Understanding the contributions of microbiome-encoded drug metabolizing enzymes

了解微生物组编码的药物代谢酶的贡献

• 批准号: 10461800
• 负责人: Andrew L Goodman
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461800
• 关键词: Address; Adverse reactions; Applications Grants; Bacteria; Bile fluid; Biological Availability; Biological Markers; Blood Circulation; Chemicals; Data; Drug Kinetics; Engineering; Enterohepatic Circulation; Enzymes; Exhibits; FDA approved; Formulation; Gastrointestinal tract structure; Genes; Genetic; Genetic Techniques; Gnotobiotic; Hepatic; Hepatocyte; Human; Human Genome; In Vitro; Individual; Measurement; Measures; Mediating; Medical; Metabolic Biotransformation; Metabolism; Metagenomics; Methods; Microsomes; Modeling; Mus; Oral; Parents; Pharmaceutical Preparations; Physiological; Process; Production; Safety; Series; Serum; Surveys; System; Techniques; Testing; Time; Toxic effect; Variant; base; commensal bacteria; density; drug candidate; drug metabolism; experimental study; gut bacteria; gut microbes; gut microbiome; gut microbiota; host microbiome; in vivo; loss of function; metabolomics; microbial; microbiome; mouse model; pharmacokinetic model; physiologically based pharmacokinetics; predictive marker; repository; small molecule; tool

Project Summary Drug metabolites can have distinct efficacy and toxicity profiles relative to the parent compound, and interpersonal variation in drug metabolism can determine adverse reactions. Notably, oral drugs that exhibit low bioavailability, are delivered in delayed release formulations, or are excreted through bile can encounter enormous densities of bacteria in the gastrointestinal tract. The gut microbiome carries a collective gene content 150-fold larger than the human genome, encodes a rich repository of enzymes with the potential capacity to metabolize drugs, and varies widely between individuals. The microbiome thus has the potential to impact serum drug and metabolite exposure. However, scalable in vitro systems for identification of active microbial species, enzymes, and candidate drug metabolites are not available. Our understanding of microbiome-mediated drug metabolism is largely limited to anecdotal examples, and it is unknown whether gut microbes encode enzymes that metabolize many drugs. Strategies for determining the quantitative contribution of gut microbial drug metabolism to serum drug and metabolite exposure are also not available. We developed high-throughput approaches that generate metabolomic time-series profiles of the metabolism of hundreds of drugs by hundreds of human gut microbial communities and species, uncover the microbiome- encoded enzymes responsible for these transformations, and identify candidate drug metabolites produced as a result. We also provide evidence that combining gnotobiotics with physiologically-based pharmacokinetic modeling can quantitatively disentangle host and microbial contributions to serum drug metabolite exposure in vivo, using a drug that is converted into a single metabolite by host and microbiome as a proof of concept. In Aim 1 of this proposal, we present a plan to establish the first repertoire of drug-metabolizing enzymes in the human gut microbiome. These results will reveal whether human gut microbes encode enzymes that metabolize many drugs and whether microbiome genes encoding drug-metabolizing enzymes serve as predictive biomarkers of the drug-metabolizing capacity of an individual's microbiome. In Aim 2, we describe a strategy to develop and test generalized host-microbiome pharmacokinetic models that capture host and microbial conversion of a drug into multiple metabolites and include enterohepatic circulation in the model topology. If successful, these aims will establish broadly applicable approaches to identify when and how the microbiome could contribute to the metabolism of drugs and other small molecules.

项目摘要 药物代谢产物可以相对于母体化合物具有不同的功效和毒性特征，并且 药物代谢的人际变异可以确定不良反应。值得注意的是，表现出的口服药物 低生物利用度，以延迟的释放配方交付或通过胆汁排泄 胃肠道中细菌的巨大密度。肠道微生物组带有集体基因 含量比人类基因组大150倍，编码具有潜力的丰富酶库 代谢药物的能力，个人之间的变化很大。因此，微生物组具有 影响血清药物和代谢物暴露。但是，可扩展的体外系统用于识别活动 微生物物种，酶和候选药物代谢物不可用。我们对 微生物组介导的药物代谢在很大程度上仅限于轶事示例，尚不清楚是否肠道 微生物编码代谢许多药物的酶。确定定量贡献的策略 肠道微生物药物代谢对血清药物和代谢产物暴露也不可用。 我们开发了产生代谢代谢的代谢时间序列曲线的高通量方法 数百种人类肠道微生物群落和物种数百种药物，发现了微生物组 负责这些转化的编码酶，并确定产生的候选药物代谢物为 结果。我们还提供证据表明将gnotobiotics与生理上的药代动力学相结合 建模可以定量地解开宿主和微生物对血清药物代谢物暴露的贡献 体内使用宿主和微生物组转化为单一代谢产物的药物作为概念证明。 在本提案的目标1中，我们提出了一项计划，以建立在该提案中建立第一批药物代谢酶的曲目 人肠道微生物组。这些结果将揭示人类肠道微生物是否编码酶 代谢许多药物以及编码药物代谢酶的微生物组基因是否为 个人微生物组的药物代谢能力的预测生物标志物。在AIM 2中，我们描述了一个 开发和测试概述宿主和 将药物的微生物转化为多种代谢产物，并在模型中包括肠肝循环 拓扑。如果成功，这些目标将建立广泛适用的方法，以确定何时以及如何 微生物组可能有助于药物和其他小分子的代谢。