Abstract: This study aimed to explore the impact of cordycepin (COR) on colitis in mice and the underlying mechanism. C57BL/6J male mice were orally administered with COR at three different daily doses: H-COR (80 mg/kg), M-COR (40 mg/kg), and L-COR (20 mg/kg). H-COR treatment promoted the secretion of mucin 2 (MUC2) by colonic goblet cells, up-regulated the expression of zonula occludens-1 (ZO-1), inhibited epithelial cell apoptosis, and alleviated colitis, while M-COR and L-COR treatments showed no protective effects. Additionally, the activities of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were enhanced by H-COR. H-COR treatment suppressed the nuclear factor kappa B (NF-κB) pathway, regulating the levels of interleukin (IL)-1β, IL-10, and TNF-α, whereas M-COR and L-COR had no significant effects. Furthermore, H-COR improved intestinal microbiota dysbiosis induced by dextran sulfate sodium (DSS), increasing the relative abundance of Akkermansia and Bifidobacterium, while reducing that of Escherichia-Shigella and Parabacteroides. H-COR treatment also promoted the production of beneficial metabolites such as L-tryptophan and lisofylline, thereby modulating cytokines and ameliorating intestinal inflammation. In conclusion, COR supplementation modulates inflammatory cytokines and oxidative stress, maintains the integrity of the mucosal barrier, restores gut microbiota balance, and enhances the production of beneficial metabolites, ultimately alleviating colitis in a dose-dependent manner. These findings will help clarify the mechanism by which COR exerts health regulatory effects, providing a theoretical basis for the development of dietary supplements specifically targeting colitis.

Key words: cordycepin; colitis; gut microbiota