A review on the system-level bioactivity of polysaccharides along the structure-target-microbiome axis.

Polysaccharides are structurally diverse biological macromolecules whose functional properties extend beyond simple structure-activity relationships. This review synthesizes current literature on bioactive polysaccharides from fungal, plant, algal, marine, and microbial sources, spanning foundational studies to recent advances up to 2026, with emphasis on structural glycobiology, host-microbe interactions, and translational glycoscience. We propose the Structure-Target-Microbiome (STM) axis as a mechanistic framework in which polysaccharide bioactivity arises from the integrated interplay of molecular architecture, host receptor engagement, and microbiome-mediated biotransformation. Unlike conventional structure-activity models that correlate individual structural features with single endpoints, the STM axis integrates structural determinants (monosaccharide composition, glycosidic linkages, branching, molecular weight, and chemical modifications), microbial carbohydrate-active enzymes, metabolite production, and host physiological responses into a systems-level perspective. Accumulating evidence indicates that major polysaccharide classes, including β-glucans, pectins, hemicelluloses, arabinogalactans, sulfated marine polysaccharides, and microbial exopolysaccharides, exert biological effects through both direct host signaling and microbiota-dependent metabolic conversion. However, the literature also reveals substantial inconsistency, with many polysaccharides showing weak, absent, or context-dependent activity influenced by structural heterogeneity, purity, dosage, microbial composition, and experimental variability. Limited fermentability and inter-individual microbiome differences further contribute to divergent outcomes across experimental models. Current limitations include incomplete structural characterization, batch-to-batch variability, contamination in crude extracts, and poor reproducibility across in vitro and in vivo systems, all of which restrict translational confidence. Overall, polysaccharide bioactivity is best understood as an emergent property of structure-host-microbiome interactions rather than molecular structure alone. Future advances require standardized structural annotation, harmonized experimental protocols, microbiome-informed study design, and clinical validation to enable predictive and translational applications in functional foods and biomedicine.