Natural polysaccharides as immunometabolic modulators in metabolic diseases: mechanisms and translational challenges

Metabolic disorders, especially obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated steatotic liver disease, are becoming increasingly prevalent and have imposed a growing burden on public health systems. These diseases are commonly associated with insulin resistance and abnormal lipid metabolism, and increasing evidence indicates that immune imbalance and chronic low-grade inflammation are involved in their development. Natural polysaccharides are important bioactive components derived from plants, fungi, algae, and other natural sources. Current evidence supporting their beneficial effects in metabolic diseases is predominantly preclinical, mainly from cell-based and animal studies, while clinical evidence remains limited and heterogeneous. Natural polysaccharides have attracted interest as candidate bioactive compounds because some preparations have shown immunomodulatory and metabolic regulatory activities in experimental models. Their activities are closely related to structural features, including monosaccharide composition, glycosidic linkage types, molecular weight, branching structure, and chemical modification. Current preclinical evidence suggests that natural polysaccharides may alleviate metabolic inflammation by regulating macrophage polarization, suppressing pro-inflammatory cytokine production, modulating MAPK, NF-κB, AMPK, and related signaling pathways, and reshaping the gut microbiota-immune axis. These compounds may help improve several pathological features of metabolic disorders, such as insulin resistance, abnormal lipid metabolism, inflammatory injury, and tissue dysfunction. However, several challenges still limit their translation, including unclear structure-activity relationships, inconsistent preparation standards, limited bioavailability, and insufficient well-designed clinical trials. Therefore, this review provides an overview of the natural sources, structural properties, immunomodulatory actions, and therapeutic prospects of natural polysaccharides in metabolic diseases, with a focus on their involvement in immune regulation and metabolic inflammation.