BACKGROUND AND AIMS Pregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor expressed ubiquitously along gut-liver-axis. Inflammatory bowel disorders have been reported to implicate PXR in maintaining tight junction (TJ) integrity and countering inflammation. However, the hepatoprotective role of PXR activation in soothing bacterial translocation in liver cirrhosis has not been explored. Ginkgolide A (GA), a terpene trilactone from Ginkgo Biloba extract, is a natural ligand of rodent and human PXR. This study aims to investigate the effect of GA in activating PXR and improving associated tight junction integrity and reducing bacterial translocation in gut-liver axis of CCl4 induced cirrhosis model. METHODS Swiss albino mice were administered with CCl4 (0.5 ml/kg body weight, i.p) in corn oil for 12 weeks at an interval of two times a week. Following ascites induction, mice were randomized & administered 100 mg/kg body weight of GA through oral gavage for 2 weeks. At termination, blood, gut and liver tissues were collected for biochemical and molecular studies. RESULTS When compared to naïve mice, protein expression of hepatic and small intestinal PXR, CYP3A, ZO-1 and occludin were found to be significantly (p < 0.01) decreased in CCl4 induced cirrhotic mice. Treatment with GA to cirrhotic mice significantly (p < 0.05) induced the expression of both hepatic and small intestinal PXR, CYP3A, ZO-1 and Occludin. Furthermore, increased (p < 0.01) hepatic and small intestinal NFκB was observed in CCl4 induced cirrhotic mice that was significantly (p < 0.05) lowered following GA treatment. Over expression of TLR4/MyD88/NFκB axis and its downstream pro-inflammatory mediators TNF-α, IL6 and IFN-γ were observed in CCl4 induced mice, and these indices were abrogated significantly after GA treatment. Furthermore, significantly increased plasma levels of bacterial translocation markers LBP and procalcitonin were found in CCl4 mice, which were reduced significantly (p < 0.05 & p < 0.0001) after GA treatment. CONCLUSION In conclusion, our data supports the hypothesis that, GA treatment to CCl4 induced cirrhotic mice, activated hepatic and small intestinal PXR and diminished inflammation, thereby improving tight junction integrity and attenuating bacterial translocation.

中文翻译：

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天然配体银杏内酯-A激活Pregnane X受体可改善紧密连接蛋白的表达并减弱肝硬化中的细菌易位。

背景与目的孕烷X受体（PXR）是沿肠肝轴普遍表达的配体激活转录因子和核受体。据报道，炎症性肠病暗示PXR维持紧密连接（TJ）完整性并抵抗炎症。但是，尚未探索PXR活化在肝硬化中舒缓细菌移位中的肝保护作用。银杏内酯A（GA）是来自银杏叶提取物的萜烯三内酯，是啮齿动物和人PXR的天然配体。这项研究旨在研究GA在激活PXR和改善相关的紧密连接完整性以及减少CCl4诱导的肝硬化模型的肠肝轴中细菌移位的作用。方法对瑞士白化病小鼠给予CCl4（0.5 ml / kg体重，即1。p）在玉米油中放置12周，每周两次。腹水诱导后，将小鼠随机分组并通过管饲法给予100 mg / kg体重的GA 2周。终止时，收集血液，肠和肝组织用于生化和分子研究。结果与幼稚小鼠相比，CCl4诱导的肝硬化小鼠肝和小肠PXR，CYP3A，ZO-1和occludin的蛋白表达显着降低（p <0.01）。GA对肝硬化小鼠的治疗显着（p <0.05）诱导肝和小肠PXR，CYP3A，ZO-1和Occludin的表达。此外，在CCl4诱导的肝硬化小鼠中观察到肝和小肠NFκB升高（p <0.01），在GA治疗后明显降低（p <0.05）。在CCl4诱导的小鼠中观察到TLR4 / MyD88 /NFκB轴及其下游促炎介质TNF-α，IL6和IFN-γ的过度表达，GA处理后这些指标被显着消除。此外，在CCl4小鼠中发现了细菌转运标记LBP和降钙素原的血浆水平显着升高，经GA处理后，血浆水平显着降低（p <0.05＆p <0.0001）。结论总之，我们的数据支持以下假设：GA处理CCl4诱导的肝硬化小鼠，激活了肝和小肠PXR，并减轻了炎症，从而改善了紧密连接的完整性并减弱了细菌的移位。GA处理后，这些指标被显着废除。此外，在CCl4小鼠中发现了细菌转运标记LBP和降钙素原的血浆水平显着升高，经GA处理后，血浆水平显着降低（p <0.05＆p <0.0001）。结论总之，我们的数据支持以下假设：GA处理CCl4诱导的肝硬化小鼠，激活了肝和小肠PXR，并减轻了炎症，从而改善了紧密连接的完整性并减弱了细菌的移位。GA处理后，这些指标被显着废除。此外，在CCl4小鼠中发现了细菌转运标记LBP和降钙素原的血浆水平显着升高，经GA处理后，血浆水平显着降低（p <0.05＆p <0.0001）。结论总之，我们的数据支持以下假设：GA处理CCl4诱导的肝硬化小鼠，激活了肝和小肠PXR，并减轻了炎症，从而改善了紧密连接的完整性并减弱了细菌的移位。