Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, 100069, Beijing, China.
Department of Pharmacy, Beijing Children's hospital, Capital Medical University, National Center for Children Health, Beijing, 100045, China.
J Ethnopharmacol. 2022 Aug 10;294:115333. doi: 10.1016/j.jep.2022.115333. Epub 2022 Apr 29.
Penthorum chinense Pursh. (PCP) is commonly used as a Miao ethnomedicine and health food for liver protection in China. Gansukeli (WS3-B-2526-97) is made from the extract of PCP (PCPE) for the treatment of viral hepatitis. In recent years, PCPE has been reported in the treatment of non-alcoholic fatty liver disease (NAFLD), however its potential mechanism is not fully elucidated.
To investigate the ameliorating effect of PCPE on high-fat diet (HFD)-induced NAFLD mice and demonstrate whether its protective effect is gut microbiota dependent and associated with bile acid (BA) metabolism.
The alleviating effect of PCPE on NAFLD was conducted on male C57BL/6J mice fed an HFD for 16 weeks, and this effect associated with gut microbiota dependent was demonstrated by pseudo-germfree mice treated with antibiotics and fecal microbiota transplantation (FMT). The composition of the gut microbiota in the cecum contents was analyzed by 16S rRNA sequencing, and the levels of BAs in liver and fecal samples were determined by UPLC/MS-MS.
The results showed that administration of PCPE for 8 weeks could potently ameliorate HFD-induced NAFLD and alleviate dyslipidemia and insulin resistance. Moreover, PCPE treatment alleviated gut dysbiosis, especially reducing the relative abundance of bile salt hydrolase (BSH)-producing bacteria. Furthermore, PCPE significantly increased the levels of taurine-conjugated BAs in feces, such as tauro-β-muricholic acid (T-βMCA), tauroursodesoxycholic acid (TUDCA), and taurochenodeoxycholic acid (TCDCA), and increased hepatic chenodeoxycholic acid (CDCA). The protein and mRNA expression of farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15) were decreased in intestine, increased taurine-conjugated BAs inhibited the intestinal signaling pathway, which was associated with increased genes expression of enzymes in the alternative BA synthesis pathway that reduced the levels of cholesterol. The increased CDCA produced via the alternative BA synthesis pathway promoted hepatic FXR activation and BA excretion.
Our study is the first time to demonstrate that PCPE could ameliorate NAFLD in HFD-induced mice by regulating the gut microbiota and BA metabolism, and from a novel perspective, to clarify the mechanism of PCPE in NAFLD.
在中国，贯叶连翘（Penthorum chinense Pursh.）常被用作苗族民族医学和护肝保健品。肝苏颗粒（WS3-B-2526-97）是从贯叶连翘提取物（PCPE）中提取的，用于治疗病毒性肝炎。近年来，PCPE 已被报道可用于治疗非酒精性脂肪性肝病（NAFLD），但其潜在机制尚未完全阐明。
研究 PCPE 对高脂肪饮食（HFD）诱导的 NAFLD 小鼠的改善作用，并证实其保护作用是否依赖于肠道微生物群及其与胆汁酸（BA）代谢的关系。
采用雄性 C57BL/6J 小鼠进行实验，给予 HFD 喂养 16 周，以评估 PCPE 对 NAFLD 的改善作用。通过给予抗生素和粪便微生物移植（FMT）处理的拟无菌小鼠，证实了 PCPE 对肠道微生物群的改善作用。采用 16S rRNA 测序分析盲肠内容物中的肠道微生物群组成，采用 UPLC/MS-MS 测定肝和粪便样本中的 BA 水平。
结果表明，PCPE 给药 8 周可有效改善 HFD 诱导的 NAFLD，并改善血脂异常和胰岛素抵抗。此外，PCPE 治疗可改善肠道菌群失调，特别是降低胆盐水解酶（BSH）产生菌的相对丰度。此外，PCPE 显著增加了粪便中牛磺酸结合型 BA 的水平，如牛磺-β-熊去氧胆酸（T-βMCA）、牛磺熊脱氧胆酸（TUDCA）和牛磺鹅去氧胆酸（TCDCA），并增加了肝脱氧胆酸（CDCA）的水平。FXR 和成纤维细胞生长因子 15（FGF15）在肠道中的蛋白和 mRNA 表达降低，牛磺酸结合型 BA 增加抑制了肠道信号通路，这与替代 BA 合成途径中酶的基因表达增加有关，从而降低了胆固醇水平。替代 BA 合成途径增加的 CDCA 促进了肝脏 FXR 激活和 BA 排泄。
本研究首次证明，PCPE 通过调节肠道微生物群和 BA 代谢可改善 HFD 诱导的 NAFLD 小鼠的病情，从新的角度阐明了 PCPE 在 NAFLD 中的作用机制。
