基于肠道菌群-胆汁酸-肠FXR轴研究贯叶连翘调节更年期脂代谢紊乱的作用机制

Menopausal dyslipidemia is a disorder of lipid metabolism caused by estrogen deficiency. Recent studies have found that estrogen deficiency can change the composition of gut microbiota and metabolism of bile acid, which was thought the important reason of causing dyslipidemia. Thus, maintaining the steady state of gut microbiota-bile acid axis will be a new strategy to curve menopausal dyslipidemia. Previous studies have found that Hyperforin perforatum L. (HP) can regulate menopausal dyslipidemia, significantly reducing the serum lipid level and liver lipid deposition in ovariectomized (OVX) rat, and restoring the composition of gut microbiota and increasing bile acid synthesis and CYP7A1 expression in the liver. Based on this, the hypothesis was proposed that HP might regulate menopausal dyslipidemia disorder by regulating the composition of gut microbiota, changing the metabolism profile of bile acid in gut-liver axis, further reducing the negative feedback regulation of intestinal FXR-FGF19/15 pathway on liver CYP7A1, and increasing bile acid synthesis in the liver. This project will take the gut microbiota-bile acid-intestinal FXR axis as the target, elucidate the molecular mechanism of HP regulating menopausal lipid metabolism disorder in vitro and in vivo, using the research method of gut microbiota and the technologies including targeted metabonomics, fecal transplant and molecular biology. This project will provide scientific basis for the clinical application of HP.

更年期脂代谢紊乱是由雌激素缺乏导致的机体脂代谢异常。近年来发现雌激素缺乏可使宿主肠道菌群组成和胆汁酸代谢发生变化，是导致脂代谢紊乱的重要原因，维持肠道菌群-胆汁酸轴稳态成为治疗更年期脂代谢紊乱的新策略。前期发现贯叶连翘（HP）对更年期脂代谢紊乱具有调节作用，可显著降低卵巢摘除（OVX）大鼠血脂异常和肝脏脂质沉积，恢复其肠道菌群结构、增加肝脏胆汁酸含量和CYP7A1表达，但有待进一步机制研究。基于此本项目提出研究假说：HP通过调节OVX大鼠肠道菌群结构，改变胆汁酸代谢轮廓，降低肠FXR-FGF19/15通路对肝CYP7A1的负反馈调节作用，增加肝脏胆汁酸合成，达到调节更年期脂代谢的目的。为此，本项目以肠道菌群-胆汁酸-肠FXR轴为研究靶点，利用肠道菌群研究方法和靶向代谢组学、粪便移植、分子生物学等技术，整体和细胞水平阐明HP调节更年期脂代谢紊乱的分子机制。本项目为HP的临床应用提供科学依据。

更年期脂代谢紊乱是由雌激素缺乏导致的机体脂代谢异常。近年来发现雌激素缺乏可使宿主肠道菌群组成和胆汁酸代谢发生变化，是导致脂代谢紊乱的重要原因，维持肠道菌群-胆汁酸轴稳态成为治疗更年期脂代谢紊乱的新策略。课题组进行了贯叶连翘（Hypericum perforatum L., HP）对肠道微生物群组成及其活性代谢物影响的研究，并揭示了肠道菌群-胆汁酸-肠FXR轴在HP调节更年期脂代谢紊乱中的作用。课题组研究发现，卵巢摘除（OVX）大鼠饲养12周，可出现TC和TG升高、肝脏脂质沉积、肝脏炎症等脂代谢紊乱症状，可用于制作更年期脂代谢紊乱模型；卵巢摘除后的大鼠出现肠道菌群紊乱、SCFA和胆汁酸等代谢轮廓结构改变等现象，并且肠道菌群及其代谢产物的失衡与激素缺乏状态下的脂代谢紊乱症状具有高度相关性。HP给药可改善OVX大鼠的脂代谢紊乱症状，并能改善肠道微生物群组成，说明维持肠道菌群稳态是HP调节更年期脂代谢紊乱的作用机制之一。短链脂肪酸（SCFAs）是肠道菌群的重要产物，HP可增加肠道内容物中乙酸、丙酸、丁酸、戊酸和己酸等SCFAs的含量，且上调GPR41和GPR43的基因表达，表明HP可通过调节SFCAs组成激活GPR43和GPR41信号通路，进而对雌激素缺乏下的脂质紊乱有保护作用。肠道菌群产生的胆盐水解酶（BSH）在胆汁酸代谢中起重要作用，HP可增加OVX大鼠肝脏及肠道内容物中BSH含量，进一步说明HP可通过影响肠道菌群进而影响胆汁酸代谢轮廓。HP可逆转OVX大鼠的胆汁酸代谢轮廓，上调肝脏CYP7A1的基因和蛋白表达水平，进一步揭示增加胆汁酸合成、维持胆汁酸稳态是HP调节更年期脂代谢紊乱的重要机制之一。另外HP可增加OVX大鼠肠FGF15的基因表达，推测HP给药增加胆汁酸合成，进一步启动了肠FXR-FGF19/15通路对肝CYP7A1的负反馈调节作用。因此，我们猜测除肠FXR-FGF19/15通路外，还存在其他通路共同调控CYP7A1的表达。该研究为HP在更年期脂代谢紊乱的应用提供了理论基础，并为其他天然补充剂在脂代谢紊乱的保护作用研究中提供了思路。