Polysaccharides from food and medicinal sources are promising candidates for nutritional interventions in chronic metabolic diseases. Because intact polysaccharides are generally poorly absorbed after oral administration, their systemic effects cannot be fully explained by conventional models of absorption and direct action on target organs. Increasing attention has therefore focused on their gastrointestinal fate and on how microbial utilization and gut-derived metabolites may influence host metabolism. This review examines how molecular weight, monosaccharide composition, glycosidic linkage type, branching, charge, and conformation affect resistance to upper gastrointestinal digestion, microbial recognition, and fermentation. It further evaluates the roles of short-chain fatty acids, bile acids, tryptophan-derived metabolites, and barrier-associated inflammatory signals in glucose homeostasis, lipid metabolism, and immune regulation. The strength of evidence varies substantially across these pathways. Short-chain fatty acid-related mechanisms and the gut-liver axis have relatively consistent preclinical support, whereas bile acid signaling and intestinal barrier pathways are supported by moderate mechanistic evidence. Tryptophan metabolite-mediated regulation and the gut-brain axis remain largely associative or preclinical, with limited validation in controlled human studies. These gut-derived processes may contribute to the regulation of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, insulin resistance, and cardiometabolic disorders. Future studies should establish causal links among defined glycan structures, selective microbial utilization, gut-derived mediators, and clinically relevant outcomes, while advancing standardized characterization, biomarker-guided evaluation, and carefully validated precision nutrition strategies.
