Lipid-derived microbial metabolites at the gut-liver interface: regulation of intestinal barrier function, immune signaling, and metabolic inflammation

Lipid-derived and lipid-related microbial metabolites form a functional interface between the gut microbiota, intestinal barrier integrity, mucosal immunity, hepatic metabolism, and systemic immunometabolic homeostasis. At the gut-liver axis, these molecules should not be regarded as passive end-products of microbial metabolism, but as compartment-sensitive signals whose biological effects depend on site of production, mucosal exposure, epithelial utilization, portal delivery, hepatic handling, receptor distribution, and inflammatory context. This narrative review examines five major metabolite classes: short-chain fatty acids, including branched-chain fatty acids; microbially transformed bile acids; bacterial sphingolipids; PUFA-derived or microbially modulated lipid mediators; and choline-, carnitine-, and phospholipid-derived co-metabolites such as trimethylamine N-oxide. We discuss how these pathways regulate tight-junction architecture, epithelial energy metabolism, mucus-associated defense, antimicrobial programs, innate and adaptive immune-cell signaling, bile-acid receptor networks, and portal inflammatory exposure. The evidence is most mature for classical short-chain fatty acids and bile-acid signaling, emerging but mechanistically compelling for bacterial sphingolipids and PUFA-derived mediators, context-dependent for TMAO, and still limited for aging-specific and sarcopenia-related extrapolations. Across classes, translation is constrained by incomplete causal inference, preclinical predominance, heterogeneous human evidence, inconsistent metabolomic and lipidomic standardization, and the non-equivalence of fecal concentrations, mucosal exposure, portal delivery, and systemic availability. Future studies should move beyond single-metabolite associations toward longitudinal, multi-compartment, mechanism-informed models integrating targeted metabolomics/lipidomics, permeability markers, immune phenotyping, liver and cardiometabolic endpoints, and functional outcomes relevant to frailty and sarcopenia.