mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity PMID: 40836099

ADC Targets in Oncology

2026-04-10

mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity

Nature. 2025 Aug 20. doi: 10.1038/s41586-025-09395-z.

Cristina Llorente ^# ¹ , Fernanda Raya Tonetti ^# ² , Ryan Bruellman ² , Rocío Brea ² , Nuria Pell ² , Phillipp Hartmann ³ ⁴ , Luca Maccioni ⁵ , Hui Han ² , Noemí Cabré ² , Junlai Liu ⁶ , Alvaro Eguileor ² , Marcos F Fondevila ² , Abraham S Meijnikman ² ⁷ , Cynthia L Hsu ² , Ameera Alghafri ² , Rongrong Zhou ² ⁸ , Bei Gao ² , Yi Duan ² , Peng Zhang ⁶ , Mark A Febbraio ⁹ , Koji Taniguchi ⁶ ¹⁰ ¹¹ , Rodney D Newberry ¹² , Derrick E Fouts ¹³ , David A Brenner ² ¹⁴ , Peter Stärkel ⁵ ¹⁵ , Michael Karin ¹⁶ , Bernd Schnabl ¹⁷ ¹⁸

Affiliations

1. Department of Medicine, University of California San Diego, La Jolla, CA, USA. [email protected].
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. [email protected].
17. Department of Medicine, University of California San Diego, La Jolla, CA, USA. [email protected].
18. Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. [email protected].
# Contributed equally.

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.