Gut Microbiome and Pharmacokinetic Variability in Tuberculosis and Diabetes

项目摘要/摘要 在了解低毒药物的作用机制和生物学预测因素方面存在着显著的知识差距。 结核病(TB)和2型糖尿病(DM)患者的暴露和治疗失败。致信地址 糖尿病对不良结核病结局的影响，我们提出了一个跨学科指导的研究和培训计划，以 糖尿病与非糖尿病患者肠道微生物群介导的抗结核药物药代动力学差异研究 在一项正在进行的前瞻性、观察性PK试验中，患者研究了异烟肼、利福平和吡嗪酰胺在 结核病患者。具体目标1将量化DM和肠道微生物区系α多样性对 口服抗结核药物在活动性肺结核治疗患者中的生物利用度 合并糖尿病的活动性肺结核患者和不合并糖尿病的活动性肺结核患者的肠道生态失调的措施。特定目标2将 描述活动性肺结核患者肠道微生物区系α多样性与糖尿病的关系 通过对临床粪便标本中的人体肠道微生物群进行全面的前瞻性分析。 在成功完成拟议的K23研究后，我们预计我们的贡献如下：1)建立 以前未描述的人类肠道微生物组作为重要协变量的影响解释 接受活动性结核病治疗的患者中药物PK的异质性，以及，2)显示出独特的关系 结核病患者中糖尿病和肠道微生物群多样性和组成之间的关系。这些贡献将是 意义重大，因为它们有望为一种新的机制提供强有力的科学依据 先前未解释的抗结核药物PK和结核病治疗反应在结核病/糖尿病患者中的变异性。 这项拟议的研究具有创新性，因为它的目标是将肠道微生物群确定为一种新的机制 抗结核药物PK的异质性。这项K23提案的总体目标是培训纳瓦内斯 纳拉亚南，药学博士，公共卫生硕士，职业生涯是药物微生物学的独立研究员，研究 微生物组变异通过调节药物PK和药效学(PD)对疗效的影响 在职业上特别强调结核病和其他传染病的治疗和结果。职业生涯 发展计划包括在马丁·布拉泽博士的指导下进行人类微生物组研究方面的培训， 以及药物计量学，一门定量临床药理学和系统生物学的交叉学科， 涉及数学建模方面的专业知识，以表征和预测药物PK和PD。纳拉亚南博士会 还得到了国际抗结核药理学和结核病临床研究专家Scott Heysell博士的指导。 拟议的K23项目将提供一个以患者为导向的指导研究、职业生涯的综合计划 微生物组研究和药物计量学方面的开发活动和正式培训。由专家指导 导师和合作者，本申请中概述的研究和培训活动将使Dr。 Narayanan将成熟为一名独立的临床/翻译研究员。这些机会将使这一点 拥有更多技能来回答有关全球传染病的重要和新问题的调查人员。

PROJECT SUMMARY/ABSTRACT There are significant knowledge gaps in understanding the mechanisms and biological predictors of low drug exposures and treatment failure in patients with tuberculosis (TB) and type 2 diabetes mellitus (DM). To address the impact of DM on poor TB outcomes, we propose an interdisciplinary mentored research and training plan to investigate gut microbiome-mediated variation of anti-TB drug pharmacokinetics (PK) in DM and non-DM TB patients in an ongoing prospective, observational PK trial investigating isoniazid, rifampin, and pyrazinamide in TB patients. Specific Aim 1 will quantify the effect of DM and gut microbiota alpha diversity on the bioavailability of oral anti-TB drugs in patients treated for active TB, by linking pharmacometric modeling with DM and measures of the gut dysbiosis in active TB patients with and without DM. Specific Aim 2 will characterize the relationship of gut microbiota alpha diversity and diabetes in patients with active TB, by conducting a comprehensive prospective analysis of the human gut microbiome from clinical stool specimens. Upon successful completion of the proposed K23 research, we expect our contribution to 1) establish the previously undescribed impact of the human gut microbiome as a significant covariate to explain the heterogeneity of drug PK in patients receiving active TB treatment and, 2) demonstrate the distinctive relationship between DM and gut microbiome diversity and composition among patients with TB. These contributions will be significant because they are expected to provide strong scientific justification for a novel mechanism for the previously unexplained variability of anti-TB drug PK and TB treatment response among patients with TB/DM. The proposed research is innovative because it aims to identify the gut microbiome as a novel mechanism underlying the heterogeneity of anti-TB drug PK. The overall goal of this K23 proposal is to train Navaneeth Narayanan, PharmD, MPH for a career as an independent investigator in pharmacomicrobiomics, the study of the effect of microbiome variation on therapeutic response by regulating drug PK and pharmacodynamics (PD), with a specific career emphasis on the treatment and outcomes of TB and other infectious diseases. The career development plan includes training in human microbiome research, under the mentorship of Dr. Martin Blaser, and pharmacometrics, an interdisciplinary science of quantitative clinical pharmacology and systems biology that involves expertise in mathematical modeling to characterize and predict drug PK and PD. Dr. Narayanan will also be mentored by Dr. Scott Heysell, an international expert in anti-TB pharmacology and TB clinical research. The proposed K23 project will provide an integrated plan of mentored patient-oriented research, career development activities, and formal training in microbiome research and pharmacometrics. Guided by expert mentors and collaborators, the research and training activities outlined in this application will enable Dr. Narayanan to mature into an independent clinical/translational researcher. These opportunities will equip this investigator with a larger set of skills to answer important and novel questions about global infectious diseases.