Molecular Mechanisms of Gut Microbiota-Immune System Crosstalk: From Mucosal Architecture to Adaptive Immunity Programming.

The mammalian gut microbiome functions as a metabolically active immunological organ and has co-evolved with its host to maintain systemic homeostasis. This review integrates current evidence on the molecular mechanisms governing bidirectional microbiota-immune communication, emphasizing evolutionary conservation, receptor-mediated signaling, and translational implications. Microbial structural ligands and metabolites-including short-chain fatty acids, bile-acid derivatives, and tryptophan catabolites-engage host receptors such as G-protein-coupled receptors, FXR/TGR5, and the aryl hydrocarbon receptor (AhR), thereby regulating epithelial barrier integrity, regulatory T-cell differentiation, Th17 polarization, mucosal IgA production, and systemic immune tone. Riboflavin-derived metabolites presented via major histocompatibility complex class-I-related molecule (MR1) further shape mucosal-associated invariant T-cell development (MAIT), illustrating metabolite-driven immune system programming. Dysbiosis induced by antibiotics, dietary perturbation, or aging disrupts these molecular networks, promoting chronic inflammatory, metabolic, autoimmune, and neuroimmune disorders. Comparative analyses across mammalian systems underscore conserved pathways of host-microbe coadaptation and immune education. Therapeutically, microbiota-modulating strategies-including probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), postbiotics, and IgY-based passive immunotherapy-aim to restore immunometabolic signaling. Emerging in vitro and in silico platforms further provide mechanistic precision while supporting ethically aligned translational research. Collectively, these insights position microbiota-derived molecular signaling as a central determinant of adaptive immune architecture and a targetable axis in precision immunotherapy.