Salidroside protects mice from high-fat diet-induced obesity by modulating the gut microbiota

•SAL alleviated HFD-induced obesity in mice.•SAL treatment alleviated intestinal damage induced by HFD.•SAL restored the microbial community structure and diversity of gut microbiota.•Fecal transplantation (FM) from the SAL-treated mice significantly mitigate the symptoms of obesity mice. Obesity is a systemic disease with multisystem inflammation associated with gut dysbiosis. Salidroside (SAL) which is a major glycoside extracted from Rhodiola rosea L. has a wide range of pharmacological effects, but the role of gut microbiota in the protective effects of SAL on obesity has not been studied. Herein, we aim to explore whether SAL could ameliorate high-fat diet (HFD)-induced obesity in mice by modulating microbiota. Results showed that oral treatment with SAL alleviated HFD-induced obesity in mice as evidenced by body weight and fat weight. SAL supplementation effectively attenuated fat accumulation, lipid synthesis genes expression, liver inflammation, and metabolic endotoxemia. In addition, SAL treatment alleviated intestinal damage and increased the expression of mucin protein (Mucin-2) and tight junction (TJ) proteins (Occludin and Zonula Occludens-1). 16S rRNA sequencing analysis revealed that the gut microbiota of obese mice was also partly improved by SAL via restoring the microbial community structure and diversity. A fecal microbiota transplantation (FMT) study was designed to verify the causality. Compared with fecal transplantation (FM) from the HFD-treated mice, FM from the SAL-treated mice significantly mitigate the symptoms of obese mice, including decreasing body weight, fat accumulation, and attenuating pathological damage in the gut. Thus, SAL could be a remarkable candidate to prevent obesity.