Combined metabolomics and gut microbiota analysis reveals the protective effects of α-monoglucosyl rutin against cyclophosphamide-induced intestinal injury.

α-Monoglucosyl rutin (α-GR) is a structurally optimized rutin derivative, and its higher water solubility and bioavailability may help it exert better pharmacological effects in vivo. The present study examined the protective effects and potential mechanisms of α-GR on cyclophosphamide (CTX)-induced colonic injury in mice. The findings showed that α-GR significantly reduced serum levels of lipopolysaccharide (LPS) and diamine oxidase (DAO), effectively alleviating the histopathological damage in colon tissues caused by CTX exposure. Additionally, α-GR maintained the integrity of intestinal epithelial cells by promoting the secretion of secretory immunoglobulin A (sIgA) and upregulating the expression of tight junction proteins (Claudin-1 and ZO-1), while also reducing the levels of colonic pro-inflammatory factors and oxidative stress. In terms of gut microbiota, 16S rRNA gene sequencing and metabolomic analyses revealed that α-GR could effectively reverse the gut metabolic disorders and microbiota structural changes induced by CTX, promoted the growth of beneficial bacteria like norank_f_Muribaculaceae, Bacteroides, and Alloprevotella, and reduced the relative abundance of pathogenic bacteria (Desulfovibrio), while also revealing the complex correlation between them. In terms of mechanism research, α-GR further attenuated intestinal damage by regulating the TLR4/NF-κB and Nrf2/HO-1 pathways. This provides new ideas for the development of functional dietary supplements to treat CTX-associated intestinal toxicity.