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: 10159190
• 负责人: MARTIN J BLASER
• 金额: $ 34.06万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159190
• 关键词: 18 year old; Acute; Adult; Affect; Aftercare; Ambulatory Care; Amoxicillin; Antibiotics; Bacteria; Blood; Carbohydrates; Cells; Child; Clinical; Clinical Protocols; Clinical Trials; Cognitive; Complex; Data; Data Analyses; Development; Diet; Diffuse; Disincentive; Doxycycline; Energy Metabolism; Evaluation; Experimental Animal Model; Fatty acid glycerol esters; Feces; Fingerprint; Functional disorder; Genes; Hormonal; Hour; Human; Human Microbiome; Human Volunteers; Human body; Immune; Immune response; Immunity; Immunologics; Informatics; Institutional Review Boards; Instruction; Lead; Life; Measurable; Measures; Metabolic; Metabolic Marker; Metabolism; Modeling; National Institute of Allergy and Infectious Disease; Natural Immunity; Perception; Persons; Pharmacology; Physicians; Physiology; Plasma; Play; Population; Radar; Randomized Clinical Trials; Residual state; Resistance; Role; Shapes; Site; Sleep; Specificity; Specimen; Testing; Tetracyclines; Therapeutic; Time; Toxic effect; United States; United States National Institutes of Health; Urine; adaptive immunity; bacterial community; beta-Lactams; clinical center; insight; metagenome; microbial; microbiome; microbiome composition; microbiota; side effect; volunteer

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 bidirectional 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 for 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. RELEVANCE (See instructions): Antibiotic use is extremely common in the United States, with over 250 million courses given each year. Although antibiotics are largely safe, we believe that they play a role in shaping the composition of the bacteria that normally live in and on the human body, and changing composition has the potential to change immune responses, as well as lead to metabolic consequences. In a clinical trial, we will test whether short courses of antibiotics given to healthy human adult volunteers will affect the microbiome composition and perturb metabolism and immunity, and we will assess the magnitude, and specificity of the perturbations, and how long they will last.

每年在门诊医疗机构中开出超过 2.5 亿个疗程的抗生素 仅美国就包括超过 4000 万 18 岁以下儿童。 抗生素的使用所带来的不良副作用极小，导致抗生素的过度使用 因此，在医生和公众中， 由于抗生素的使用似乎相对无毒性，因此似乎不会阻碍使用抗生素 尽管感知到或测量到的益处微乎其微，但它们的使用我们已经了解了很多关于人类的知识。 微生物组——生活在我们体内和体表的大型、高度多样化的细菌群落。 从本质上讲，我们的微生物群和细胞之间存在着终生深刻的双向相互作用； 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新陈代谢， 实验动物模型中的免疫和认知生理学当一个人服用抗生素时， 抗生素通过血液扩散到身体的各个部位，我们建议选择耐药性。 检查两种常用抗生素的作用[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，研究健康 我们的假设是，在 NIH 临床中心 (CC) 的一项随机临床试验中，人类志愿者。 除了严重扰乱人类微生物组之外，这些药物还将具有可测量的代谢和 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，我们将评估抗生素短期治疗疗程的效果 在初步评估期后，将给予抗生素。 为期 7 天，并且将进行长时间的治疗后评估。 总共 10 个时间点的多个位点，用于估计细菌和真菌组成 在目标 2 中，我们将评估抗生素疗程对免疫的影响。 在每个时间点，将获取血液、尿液和粪便来测定血浆和细胞。 在目标 3 中，我们将评估先天免疫和适应性免疫标志物的水平。 将评估所获得的血液和尿液样本的代谢生理学抗生素课程。 对于代谢和激素生理学的标志物，我们将在一部分受试者中利用独特的 CC。 代谢室可量化 24 小时能量消耗及其组成部分（睡眠、饮食引起的、 除了主要数据分析之外，我们还将建立一个数据分析模型。 信息模型整合时间数据以深入了解复杂的相互交织的生理学 这个项目是一个在微生物组和宿主之间进行全面和整合的机会。 每年对数以千万计的人进行仔细的分析和评估。 开发一个综合模型来理解扰动的病理生理学可以确定 那些未被注意到的问题的指纹。 相关性（参见说明）： 在美国，抗生素的使用极为普遍，每年有超过 2.5 亿个疗程。 尽管抗生素在很大程度上是安全的，但我们相信它们在塑造抗生素的组成方面发挥着作用。 通常生活在人体内部和表面的细菌，改变成分有可能 改变免疫反应，并导致代谢后果，我们将在临床试验中进行测试。 给健康成人志愿者短期服用抗生素是否会影响微生物组 成分并扰乱新陈代谢和免疫力，我们将评估其程度和特异性 扰动，以及它们会持续多久。