Polygonatum cyrtonema polysaccharides (PCP) exhibit ameliorative effects on colitis. However, whether the protective effects of PCP depend on the gut microbiota and how PCP regulates intestinal immune responses to alleviate colitis remain unclear. Therefore, this study investigated the effect of PCP against colitis focusing on the regulation of intestinal immune response. The PCP structure was reclassified as fructan. PCP treatment significantly reduced the symptoms of colitis. PCP restored IgA, ZO-1, Occludin, and MUC2 expression to enhance intestinal barrier function. Oral PCP administration markedly inhibited excessive inflammation-mediated immune response by modulating inflammatory cytokines secretion and Th17/Tregs cell balance and restored gut microbial composition. Interestingly, PCP still had a significant ameliorating effect on intestinal inflammation in colitis mice with gut microbial depletion by antibiotics. In the Caco-2/RAW264.7 co-culture inflammation model, PCP treatment improved the intestinal epithelial barrier function by regulating the inflammatory immune response through signal transduction pathways. Overall, these findings suggested that the alleviating effects of PCP on colitis are independent of gut microbiota, and that PCP can directly modulate the inflammatory immune response and intestinal barrier function, which in turn regulates gut microbiota. These findings will provide new insights into the action mechanism of natural polysaccharides in relieving colitis.
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