Polysaccharide-driven gut microbial metabolism in neurodegenerative brain diseases: from SCFAs and tryptophan catabolites to neuroinflammatory regulation.

The gastrointestinal tract constitutes the principal anatomical interface of the microbiota-gut-brain axis (MGBA), orchestrating neuroimmune and metabolic crosstalk. Dysregulation within this network drives neurodegenerative pathogenesis through altered microbial metabolism, peripheral immune activation, and subsequent aggregation of pathological proteins in the central nervous system (CNS). Natural bioactive polysaccharides modulate this axis primarily via indirect, microbiota-dependent mechanisms-acting as fermentable prebiotics that reshape gut ecology and metabolite profiles-rather than through direct CNS penetration of intact macromolecules. These macromolecules promote neuroprotective short-chain fatty acids (SCFAs) that reinforce mucosal and blood-brain barrier (BBB) integrity. At the molecular level, polysaccharide interventions attenuate the TLR4/NF-κB/NLRP3 inflammatory cascade and upregulate Nrf2/BDNF neurotrophic signaling, effects predominantly mediated by microbiota-derived metabolites and peripheral-to-central signaling, with limited evidence for direct CNS entry of low-molecular-weight fractions. This review evaluates the pharmacological mechanisms of natural polysaccharides in neurodegenerative disorders, focusing on microbe-derived metabolic regulation, immune homeostasis, and clearance of neuropathological aggregates. While preclinical efficacy is promising, clinical translation demands rigorous structure-activity relationship mapping and specialized targeted delivery platforms.