Mechanisms and therapeutic advances of gut metabolites in the regulation of neuroimmune inflammatory diseases.

Gut-derived metabolites function as critical signaling intermediaries that translate environmental cues into central nervous system (CNS) responses, playing an indispensable role in the pathogenesis and trajectory of neuroimmune inflammatory disorders. Key metabolites, including short-chain fatty acids (SCFAs) and bile acids, either traverse the blood-brain barrier directly or orchestrate immune modulation peripherally, thereby fine-tuning the dynamic crosstalk between systemic immunity and neural homeostasis. SCFAs exert potent anti-inflammatory effects by promoting regulatory T-cell (Treg) differentiation through activation of G protein-coupled receptors (GPCRs) on immune cells and inhibition of histone deacetylases (HDACs). Within the CNS, they further confer neuroprotection by suppressing the pro-inflammatory activation of microglia and astrocytes. In contrast, bile acids display a context-dependent, "double-edged sword" effect: while certain subtypes activate the anti-inflammatory TGR5 receptor, neurotoxic metabolites (e.g., taurolithocholic acid) can accumulate and directly provoke pro-inflammatory polarization of microglia, thereby fueling neuroinflammation. Dysbiosis of the gut microbiota and consequent metabolite profile alterations are strongly implicated in neuroimmune inflammatory diseases-such as multiple sclerosis (MS), Alzheimer's disease (AD), and neuromyelitis optica spectrum disorders (NMOSD) -which are characterized by both a distinct metabolite imbalance and a pervasive pro-inflammatory immune milieu. Building on this framework, novel therapeutic strategies targeting the "gut-immune-brain axis" are evolving along two complementary avenues: (1) Immune-centric approaches that directly modulate neuroimmune pathways (e.g., by tempering microglial activation or expanding Treg populations); and (2) Microbiota-centric interventions that employ specific probiotics, prebiotics, or metabolite supplements to restore gut ecological balance, systemically recalibrate immunity, and mitigate neuroinflammation. Future research must prioritize elucidating the precise molecular dialogues between metabolites and immune cell subsets, conducting large-scale clinical validation, and advancing personalized, precision-medicine strategies. Such efforts will solidify a novel systemic perspective and strategic paradigm for preventing and treating neuroimmune inflammatory diseases.