糖尿病状态下基于肠道菌介导的肠道CYP3A和P-gp的改变及机制探索

Diabetes could change the function and expression of intestinal CYP3A and P-glycoprotein (P-gp), but the mechanism is still unknown. The gut microbiota is associated with the onset and development of diabetes, and resent researches showed that gut microbiota could also regulate some metabolizing enzymes and transporters. This project is going to explore the relationship among diabetes, gut microbiota, intestinal metabolizing enzyme and transporter and pharmacokinetics of drugs. This research will emphasis on the regional changes of gut microbiota and intestinal CYP3A and P-gp of diabetic animals and patients, the species and sex difference of these changes will also be included. The mechanism of the regulation of intestinal enzyme and transporter by diabetes in which gut microbiota were taken part will be investigated. How does the antibiotic gatifloxacin influence the diabetes through the interaction with gut microbiota will be explored. Besides, the changes of oral pharmacokinetics of nifedipine and lovastatin will be compared in diabetic animals and patients simultaneously to judge whether the species difference of these changes is exist and the research about translational medicine will be studied. The findings could help elucidate the influence of gut microbiota on diabetes, the mechanism of the regulation of intestinal CYP3A and P-gp by diabetes, and the pharmacokinetic changes of the substrate drugs under diabetes states. The results may also help to give diabetic patients guidelines for drug use in clinic.

糖尿病会改变肠道CYP3A和P-gp，但作用机制尚不明确。肠道菌群与糖尿病的发生发展密切相关，并且有研究表明肠道菌群对某些代谢酶和转运体具有调控作用。由此我们推测肠道菌可能参与糖尿病对肠道CYP3A和P-gp的调控过程。本项目拟探索糖尿病、肠道菌群、肠道代谢酶和转运体以及药代动力学之间的联系。重点考察糖尿病动物和患者的肠道菌群和肠道CYP3A和P-gp的区域性变化，以及这些变化的种属差异和性别差异，并研究肠道菌参与糖尿病改变肠道代谢酶和转运体的作用机制；分析抗生素加替沙星如何通过改变肠道菌群影响糖尿病；此外通过同时比较底物药物硝苯地平、洛伐他汀在糖尿病动物和人体内的口服药代动力学变化，考察其种属差异性并进行转化医学的相关研究。其成果有助于阐明肠道菌对糖尿病的影响，糖尿病改变CYP3A和P-gp的作用机制以及底物药物在糖尿病状态下的药代动力学特征，对于指导糖尿病患者临床合理用药具有重要意义。

肠道菌群与糖尿病的发生发展密切相关。在本项目中，重点研究了糖尿病状态下肠道菌群和肠道中CYP3A和P-gp的改变，发现糖尿病对大鼠肠道上CYP3A和P-gp的表达影响具有同步性，并且呈区域性。糖尿病影响大鼠回肠和结肠段的菌群多样性，可能是影响肠道CYP3A及P-gp表达改变的机制之一。同时研究了由于肠道CYP3A和P-gp的变化而引起的药物吸收和首过效应的改变，糖尿病大鼠中CYP3A和P-gp的底物药物硝苯地平、环孢素的药代动力学均发生了显著改变。在人组织水平上研究糖尿病对肠CYP3A4和P-gp的影响，发现患有糖尿病的胰腺癌患者中十二指肠组织中P-gp的蛋白表达显着上调，而CYP3A4没有变化。通过糖尿病血清/肠道菌上清液与细胞共培养研究，在离体水平上分析糖尿病状态下肠道CYP3A和P-gp的改变的机制，结果发现糖尿病状态下胰岛素、葡萄糖以及脂肪酸浓度的异常变化可能是影响肠道CYP3A4和P-gp的功能改变的部分原因之一，另外发现糖尿病大鼠肠道菌肠道菌的改变可能是导致糖尿病改变肠道CYP3A和P-gp变化的重要作用机制。本研究成果有助于阐明肠道菌对糖尿病的影响，糖尿病改变CYP3A和P-gp的作用机制以及底物药物在糖尿病状态下的药代动力学特征，对于指导临床合理用药以及预测可能的药物不良反应均具有十分重要的意义。