Abstract

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.