biotherapeutics, BiomX, ChromoLogic, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. B.S. is the founder of Nterica Bio. UC San Diego has filed several patents with C.L., C.L.H., Y.D. and B.S. listed as inventors related to this work. M.A.F. is the founder and shareholder of Celesta Therapeutics. M.K. received research support from Jansen Pharmaceuticals, Merck and Gossamer Bio and is a founder of Elgia Bio. The other authors declare no competing interests.

References

1. Lee, B. P., Vittinghoff, E., Dodge, J. L., Cullaro, G. & Terrault, N. A. National trends and long-term outcomes of liver transplant for alcohol-associated liver disease in the United States. JAMA Intern. Med. 179, 340–348 (2019). - PubMed - PMC
1. Llorente, C. et al. Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus. Nat. Commun. 8, 837 (2017). - PubMed - PMC
1. Duan, Y. et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 575, 505–511 (2019). - PubMed - PMC
1. Bruellman, R. & Llorente, C. A perspective of intestinal immune-microbiome interactions in alcohol-associated liver disease. Int. J. Biol. Sci. 17, 307–327 (2021). - PubMed - PMC
1. Raya Tonetti, F. et al. Gut–liver axis: recent concepts in pathophysiology in alcohol-associated liver disease. Hepatology https://doi.org/10.1097/HEP.0000000000000924 (2024).

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mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity

Affiliations

mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity

Authors

Affiliations

Abstract

Conflict of interest statement

References

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