Gut-liver axis molecular mechanisms in alcohol-associated liver disease

Alcohol-associated liver disease (ALD) represents one of the most prevalent and devastating chronic liver diseases worldwide. Yet, its pathogenesis and effective therapeutic strategies remain elusive. The gut-liver axis, the bidirectional interaction between intestinal microbiota, microbial products, metabolites, bile acids, immune mediators, and the liver itself, has become a key focus in the study of ALD. Chronic alcohol consumption disrupts intestinal homeostasis, leading to microbial dysbiosis, compromised barrier integrity, and translocation of pathogen-associated molecular patterns (PAMPs) into the portal circulation, eventually reaching the liver. By interacting with pattern-recognition receptors (PRRs) on hepatic immune cells, parenchymal cells, and other non-parenchymal cells, these gut-derived PAMPs promote the development of liver inflammation and fibrosis. Furthermore, microbial metabolites, including short-chain fatty acids (SCFAs), secondary bile acids (BAs), indole derivatives, and vitamin B, modulate key hepatic and immune pathways implicated in liver homeostasis. This review summarizes recent advances in understanding how PAMPs and altered microbial metabolites influence ALD pathogenesis and highlights emerging insights into the role of central interleukins, including IL-1β, IL-6, IL-17, IL-10, IL-22, and IL-23. Collectively, this review integrates recent mechanistic insights and proposes that modulating gut microbiota composition and signaling represents a promising direction for developing safe and novel therapies for ALD.