<p>Inflammatory bowel disease (IBD) has become a global health problem. The breakdown of intestinal barrier and the imbalance of intestinal flora are key factors affecting the occurrence and development of IBD, and are also important targets for prevention and treatment. The preventive effect of Dendrobium chrysotoxum polysaccharide (DCP) on IBD was studied. A mouse model of IBD was constructed using Dexosan Sodium Sulfate (DSS) and pretreated with DCP. qPCR and Western Blotting were used to detect the expression of tight junction protein and anti-inflammatory cytokines at mRNA and protein levels. The composition and distribution of intestinal flora and the content of short-chain fatty acids (SCFAs) in each group were observed. The results showed that except the control group, the expression of claudin-2, occludin and ZO-1 in colon tissue of mice in all groups decreased significantly, indicating the impairment of intestinal barrier function. However, DCP restored the integrity of the intestinal mucosa by upregulating the expression of these tight-linking proteins. In addition, the expression of IL-10 in the model group was significantly down-regulated, and after DCP intervention, the expression level was significantly increased. It is suggested that DCP may prevent IBD in mice by protecting intestinal barrier and exerting anti-inflammatory activity. In addition, DCP can regulate the species composition and distribution of intestinal flora in mice, reverse the relative abundance changes of <i>Escherichia coli </i>and <i>Lactobacillus</i> in IBD mice, and increase the production of acetic acid, propionic acid, butyric acid, valeric acid and isobutyric acid in IBD mice. In general, the newly extracted DCP polysaccharide has a good effect on improving intestinal barrier dysfunction, and is an ideal natural medicine for the treatment of IBD.</p>