Abstract

Exopolysaccharides (EPS) produced by endophytic fungi isolated from Cyclocarya paliurus have been reported to exhibit immunostimulatory activity in vitro ; however, its in vivo immunoregulatory effects remain unclear. The study aimed to investigate its protective effects and mechanisms against cyclophosphamide (CTX)-induced immunosuppression and intestinal injury in mice. EPS treatment mitigated body weight loss, thymic atrophy, and splenomegaly, while promoting intestinal repair by modulating cytokine secretion, T cell, goblet cell, MUC2, and tight junction proteins through activation of the Nrf2/HO-1 signaling pathway. Furthermore, gut microbiota and metabolomic analyses revealed that EPS ameliorated CTX-induced dysbiosis, corrected microbial translocation and niche imbalance, and restored lipid, bile acid, and amino acid metabolism. Collectively, these findings indicate that Penicillium -derived EPS can alleviate immunosuppression and intestinal injury by regulating gut microbiota composition, restoring intestinal barrier integrity, and re-establishing metabolic homeostasis. This study provides theoretical support for the potential application of fungal polysaccharides as immunomodulatory agents and functional food ingredients.