Abstract:In this study，the model of Clostridioides difficile-associated colitis（C.difficile colitis）induced by cefoperazone was used to explore the preventive activity of fucoidan against C.difficile colitis related to antibiotics.The result showed that oral administration of 300 mg/kg fucoidan（weight-average molecular weight 126.65 kDa）for 10 d with simultaneous cefoperazone treatment could effectively alleviate diarrhea and colonic mucosal damage caused by C.difficile.The analysis of the gut microbiota community demonstrated that taking fucoidan orally could effectively inhibit the relative abundance of C.difficile and Enterococcus associated with colitis，increase the relative abundance of beneficial bacteria，such as Ruminococcus gauvreauii group and Blautia in the cecum，and reduce C.difficile toxin A （Tcd A）and B （Tcd B）.However，fucoidan treatment only had a limited effect on restoring the abundance and diversity of gut microbiota.Fucoidan could also reduce the infiltration of macrophages and neutrophils in the colon，down-regulate the gene expressions of proinflammatory factors，including tumour necrosis factor alpha（TNF-α），interferon gama（IFN-γ），interleukin 1 beta（IL-1β），and interleukin 6（IL-6），and up-regulate those of anti-inflammatory factors,namely interleukin 4 （IL-4）and interleukin 10 （IL-10）.In conclusion，fucoidan failed to restore the abundance and structure of gut microbiota，and its preventive activity against C.difficile colitis was related to inhibition on C.difficile infection or toxin production，anti-inflammation，and colonic mucosal protection.Therefore，fucoidan can be used for preventing C.difficile colitis induced by cefoperazone.