Intestinal epithelial protection and gut microbiota modulation by Ganoderma lucidum proteoglycan are associated with its hypoglycemic potential in type 2 diabetes.

The interplay between gut microbiota, oxidative stress, and intestinal barrier integrity is increasingly recognized as a driving force in the progression of type 2 diabetes mellitus. This work focuses on FYGL, a novel proteoglycan derived from Ganoderma lucidum, to evaluate its intestinal safety and modulation of gut microbiota, and to explore the association of these effects with its hypoglycemic mechanism. In vitro, FYGL demonstrated excellent biocompatibility and alleviated oxidative damage and apoptosis in H₂O₂-induced intestinal epithelial cells (IEC-6) by modulating the MAPK/NF-κB/Nrf2 signaling pathway. Furthermore, it increased the expression of tight junction proteins (ZO-1, occludin, and claudin-1), thereby enhancing intestinal barrier integrity. In vivo, FYGL effectively reversed gut microbiota dysbiosis associated with glycolipid and antioxidant parameters, while maintaining the metabolic homeostasis of short-chain fatty acids in db/db diabetic mice. These findings reveal that FYGL can be both taken up by intestinal epithelial cells and utilized as a potential prebiotic through fermentation by gut microbiota, thereby alleviating diabetes-associated intestinal dysfunction. These dual actions provide critical evidence for its multi-target mechanism in ameliorating diabetes and its complications.