A review on molecular crosstalk: Bioactive polysaccharides and gut microbiota in type 2 diabetes-Pathways, signaling, and therapeutic translation.

Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder characterized by insulin resistance, impaired glucose homeostasis, and low-grade inflammation, in which gut microbiota dysbiosis plays a pivotal role in disease progression. Natural bioactive polysaccharides (NBPs) from diverse sources have emerged as effective microbiota-targeted agents with antidiabetic potential. After colonic fermentation, NBPs are metabolized into key microbial products, including short-chain fatty acids (SCFAs), indole derivatives, and secondary bile acids (SBAs), which reshape microbial ecological composition and host metabolic signaling. This review summarizes NBPs sources, structural characteristics, and antidiabetic activities, emphasizing how monosaccharide composition, molecular weight, solubility, degree of branching, and glycosidic linkages determine fermentability and microbial diversity. Motifs such as β-(1 → 3)/(1 → 4) linkages in β-glucans and β-(1 → 4)-mannan backbones with α-(1 → 6)-galactose substitutions in galactomannans promote selective utilization by polysaccharide-degrading taxa (e.g., Bacteroides and Bifidobacterium), enriching butyrate producing genera including Faecalibacterium and Lactobacillus. NBPs also improve intestinal barrier integrity by maintaining tight junction proteins (Occludin & ZO-1) and reducing lipopolysaccharide (LPS) translocation, thereby alleviating endotoxemia. In parallel, SCFA and SBAs modulate glycemic control via GPR41/43, FXR and TGR5 signaling, promoting glucagon-like peptide-1 (GLP-1) secretion and enhancing insulin sensitivity. Integrating multi-omics profiling with AI-driven predictive modeling may further decode polysaccharide structure-microbiota-metabolite interaction and enable precision NBP-based strategies for optimized glycemic control in T2D. Overall, this review provides a mechanistic and translational framework of advance structure-guide development of microbiota targeted polysaccharides for the management of T2D.