Zhang Jun, Zhou Jing, He Zheyun, Xia Zhanyang, Liu Hongliang, Wu Yuan, Chen Si, Wu Boming, Li Hongshan
Liver Disease Department of Integrative Medicine, Ningbo No.2 Hospital, Ningbo, Zhejiang 315000, China; Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo, Zhejiang 315300, China.
Liver Disease Department of Integrative Medicine, Ningbo No.2 Hospital, Ningbo, Zhejiang 315000, China.
Int J Biol Macromol. 2025 May;307(Pt 4):142276. doi: 10.1016/j.ijbiomac.2025.142276. Epub 2025 Mar 19.
Nonalcoholic steatohepatitis (NASH) is a significant threat to human health. Our previous study revealed that salidroside attenuated NASH and regulated the gut microbiota. However, whether the therapeutic effect of salidroside depends on gut microbiota remains to be determined. Therefore, we conducted further experiments to elucidate the essential functions of gut microbiota-associated metabolic pathways in the anti-NASH effects of salidroside. Our results showed that salidroside effectively alleviated lipid accumulation and inflammatory injury in NASH mice. 16S rRNA sequencing revealed that salidroside increased the abundance of Bacteroides. Mice receiving fecal microbiota transplantation (FMT) from salidroside-treated also presented less hepatic steatosis and higher abundance of Bacteroides. Antibiotics eliminated the effects of salidroside on hepatic steatosis and the gut microbiota. Mechanistically, salidroside and FMT from salidroside-treated altered the bile acid (BA) profile by decreasing the levels of conjugated BAs and tauro-α/β-muricholic acid and activated downstream farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Furthermore, we found that inhibitors of bile salt hydrolase (BSH) and FXR/TGR5 abolished the effects of salidroside and reduced downstream carnitine palmitoyltransferase 1α and lipoprotein lipase expression. These data demonstrate that salidroside attenuated NASH via gut microbiota-BA-FXR/TGR5 signaling pathway and reveal the underlying mechanism of salidroside on NASH.
非酒精性脂肪性肝炎（NASH）对人类健康构成重大威胁。我们之前的研究表明，红景天苷可减轻NASH并调节肠道微生物群。然而，红景天苷的治疗效果是否依赖于肠道微生物群仍有待确定。因此，我们进行了进一步的实验，以阐明肠道微生物群相关代谢途径在红景天苷抗NASH作用中的重要功能。我们的结果表明，红景天苷有效减轻了NASH小鼠的脂质积累和炎症损伤。16S rRNA测序显示，红景天苷增加了拟杆菌的丰度。接受来自红景天苷治疗小鼠的粪便微生物群移植（FMT）的小鼠也表现出较少的肝脏脂肪变性和较高的拟杆菌丰度。抗生素消除了红景天苷对肝脏脂肪变性和肠道微生物群的影响。机制上，红景天苷和来自红景天苷治疗小鼠的FMT通过降低结合型胆汁酸和牛磺-α/β-鼠胆酸水平改变了胆汁酸（BA）谱，并激活了下游法尼酯X受体（FXR）和武田G蛋白偶联受体5（TGR5）。此外，我们发现胆汁盐水解酶（BSH）和FXR/TGR5抑制剂消除了红景天苷的作用，并降低了下游肉碱棕榈酰转移酶1α和脂蛋白脂肪酶的表达。这些数据表明，红景天苷通过肠道微生物群-BA-FXR/TGR5信号通路减轻NASH，并揭示了红景天苷对NASH的潜在作用机制。
