肠道菌引起的口服异喹啉生物碱药物的代谢转化及分子基础

本项目主要研究肠道菌对口服异喹啉生物碱药物的代谢转化及分子基础。肠道菌群是人体最庞大而复杂的微生物菌落，近年来作为人体的“隐形器官”被广泛关注。然而，目前肠道菌对口服药物的影响仍然是未知领域。我们前期的工作证明了口服异喹啉生物碱类药物，经肠道菌代谢后，产生了新的代谢产物。这种转化的发生，改变了原药在小肠的吸收，并解释了可能的药效作用机理。本课题将选择中国原创的、临床疗效确切而吸收较差的6个异喹啉生物碱（小檗碱、延胡索乙素、粉防己碱等）作为研究对象，运用微生物学、分析化学、生物化学及基因和蛋白分析等研究方法，初步阐明药物在肠道微生态环境作用下产生的新代谢产物和发生这种生物转化的分子基础。同时，也开展对具有代谢功能的多种细菌的鉴定和基因测序及相关代谢酶的鉴定及生化特性研究。本课题将为探索基于肠道菌作用的口服异喹啉生物碱药物体内代谢机制和药理学意义、为肠道微生态学在药物研究的运用，提供科学依据。

Mammalian intestine hosts extremely diverse and vast microorganisms, referred to as gut microbiota. Gut microbiota has been recently considered as a “hidden organ” of the body and might be associated with pathogenesis of diseases like obesity, diabetes and others. It is also an unexplored field for drug metabolism especially for those administrated through oral route, because drug metabolism by gut microbiota might generate metabolites different from those by host organs. However, regulation of drug metabolism by intestinal flora is still unknown. In this project, using genomics and proteomics, six isoquinoline alkaloid drugs used in clinics, with characteristics of being active in pharmacology but low in bioavailability (such as berberine, tetrahydropalmatine, and tetrandrine et al.) are taken as study objects, aiming to identify the participated metabolic enzymes, pivotal bacteria and its genome, and to seek the common intestinal flora for metabolizing alkaloids as well as the metabolic enzymes for catalyzing reduction and hydrolysis reaction. Based on the above, isoquinoline alkaloid drugs will be studied further for their regulation mechanism of intestinal flora, providing scientific evidence for explaining the pharmacology effect in clinics.