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Outline
Salidroside (SAL), a principal active constituent of the medicinal plant Rhodiola crenulata, exerts diverse pharmacological activities including antioxidation, anti-inflammation, and anti-aging. However, its protective efficacy against liver injury and the underlying molecular mechanisms remain incompletely elucidated. The low oral bioavailability of SAL implies potential interactions with the gut microbiota. Therefore, this study focused on the metabolic transformation of SAL mediated by the gut microbiota. The results demonstrated that SAL is metabolized to tyrosol (TYR) in the gut microbiota. Virtual molecular docking and pure enzyme metabolic experiments further validated the critical role of β-glucosidase (β-G) in this transformation process. In vitro cellular experiments have demonstrated that SAL and its primary metabolite TYR exert a synergistic hepatoprotective effect. Based on network pharmacology screening, hub targets including NF-κB1, ESR1, BCL2, MMP9, and TLR4 were revealed. Furthermore, SAL intervention significantly increased the levels of short-chain fatty acids (SCFAs) by the gut microbiota in an in vitro culture system. Untargeted metabolomics analysis suggested that SAL may reshape the metabolic profile of the gut microbiota by modulating pathways including the urea cycle and tryptophan metabolism. This study provides a novel perspective for a deeper understanding of the hepatoprotective mechanism of SAL and offers valuable scientific evidence for future clinical translational research on natural medicines. The experimental protocol was approved by the Laboratory's Institutional Animal Care and Use Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College (Approval No.: 00009927).
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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