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.

每年在室内护理环境中规定了超过2.5亿种抗生素课程 仅美国，包括18岁以下的儿童超过4000万。感知 抗生素使用的不利副作用最少有助于过度利用抗生素 临床情况并非严格指示。在医生和公众中， 由于抗生素的使用似乎相对不含毒性，因此似乎没有任何抑制 他们使用的目的地边际感知或测量的好处。我们学到了很多关于人的 微生物组 - 居住在我们身上的大型，高度多样的细菌社区。新兴观点是 我们的微生物群与我们的细胞之间的深刻终身双向相互作用；本质上，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代谢， 实验动物模型中的免疫和认知生理。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，选择抗性。我们建议 检查两种常用的抗生素[四环素（强力霉素）和β-内酰胺 （阿莫西林）]在人类微生物种群以及代谢和免疫生理学上，研究健康 在NIH临床中心（CC）的一项随机临床试验中，人类志愿者。我们的假设是 除了急性干扰人类微生物组，这些药物还将具有可测量的代谢和 免疫学效应，随后几周具有残留效应。 为了检验这一假设，在AIM 1中，我们将评估简短治疗过程的抗生素效果 关于微生物群和元基因组组成。初始评估期后，将给予抗生素 七天，将进行延长的治疗后评估。标本将从 总共10个时间点的多个位点，用于估计细菌和真菌组成 和基因含量。在AIM 2中，我们将评估抗生素课程对免疫的影响 生理。在每个时间点，将获得血液，尿液和粪便以确定血浆和细胞 先天和适应性免疫的标记水平。在AIM 3中，我们将评估 代谢生理学的抗生素课程。将评估获得的血液和尿液标本 用于代谢和荷尔蒙生理的标记。在主题的子集中，我们将利用唯一的CC 代谢室量化24小时能量消耗及其成分（睡眠，饮食引起的， 和活动）和碳水化合物和脂肪利用。除了主要数据分析外，我们还将建立一个 内容丰富的模型集成了临时数据，以洞悉复杂的相互交织的生理学 在微生物组和主机之间。该项目是执行全面和整合的机会 每年对数千万人提供的药物的评估。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 雷达以下的问题的指纹。 相关性（请参阅说明）： 在美国，抗生素的使用极为普遍，每年提供超过2.5亿门课程。 尽管抗生素在很大程度上是安全的，但我们认为它们在塑造构图中发挥了作用 通常生活在人体上和人体上的细菌，而不断变化的组成有可能 改变免疫反应，并导致代谢后果。在临床试验中，我们将测试 对健康的人类成人志愿者提供的抗生素的简短课程是否会影响微生物组 组成和扰动代谢和免疫力，我们将评估 扰动，以及他们将持续多长时间。