2025-08-26 カリフォルニア大学サンディエゴ校(UCSD)
This micrograph shows a small intestine organoid, a miniature model of mouse intestinal tissue. Experiments in these organoids helped UC San Diego researchers reveal a new underlying mechanism driving alcoholic liver disease. Photo Credit: UC San Diego Health Sciences
<関連情報>
- https://today.ucsd.edu/story/alcohol-opens-the-floodgates-for-bad-bacteria
- https://www.nature.com/articles/s41586-025-09395-z
mAChR4はGAP誘導性抗菌免疫を介して肝疾患を抑制する 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,… Bernd Schnabl
Nature Published:20 August 2025
DOI:https://doi.org/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.
