Yan Wang, Yongxuan Zhang, Shiqi Yue, Menglu Liu, Kexin Li, Jinhan Wu, Junlong Wang, Minghui Xiu, Jianzheng He
Intestinal mucositis is one of the most debilitating side effects of chemotherapeutic agents. Angelica sinensis polysaccharide (ASP), the crucial active ingredient of Angelica sinensis, has been reported to possess anti-colitis activity. However, the efficacy of ASP against chemotherapy-induced intestinal mucositis (CIM) remain to be clarified. The aim of this study using Drosophila melanogaster and mouse models was to investigate the potential effect of ASP on intestinal mucositis and its underlying mechanism. ASP significantly alleviated overall physiological and intestinal damage caused by CPT-11 in adult flies, including increased survival rate and intestinal length, improved digestive capacity, restored intestinal acid-base balance and reduced death of intestinal epithelial cells. NIR imaging indicated that ASP was absorbed through the intestine and metabolized via the hepatic and renal systems in mice. Furthermore, ASP reduced intestinal damage and restored the intestinal barrier function in CPT-11 treated mice, including increased intestinal length, elevated levels of ZO-1 and an increased number of goblet cells. Mechanistically, ASP markedly down-regulated the over-activated innate immunity by inhibiting the Toll-IMD and TLR4/NF-κB/MyD88 signaling pathways in CPT-11 induced flies and mice. Besides, ASP also exerted a protective effect against structural damage to the spleen induced by CPT-11. Moreover, ASP ameliorated gut microbiota imbalances and increased the levels of short-chain fatty acids (SCFAs), particularly propionate and butyrate. Fecal microbiota transplantation (FMT) further confirmed that ASP could modulate gut microbiota and protect against intestinal mucositis in mice. Collectively, these results demonstrate that ASP effectively ameliorates CIM and has the potential to serve as a novel adjunctive therapy to CPT-11.