Epimedium polysaccharides ameliorate ulcerative colitis by inhibiting oxidative stress and regulating autophagy

Abstract BACKGROUND Epimedium polysaccharide (EPS) is a bioactive compound derived from the traditional Chinese herb Epimedium brevicornum . The objective of this study was to investigate the protective effects of EPS on ulcerative colitis (UC) and to elucidate the underlying mechanisms involved. RESULTS The findings showed that EPS treatment mitigated UC symptoms, including weight loss, anal bleeding, elevated disease activity index (DAI), and colon shortening. Hematoxylin and eosin (H&E) and Alcian blue–periodic acid–Schiff (AB‐PAS) staining demonstrated that EPS alleviated histopathological damage and improved the integrity of the colonic mucosa. Mechanistically, EPS was found to substantially decrease inflammation by inhibiting the Toll‐like receptor 4/nuclear factor‐κB (TLR4/NF‐κB) signaling pathway and to alleviate oxidative stress through modulation of the Kelch‐like ECH‐associated protein 1/nuclear factor erythroid‐derived 2‐like 2 (Keap1/Nrf2) pathway. Notably, EPS failed to exert protective effects against dextran sulfate sodium (DSS)‐induced UC in Nrf2‐knockout (Nrf2 −/− ) mice. Additionally, Western blotting and immunohistochemical analysis demonstrated that EPS facilitated autophagy via the adenosine monophosphate‐dependent protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway. In vitro experiments revealed that EPS effectively suppressed lipopolysaccharide (LPS)‐mediated cellular damage and oxidative stress by regulating Keap1/Nrf2 pathway. Transcriptomic analysis of LPS‐treated Caco‐2 cells following EPS treatment revealed a significant up‐regulation of Nrf2 expression. CONCLUSION In conclusion, the findings of this study suggest that EPS exerts protective effects against DSS‐induced UC through the inhibition of the TLR4/NF‐κB signaling pathway, regulation of the Keap1/Nrf2 pathway, and promotion of autophagy via the AMPK/mTOR pathway. Consequently, EPS may represent a potential therapeutic target for the treatment of UC. © 2024 Society of Chemical Industry.