Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues for alternative therapies to alleviate alcohol-associated liver disease based on the interaction of the commensal gut microbiome as a key player in the regulation of the immune response. This review describes the relevance of the intestinal immune system, the gut microbiota, and specialized and non-specialized intestinal cells in the regulation of intestinal homeostasis. It also reflects how these components are altered during alcohol-associated liver disease and discusses new approaches for potential future therapies in alcohol-associated liver disease.

Alcohol consumption is the seventh leading risk factor for death worldwide 1 48 and alcoholic liver disease (ALD) is the major cause of liver transplantation in the West 2 49 . Alcohol metabolites can 50 directly damage the liver, but the gut-liver axis also plays an important role in ALD pathogenesis, 51 acting through complex and obscure mechanisms. Although alcohol intake is associated with increased intestinal permeability 3 52 , it is not clear how the intestinal immune system affects liver 53 disease. Paradoxically, we found that chronic alcohol use increases intestinal goblet cell (GC) 54 number and mucin production in patients and mice. This, however, comes with the expense of 55 GC associated antigen passages (GAPs) closure and defective delivery of luminal antigens and 56 bacteria to lamina propria (LP) antigen presenting cells (APCs). IL-6 is one of several cytokines elevated in ALD that affects the liver and the intestine 4 57 . Although IL-6 expression correlates with disease severity 5 , IL-6 also exerts barrier protective effects 6 58 . We now show that GAPs are 59 controlled by intestinal IL-6 signal transducer (IL6ST/gp130). Although mice that express constitutively active gp130 in intestinal epithelial cells (IEC; gp130 60 Act/IEC mice) have fewer GCs 7 61 , they are ALD resistant due to increased GAP formation, which enhances the generation of 62 tolerogenic LP-APCs and production of IL-22 by type-3 innate lymphoid cells (ILC3s). GAP 63 opening induces an intestinal C-type regenerating islet derived-3 (Reg3) lectin-mediated 64 antibacterial defense, reducing bacterial translocation to the liver and preventing alcoholic 65 steatohepatitis. gp130 signaling exerted its protective effects via muscarinic acetylcholine (ACh) 66 receptor 4 (mAChR4), whose GC expression was induced by IL-6. Based on these findings, we 67 developed a new therapeutic approach, administering a mAChR4 positive allosteric modulator 68 (PAM) to stimulate intestinal GAP formation, thereby increasing tolerogenic LP-APCs and Reg3 69 expression, to prevent microbial translocation and protect mice from alcoholic steatohepatitis. 70 Our results show that IL6ST signaling modulates intestinal immunity through mAChR4. GAP 71 induction by mAChR4 PAMs is a promising strategy for enhancing intestinal immune tolerance 72 and interception in ALD and other diseases linked to uncontrolled microbial translocation.