Beneficial Effects of Celastrol on Immune Balance by Modulating Gut Microbiota in Experimental Ulcerative Colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by many factors including colonic inflammation and microbiota dysbiosis. Previous studies have indicated that celastrol (CSR) has strong anti-inflammatory and immune-inhibitory effects. Here, we investigated the effects of CSR on colonic inflammation and the mucosal immunity in an experimental colitis model, and addressed the mechanism by which CSR exerts the protective effects. We characterized the therapeutic effects and the potential mechanism of CSR in treating UC with histological staining, intestinal permeability assay, cytokine assay, flow cytometry, fecal microbiota transplantation (FMT), 16S rRNA sequencing, untargeted metabolomics, and cell differentiation. CSR administration significantly ameliorated dextran sodium sulfate (DSS)-induced colitis in mice, which was evidenced by the recovered body weight, colon length, and the decreased disease activity index (DAI) score, as well as intestinal permeability. Meanwhile, CSR down-regulated the secretion of pro-inflammatory cytokines, up-regulated the anti-inflammatory mediators at both mRNA and protein levels, and improved the balances of Treg/Th1 and Treg/Th17 to maintain the colonic immune homeostasis. It’s worth noting that all the therapeutic effects were exerted in a gut microbiota-dependent manner. Furthermore, CSR treatment increased the gut microbiota diversity and composition, and changed the metabolic productions, which was probably associated with the gut microbiota-mediated protective effects. In conclusion, this study provided the strong evidence that CSR may be a promising therapeutic drug for UC.