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）

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：抗生素对微生物、免疫、代谢的干扰（MIME 研究）仅在美国，门诊医疗机构每年就开出超过 2.5 亿个疗程的抗生素，其中包括超过 4000 万个 18 岁以下儿童。因此，医生和公众都认为，在没有严格指示的情况下，抗生素使用的副作用很小，这导致了抗生素的过度使用。抗生素的使用似乎相对没有毒性，尽管感知到或测量到的益处有限，但似乎并没有抑制它们的使用。新兴的观点是我们的微生物群和细胞之间存在终生的深刻的双向相互作用；本质上，微生物群的扰动会影响实验中的代谢、免疫和认知生理学。动物当一个人服用抗生素时，抗生素会通过血液扩散到所有身体部位，从而选择耐药性。我们建议检查两种常用抗生素[四环素（强力霉素）和β-内酰胺（阿莫西林）]的效果。在 NIH 临床中心 (CC) 的一项随机临床试验中研究健康人类志愿者，我们的假设是，除了严重扰乱人类微生物组之外，这些药物还会对人类微生物种群以及代谢和免疫生理学产生影响。具有可测量的代谢和免疫学影响，并在接下来的几周内产生残余影响。为了检验这一假设，在目标 1 中，我们将在初始评估期后评估抗生素的简短治疗过程对微生物群和宏基因组组成的影响。将进行 7 天，并且将在总共 10 个时间点从多个地点获取样本，并用于估计细菌和真菌组成以及基因含量。目标 2，我们将评估抗生素疗程对免疫生理学的影响。在目标 3 中，我们将获取血液、尿液和粪便，以确定先天免疫和适应性免疫标志物的血浆和细胞水平。将评估抗生素疗程对代谢生理学的影响。将评估所获得的血液和尿液样本的代谢和激素生理学标记。在一部分受试者中，我们将利用独特的 CC 代谢室来量化 24 小时能量消耗。和除了主要数据分析之外，我们还将构建一个整合时间数据的信息模型，以深入了解微生物组和宿主之间复杂的相互交织的生理学。该项目是每年对数以千万计的人进行全面综合评估的机会，仔细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预期的问题的指纹。雷达。