Polysaccharides derived from Aconitum carmichaelii Debx attenuate intestinal mucositis through anti-inflammatory activity and regulation of intestinal microbiota metabolism in mice

Abstract

Polysaccharides of Aconitum carmichaelii Debx (ACP) exhibited various pharmacological effects, including anti-inflammatory, immunomodulatory, anti-oxidative, and gut microbiota regulatory activities. This study aimed to evaluate the effect of ACP on 5-Fluorouracil (5-Fu)–induced intestinal mucositis (IM) and investigate its mechanisms of action. The anti-IM effect of ACP was investigated in C57BL/6 mice. Transcriptomics, western blot and enzyme-linked immunosorbent assay were used to detect its anti-inflammatory mechanism. 16sRNA sequencing, short-chain fatty acid analysis, fecal microbiota transplantation, and non-targeted metabolome detection were used to determine the impact of ACP on the metabolism of gut microbiota. The average molecular weight of ACP was 5.25 × 10³ Da, and ACP mainly comprised Arabinose, Galactose, Glucose, Galacturonic acid, and Mannuronic acid. ACP (25 and 50 mg/kg) significantly mitigated weight loss, colon shortening, and pathological injuries caused by 5-Fu treatment in mice. Moreover, ACP administration reduced the levels of inflammatory cytokines of IL-1β, TNF-α, and IL-6, within the colon, potentially through the inhibition of the NLRP3/NF-κB signaling pathway. Furthermore, changes in the abundance of several genera were closely associated with the efficacy of ACP in mitigating intestinal inflammatory responses. Meanwhile, ACP (50 mg/kg) significantly reversed the changes of acetic acid, hexanoic acid, and butyric acid levels in feces. Glycerophospholipid, purine, choline and glycerolipid metabolism pathways may contribute to the anti-IM effect of ACP. ACP may possess a potential to alleviate 5-Fu-related IM by modulating gut microbiota, regulating multiple metabolic pathways, and exerting anti-inflammatory effects.