Microbial, immune, metabolic perturbations by antibiotics (MIME study)

抗生素对微生物、免疫、代谢的干扰（MIME 研究）

• 批准号: 9246429
• 负责人: MARTIN J BLASER
• 金额: $ 41.3万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246429
• 关键词: 18 year old; Accounting; Acute; Adult; Adverse effects; Affect; Aftercare; Age; Ambulatory Care; Amoxicillin; Anaerobic Bacteria; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Genes; Belief; Biological Models; Blood; Calcium Oxalate; Carbohydrates; Cells; Censuses; Child; Childhood; Clinical; Clinical Trials; Cognitive; Communities; Complex; Consensus; Data; Data Analyses; Developing Countries; Development; Diet; Diffuse; Disincentive; Doxycycline; Elements; Energy Metabolism; Enrollment; Evaluation; Experimental Animal Model; Fatty acid glycerol esters; Feces; Fingerprint; Functional disorder; Genes; High-Throughput DNA Sequencing; Hormonal; Hour; Human; Human Microbiome; Human Volunteers; Human body; Hypersensitivity; Immune; Immune response; Immunity; Immunologics; Infection; Informatics; Kidney Calculi; Lead; Life; Link; Measurable; Measures; Metabolic; Metabolic Marker; Metabolism; Metagenomics; Microbiology; Modeling; Natural Immunity; Organism; Oxalates; Perception; Persons; Pharmacology; Physicians; Physiology; Plasma; Play; Population; Radar; Randomized Clinical Trials; Research Design; Residual state; Resistance; Resources; Rest; Risk; Role; Saliva; Sampling; Serum; Shapes; Shotgun Sequencing; Site; Sleep; Specificity; Specimen; Testing; Tetracyclines; Therapeutic; Time; Toxic effect; United States; United States National Institutes of Health; Urine; Waste Products; adaptive immunity; beta-Lactams; experimental study; fungus; healthy volunteer; insight; killings; metagenome; microbial; microbiome; microbiota; oxidation; programs; public health relevance; rRNA Genes; volunteer; young adult

 DESCRIPTION (provided by applicant): Microbial, immune, metabolic perturbations by antibiotics (MIME study). More than 250 million courses of antibiotics are prescribed annually in the ambulatory care setting in the United States alone, including more than 40 million in children under 18 years of age. The perception that antibiotic use has minimal attendant adverse side effects contributes to the over-utilization of antibiotics in clinical circumstances when they are not strictly indicated. Thus, among physicians and the public alike, since the use of antibiotics seems to be relatively free of toxicity, there appears to be no disincentive to their use despite marginal perceived or measured benefit. We have learned much about the human microbiome -- the large, highly diverse, bacterial community that lives in and on us. The emerging view is of profound life-long bi- directional interactions between our microbiota and our cells; in essence, our microbiota are a central part of human physiology. Perturbations in the microbiota affect metabolic, immune, and cognitive physiology in experimental animal models. When a person takes an antibiotic, the antibiotic diffuses via the blood into all body compartments, selecting fo resistance. We propose to examine the effects of two commonly used antibiotics [a tetracycline (doxycycline) and a beta-lactam (amoxicillin)] on human microbial populations and on metabolic and immune physiology, studying healthy human volunteers in a randomized clinical trial at the NIH Clinical Center (CC). Our hypothesis is that in addition to acutely perturbing the human microbiome, these agents will have measurable metabolic and immunologic effects, with residual effects in the weeks that follow. To test this hypothesis, in Aim 1, we will assess the effects of a brief therapeutic course of antibiotics on microbiota and metagenome composition. After an initial evaluation period, antibiotics will be given for seven days, and there will be a prolonged post-treatment evaluation. Specimens will be obtained from multiple sites at each of 10 time-points in total, and used for estimating bacterial and fungal composition and gene content. In Aim 2, we will assess the effects of the antibiotic course on immune physiology. At each time point, blood, urine, and feces will be obtained to determine plasma and cellular levels of markers of both innate and adaptive immunity. In Aim 3, we will assess the effects of the antibiotic course on metabolic physiology. The obtained blood and urine specimens will be assessed for markers of metabolic and hormonal physiology. In a subset of subjects, we will utilize the unique CC Metabolic Chamber to quantify 24-hour energy expenditure and its components (sleeping, diet-induced, and activity) and carbohydrate and fat utilizations. In addition to the primary data analyses, we will build an informatic model integrating the temporal data to provide insight into the complex intertwined physiology between microbiome and host. This project is an opportunity to perform comprehensive and integrated evaluations of pharmacologic agents given to tens of millions of people every year. Careful analysis and development of an integrated model to understand the pathophysiology of the perturbations may identify the fingerprints of problems that had been below the radar.

 描述（应用程序提供）：微生物，免疫，抗生素代谢扰动（MIME研究）。仅在美国的门诊护理环境中，每年都有超过2.5亿种抗生素的抗生素课程，其中包括18岁以下的儿童超过4000万。当不严格指出抗生素的情况下，人们认为抗生素使用最少的不利副作用会导致抗生素过度利用抗生素。在医生和公共的情况下，由于使用抗生素似乎相对不含毒性，因此似乎对他们使用的目的地的使用边际感知或测量的益处并没有抑制。我们已经了解了人类微生物组的知识，这是一个生活在我们身上的大型，高度多样化的细菌群落。新兴的观点是我们的微生物群与我们的细胞之间深刻的终身双向相互作用。从本质上讲，我们的菌群是人类生理的核心部分。微生物群的扰动会影响实验动物模型中的代谢，免疫和认知生理。当一个人服用抗生素时，抗生素通过血液扩散到所有身体室中，选择FO耐药性。我们建议检查两种常用的抗生素[四环素（强力霉素）和一个β-内酰胺（阿莫西林）对人类微生物种群以及对NIH临床中心（CC）随机临床试验的健康人类志愿者的影响。我们的假设是，除了急剧扰动人类微生物组外，这些药物还将具有可测量的代谢和免疫学效应，并在随后的几周内产生残留效应。为了检验这一假设，在AIM 1中，我们将评估抗生素简短治疗过程对菌群和元基因组组成的影响。初始评估期后，将进行7天的抗生素，并将进行延长的治疗后评估。标本将从10个时间点中的每个位点获得，并用于估计细菌，真菌组成和基因含量。在AIM 2中，我们将评估抗生素病程对免疫生理学的影响。在每个时间点，将获得血液，尿液和粪便，以确定先天和适应性免疫学标记的血浆和细胞水平。在AIM 3中，我们将评估抗生素过程对代谢生理的影响。将评估获得的血液和尿液标本的代谢生理学标记。在受试者的一部分中，我们将利用独特的CC代谢室来量化24小时的能量消耗及其成分（睡眠，饮食诱导的和活动）以及碳水合物和脂肪利用。除了主要数据分析外，我们还将建立一个信息丰富的模型，该模型整合了临时数据，以洞悉微生物组和主机之间的复杂相互交织的生理学。该项目是对每年对数千万人的药理代理进行全面和综合评估的机会。仔细的分析和开发综合模型以了解扰动的病理生理学可能会识别出低于雷达的问题的指纹。