Polysaccharide from Artocarpus heterophyllus Lam. Pulp Ameliorates Cyclophosphamide-Induced Intestinal Damage by Regulating Gut Microbiota and Co-Metabolites

Background: Polysaccharides modulate host health by interacting with gut microbiota and reshaping the host–microbial metabolome, potentially facilitating immune regulation. Methods: This study evaluated the modulatory effect ofArtocarpus heterophyllusLam. (jackfruit) polysaccharide (JFP-Ps) against cyclophosphamide (Cy)-induced immunosuppression in mice, focusing on gut microbiota modulation and metabolite changes. Results: JFP-Ps effectively increased the beneficial bacteria ratio, such asLactobacillusandLachnospiraceae, while inhibiting some species likeAkkermansia. Metabolomic analysis showed that JFP-Ps notably regulated gut microbe-associated metabolites, including short-chain fatty acids (SCFAs), amino acids, bile acids, indoles, and derivatives. These metabolites were involved in various metabolic pathways, including primary bile acid synthesis and biosynthesis of phenylalanine, tyrosine, and tryptophan, along with tryptophan catabolism, purine metabolic processes, and unsaturated fatty acid production. Additionally, significant correlations between microbial groups and functional metabolites were identified. Overall, JFP-Ps exerted an immuno-modulatory effect by reshaping gut microbiota and enhancing co-metabolism with the host. Conclusions: These results provided valuable insights into host–microbiota interactions and gut microbiota-targeted intervention strategies of tropical natural bioactive polysaccharides.