Glycosylation of oyster peptides generates supramolecular assembly of glycopeptides to relieve DSS-induced colitis.

The incidence of colitis is increasing annually, however, effective treatment options remain limited. Oyster peptides are a food source that has shown promising nutritional strategy for colitis alleviation. However, their clinical translation is hindered by poor stability and rapid in vivo metabolism. To address these limitations, we employed glycosylation modification to enhance the stability and functional properties of oyster peptides. Using a Maillard reaction-driven supramolecular assembly approach, we synthesized glycopeptides with a glycosylation degree of 42.5%. In a murine model of dextran sulfate sodium (DSS)-induced colitis, the glycosylated oyster peptides (GOP) demonstrated significantly superior efficacy compared to their native counterparts. Treatment resulted in marked alleviation of disease symptoms, including reduced fecal bleeding and inflammation, attenuated colonic shortening, and preserving epithelial integrity. Metabolomic profiling revealed that oyster peptides significantly influenced amino acid metabolism, particularly pathways involving arginine/proline/glycine, and glutathione pathways. GOP ameliorate colitis by reprogramming amino acid metabolism, notably through glycine/serine/threonine and arginine/proline pathways, enhancing post-translational modifications, and modulating proline/aromatic-rich di- and tripeptides. These findings provide a foundation for developing glycopeptide-based interventions targeting metabolic reprogramming and mucosal healing in colitis.