Microbial, immune, metabolic perturbations by antibiotics (MIME study)

在美国，每年在门诊护理环境中开出超过2.5亿个抗生素疗程。 仅美国就有4000多万18岁以下的儿童。人们认为 抗生素的使用具有最小的伴随不良副作用， 在临床上，他们没有严格的指示。因此，在医生和公众中， 由于抗生素的使用似乎相对无毒，似乎没有抑制因素， 他们的使用，尽管边际感知或测量的好处。我们已经了解了很多关于人类 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。新出现的观点是， 我们的微生物群和我们的细胞之间的深刻的终身双向相互作用;本质上，我们的 微生物群是人类生理学的核心部分。微生物群的扰动影响代谢， 免疫和认知生理学的研究。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分，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]的作用 （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，研究健康 在NIH临床中心（CC）的随机临床试验中的人类志愿者。我们的假设是 除了急性干扰人体微生物组之外，这些试剂还具有可测量的代谢和 免疫学效应，在接下来的几周内产生残留效应。 为了验证这一假设，在目标1中，我们将评估抗生素的简短治疗过程的效果 微生物群和宏基因组组成。经过初步评估后，将给予抗生素 为期七天，并将有一个长期的治疗后评估。样本将从以下地点获得： 在总共10个时间点的每个时间点的多个部位，用于估计细菌和真菌组成 和基因含量。在目标2中，我们将评估抗生素疗程对免疫系统的影响。 physiology.在每个时间点，将采集血液、尿液和粪便，以测定血浆和细胞计数。 先天免疫和适应性免疫的标志物水平。在目标3中，我们将评估 代谢生理学的抗生素课程将对获得的血液和尿液样本进行评估 代谢和激素生理学的标记。在受试者的一个子集中，我们将利用独特的CC 代谢室量化24小时能量消耗及其组成部分（睡眠，饮食诱导， 以及碳水化合物和脂肪的利用。除了主要的数据分析，我们还将建立一个 整合时间数据的信息模型，以深入了解复杂交织的生理学 微生物和宿主之间的联系这个项目是一个机会，执行全面和综合 每年对数千万人进行药物评估。认真分析和 开发一个综合模型来了解扰动的病理生理学， 那些一直被忽视的问题的痕迹 相关性（参见说明）： 抗生素的使用在美国非常普遍，每年有超过2.5亿个疗程。 虽然抗生素在很大程度上是安全的，但我们认为它们在塑造细菌的组成方面发挥着作用。 通常生活在人体内和人体上的细菌，改变成分有可能 改变免疫反应，并导致代谢后果。在临床试验中，我们将测试 给予健康成人志愿者短期抗生素是否会影响微生物组 组成和干扰代谢和免疫，我们将评估的幅度，和特异性的， 干扰，以及它们将持续多久。

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.