The antiobesity effect of celastrol has been reported in numerous studies, but the underlying mechanism remains unclear. It is widely accepted that gut dysbiosis is closely related to obesity. The potential effect of celastrol on microbiota is worth exploring. In this study, the celastrol-induced weight loss was validated in high-fat diet (HFD)-induced obese mice, with the detection of reported phenotypes including a reduction in food intake, augments in dyslipidemia and glucose metabolism, and adipose thermogenesis. The anti-inflammatory effect of celastrol was also proved based on the alterations in serum cytokines. Antibiotic interference showed that gut microbiota contributes to celastrol-induced weight loss. Several key bacteria were identified using shotgun metagenomic sequencing to display the alterations of the intestinal microbiome in obese mice treated with celastrol. Meanwhile, the fecal and serum metabolic profiles were generated by pseudotargeted metabolomics, and changes in some critical metabolites related to appetite and metabolism were detected. Importantly, we applied in silico bidirectional mediation analysis to identify the precise connections among the alterations in gut microbes, serum metabolome, and host phenotypes induced by celastrol treatment for the first time. Therefore, we concluded that the celastrol-induced microbial changes partially contribute to the antiobesity effect via the serum metabolome. The mass spectrometry data are deposited on MetaboLights (ID: MTBLS3278).
Keywords: antiobesity; celastrol; gut microbiota; mediation analysis; metabolome.