mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity

Cristina Llorente (), Fernanda Raya Tonetti, Ryan Bruellman, Rocío Brea, Nuria Pell, Phillipp Hartmann, Luca Maccioni, Hui Han, Noemí Cabré, Junlai Liu, Alvaro Eguileor, Marcos F. Fondevila, Abraham S. Meijnikman, Cynthia L. Hsu, Ameera Alghafri, Rongrong Zhou, Bei Gao, Yi Duan, Peng Zhang, Mark A. Febbraio, Koji Taniguchi, Rodney D. Newberry, Derrick E. Fouts, David A. Brenner, Peter Stärkel, Michael Karin () and Bernd Schnabl ()
Additional contact information
Cristina Llorente: University of California San Diego
Fernanda Raya Tonetti: University of California San Diego
Ryan Bruellman: University of California San Diego
Rocío Brea: University of California San Diego
Nuria Pell: University of California San Diego
Phillipp Hartmann: University of California San Diego
Luca Maccioni: Université Catholique de Louvain
Hui Han: University of California San Diego
Noemí Cabré: University of California San Diego
Junlai Liu: University of California San Diego
Alvaro Eguileor: University of California San Diego
Marcos F. Fondevila: University of California San Diego
Abraham S. Meijnikman: University of California San Diego
Cynthia L. Hsu: University of California San Diego
Ameera Alghafri: University of California San Diego
Rongrong Zhou: University of California San Diego
Bei Gao: University of California San Diego
Yi Duan: University of California San Diego
Peng Zhang: University of California San Diego
Mark A. Febbraio: Monash University
Koji Taniguchi: University of California San Diego
Rodney D. Newberry: Washington University School of Medicine
Derrick E. Fouts: J. Craig Venter Institute
David A. Brenner: University of California San Diego
Peter Stärkel: Université Catholique de Louvain
Michael Karin: University of California San Diego
Bernd Schnabl: University of California San Diego

Nature, 2025, vol. 646, issue 8083, 180-189

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09395-z

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