The gut-liver-immune axis: structural basis, cellular architecture, molecular mediators, and disease-specific...

The gut and liver form an anatomical and functional unit linked by the portal circulation, the biliary tract, lymphatic drainage, and neuroimmune pathways. In recent years, the classical gut-liver axis has expanded from a predominantly microbial and metabolic concept into a broader framework in which immune cells are viewed as central integrators of inter-organ signaling. In health, balanced microbial sensing, intact mucosal and vascular barriers, regulated bile acid signaling, and specialized tissue-resident immune programs preserve tolerance at both intestinal and hepatic interfaces. In disease, dysbiosis, barrier failure, altered bile acid pools, endogenous hepatotoxic metabolites, and aberrant immune-cell trafficking remodel the hepatic immune niche and drive steatohepatitis, alcohol-associated liver injury, cholangiopathy, cirrhosis, acute decompensation, and hepatocellular carcinoma. This review reframes the gut-liver axis as a gut-liver-immune axis and synthesizes current evidence on its structural basis, cellular architecture, molecular mediators, and disease-specific manifestations. We discuss the roles of macrophages, dendritic cells, neutrophils, innate-like T cells, natural killer cells, and adaptive T-cell subsets in translating gut-derived signals into hepatic inflammation, tissue repair, fibrosis, or tumor surveillance. We also highlight the bidirectional role of the liver in shaping intestinal immunity, particularly through bile acids and hepatobiliary-derived mediators. Finally, we examine current therapeutic strategies targeting the microbiota, mucosal barrier, bile acid signaling, and immune-cell trafficking, and we outline major conceptual and translational gaps that should guide the next generation of mechanistic and clinical studies.