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（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 亿个抗生素疗程，其中超过 4000 万个疗程是针对 18 岁以下的儿童。人们认为抗生素的使用伴随的不良副作用很小，这导致了在临床情况下，当没有严格指示时过度使用抗生素。因此，对于医生和公众来说，由于抗生素的使用似乎相对无毒性，因此尽管感知到或测量到的益处微乎其微，但似乎并没有抑制其使用。我们已经了解了很多关于人类微生物组的知识——生活在我们体内和体表的庞大、高度多样化的细菌群落。新的观点认为我们的微生物群和细胞之间存在着终生的深刻的双向相互作用。从本质上讲，我们的微生物群是人类生理学的核心部分。微生物群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各个部位，从而产生耐药性。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）] 对人类微生物群以及代谢和免疫生理学的影响，在 NIH 临床中心 (CC) 的一项随机临床试验中对健康人类志愿者进行研究。我们的假设是，除了严重扰乱人类微生物组之外，这些药物还将产生可测量的代谢和免疫效应，并在接下来的几周内产生残留效应。为了检验这一假设，在目标 1 中，我们将评估短期抗生素治疗过程对微生物群和宏基因组组成的影响。初始评估期结束后，将给予抗生素 7 天，并且将进行长时间的治疗后评估。总共将在 10 个时间点的每个时间点从多个地点获取样本，用于估计细菌和真菌的组成以及基因含量。在目标 2 中，我们将评估抗生素疗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，以确定先天性免疫和适应性免疫标记物的血浆和细胞水平。在目标 3 中，我们将评估抗生素疗程对代谢生理学的影响。将评估获得的血液和尿液样本的代谢和激素生理学标志物。在一部分受试者中，我们将利用独特的 CC 代谢室来量化 24 小时能量消耗及其组成部分（睡眠、饮食引起的和活动）以及碳水化合物和脂肪的利用。除了主要数据分析之外，我们还将建立一个整合时间数据的信息模型，以深入了解微生物组和宿主之间复杂的相互交织的生理学。该项目为每年为数千万人提供全面、综合评价的机会提供了机会。仔细分析和开发集成模型以了解扰动的病理生理学可能会识别出雷达之下问题的指纹。