Orchestrating immunity and beyond: polysaccharides as multi-target regulators of inflammatory networks via gut microbiota and structure-dependent pathways.

Natural polysaccharides (NPs), as key bioactive constituents of many plants, have garnered significant attention due to their immunomodulatory properties and high safety profile. This review elucidates the molecular mechanisms underlying the immunomodulatory effects of NPs, their associated physiological outcomes, and the core structure-activity relationships. Mechanistically, NPs exert anti-inflammatory or immunostimulatory functions by modulating immune organ indices, activating or suppressing various immune cells (e.g., macrophages, dendritic cells, and NK cells), and regulating pivotal immune signaling pathways, including the TLR-NF-κB/MAPK, JAK-STAT, and cGAS-STING pathways. Notably, NPs can indirectly modulate systemic inflammation by remodeling gut microbiota composition and its metabolites (e.g., short-chain fatty acids and tryptophan derivatives). In terms of applications, leveraging these immunomodulatory properties, NPs demonstrate considerable potential in maintaining intestinal homeostasis, ameliorating neuroinflammation-related disorders, exerting anti-cancer effects, and alleviating allergic diseases. Furthermore, this review examines the structural determinants of NPs' immunomodulatory potency, including molecular weight, monosaccharide composition (with a focus on mannose, arabinogalactans, and uronic acids), chemical modifications (such as acetylation, phosphorylation, and sulfation), and degree of branching. Finally, the review outlines the shortcomings of current research and suggests future research directions, proposing that future studies should shift from "discovery and characterization" to "rational design and synthesis".