Beneficial Effects of Celastrol on Immune Balance by Modulating Gut Microbiota in Dextran Sodium Sulfate-Induced Ulcerative Colitis

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by multi-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 preforms the protective effect. We characterized the therapeutic effects and the potential mechanism of CSR in treating UC using histological staining, intestinal permeability assay, cytokine assay, flow cytometry, fecal microbiota transplantation (FMT), 16S rRNA sequencing, untargeted metabolomics, and cell differentiation approaches. CSR administration significantly ameliorated DSS-induced colitis, as evidenced by the recovery of body weight and colon length, decreased disease activity index (DAI) score, as well as decreased intestinal permeability. CSR down-regulated the secretion of proinflammatory cytokines, upregulated the anti-inflammatory mediators, and improved the balances of Treg/Th1 and Treg/Th17 to maintain colonic immune homeostasis. However, the protective effects of CSR disappeared when the antibiotic cocktail was applied to deplete the gut microbiota, and the gut microbiota-mediated effect was confirmed by FMT. Furthermore, CSR treatment increased the gut microbiota diversity and composition, and raised the metabolic productions of pyruvate and adenosine, which probably involve in gut microbiota mediated protective effect. In conclusion, CSR ameliorates colonic inflammation in a gut microbiota-dependent manner. The underlying protective mechanism is associated with the rectified Treg/Th1 and Treg/Th17 balance, and increased pyruvate and adenosine production. The study provided the solid evidence that CSR might be a promising therapeutic drug for UC.

Shifts and importance of viable bacteria in treatment of DSS-induced ulcerative colitis mice with FMT

“…Lima et al identified the speices Odoribacter splanchnicus, which plays a key role in FMT, by performing the immune response use omic analysis in donor and recipient fecal samples (pre-and post-intervention), Further through mouse experiments, they proved that Odoribacter splanchnicus is the key bacterium (Lima et al, 2021). Similarly, Li et al treated a mouse model of DSS-induced colitis with FMT in combination with a 16S rRNA analysis, revealing that FMT ultimately alleviates colitis by regulating the flora (Li et al, 2021a). Generally, in all of these analyses, the changes in metagenome-based strategy include 16S rRNA sequencing of total bacteria DNA were observed, while changes in the live bacteria DNA were neglected.…”

“…Similarly, Li et al. treated a mouse model of DSS-induced colitis with FMT in combination with a 16S rRNA analysis, revealing that FMT ultimately alleviates colitis by regulating the flora ( Li et al., 2021a ). Generally, in all of these analyses, the changes in metagenome-based strategy include 16S rRNA sequencing of total bacteria DNA were observed, while changes in the live bacteria DNA were neglected.…”