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: 9037283
• 负责人: MARTIN J BLASER
• 金额: $ 42.38万
• 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/9037283
• 关键词: 18 year old; Accounting; 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; Informatics; Kidney Calculi; Lead; Learning; Life; Link; Measurable; Measures; Metabolic; Metabolic Marker; Metabolism; Metagenomics; Modeling; Natural Immunity; Organism; Oxalates; Perception; Persons; 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; Systemic infection; Testing; Tetracyclines; Therapeutic; Time; Toxic effect; United States; United States National Institutes of Health; Urine; Waste Products; adaptive immunity; beta-Lactams; fungus; healthy volunteer; insight; killings; metagenome; metagenomic sequencing; microbial; microbiome; microbiota; oxidation; programs; public health relevance; rRNA Genes; research study; 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(申请人提供)：抗生素引起的微生物、免疫、代谢紊乱(MIME研究)。仅在美国，每年在门诊护理环境中开出的抗生素疗程就超过2.5亿个疗程，其中包括超过4000万个疗程的18岁以下儿童。认为抗生素的使用具有最小的伴随副作用的观念导致了在临床情况下抗生素的过度使用，而这些抗生素并没有得到严格的说明。因此，在医生和公众中，由于抗生素的使用似乎相对没有毒性，因此似乎没有阻止他们使用的动机，尽管他们感觉到或衡量出了边际好处。我们对人类微生物群--生活在我们体内和身上的高度多样化的大型细菌群落--已经了解了很多。新出现的观点是我们的微生物群和我们的细胞之间深刻的终身双向互动；从本质上说，我们的微生物群是人类生理学的核心部分。微生物区系的扰动会影响实验动物模型的代谢、免疫和认知生理学。当一个人服用抗生素时，抗生素会通过血液扩散到身体的所有隔室，从而产生耐药性。我们建议检测两种常用抗生素[四环素(多西环素)和β-内酰胺(阿莫西林)]对人类微生物种群以及代谢和免疫生理学的影响，在美国国立卫生研究院临床中心(CC)对健康志愿者进行随机临床试验。我们的假设是，除了严重扰乱人类微生物群外，这些药物还将具有可测量的代谢和免疫影响，并在接下来的几周内产生残余影响。为了验证这一假设，在目标1中，我们将评估一个简短的抗生素疗程对微生物区系和超基因组组成的影响。经过初步评估期后，抗生素将给予7天，并将有一个延长的治疗后评估。样本将在总共10个时间点中的每个时间点从多个地点获得，并用于估计细菌和真菌的组成和基因含量。在目标2中，我们将评估抗生素课程对免疫生理学的影响。在每个时间点，将获取血液、尿液和粪便，以确定血浆和细胞水平的先天免疫和获得性免疫标志物。在目标3中，我们将评估抗生素课程对代谢生理学的影响。获得的血液和尿液样本将被评估代谢和激素生理学的标志。在一组受试者中，我们将利用独特的CC代谢小室来量化24小时的能量消耗及其组成部分(睡眠、饮食诱导和活动)以及碳水化合物和脂肪的利用。除了主要的数据分析外，我们还将建立一个整合时间数据的信息模型，以深入了解微生物群和宿主之间复杂的相互交织的生理学。这个项目是一个机会，可以对每年给数千万人使用的药理药物进行全面和综合的评估。仔细分析和开发一个完整的模型，以了解扰动的病理生理学，可能会识别出以前没有注意到的问题的指纹。