Biochemically Active Metabolites of Gut Bacteria: Their Influence on Host Metabolism, Neurotransmission, and Immunity

The human gastrointestinal microbiota has emerged as a critical determinant of systemic health, functioning as a metabolically dynamic organ that produces a vast repertoire of bioactive compounds. This review presents a comprehensive synthesis of current insights into the role of gut microbiota-derived metabolites in regulating host metabolism, neurotransmission, and immune responses. Key microbial metabolites, such as Short-Chain Fatty Acids (SCFAs), secondary bile acids, Branched-Chain Amino Acids (BCAAs), tryptophan catabolites, and polyamines, modulate host physiology through diverse mechanisms including receptor-mediated signaling, epigenetic regulation, and neuroimmune interactions. The SCFAs influence metabolic homeostasis via G-protein-coupled receptors and histone deacetylase inhibition, while microbial transformation of bile acids affects lipid metabolism and endocrine signaling through FXR and TGR5 pathways. Additionally, gut microbes generate neuroactive molecules such as GABA, serotonin, and dopamine precursors that engage the gut-brain axis and impact cognitive and emotional states. Tryptophan metabolism along the kynurenine and indole pathways further connects microbial activity to neuroinflammation and immune tolerance via Aryl Hydrocarbon Receptor (AhR) and NMDA receptor modulation. Microbial-derived metabolites also shape mucosal and systemic immunity by promoting regulatory T-cell differentiation, modulating cytokine production, and activating pattern recognition receptors (PRRs) such as Toll-like and NOD-like receptors. Finally, parallels between gut-derived metabolic modulators and plant-based nanoparticle therapeutics highlight emerging translational avenues for microbial-mimetic interventions. By elucidating the biochemical networks underpinning host-microbe interactions, this review underscores the potential for microbiota-targeted strategies in the treatment of metabolic, neuropsychiatric, and inflammatory disorders.