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

每年有超过2.5亿疗程的抗生素被开在医院的门诊护理环境中。 仅在美国，就有4000多万18岁以下的儿童。一种看法，即 抗生素的使用具有最小的副作用，从而导致抗生素的过度使用。 没有严格说明的临床情况。因此，在医生和公众中， 由于抗生素的使用似乎相对无毒性，因此似乎没有抑制 它们的使用，尽管有边际的感知或衡量的好处。我们学到了很多关于人类的知识 微生物群--生活在我们体内和身上的大型、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深刻的终身双向相互作用；本质上，我们的 微生物区系是人类生理学的核心部分。微生物区系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所有隔室，选择抗药性。我们建议 检查两种常用抗生素[四环素(强力环素)和β-内酰胺]的效果 (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 美国国立卫生研究院临床中心(CC)的一项随机临床试验中的人体志愿者。我们的假设是，在 除了严重扰乱人类微生物群外，这些制剂还将具有可测量的新陈代谢和 免疫效应，在接下来的几周内有残留效应。 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的效果。 关于微生物区系和超基因组组成。在初步评估期后，将给予抗生素 为期七天，并将进行长时间的治疗后评估。样本将从以下地点获得 总共10个时间点中的每一个都有多个地点，用于估计细菌和真菌组成 和基因含量。在目标2中，我们将评估抗生素课程对免疫的影响。 生理学。在每个时间点，采集血液、尿液和粪便，以测定血浆和细胞 先天免疫和获得性免疫标志物的水平。在目标3中，我们将评估 新陈代谢生理学抗生素课程。将对获得的血液和尿液样本进行评估 寻找代谢和荷尔蒙生理学的标记物。在主题的子集中，我们将使用唯一的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、 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 集成时间数据的信息模型，以提供对复杂交织生理的洞察 微生物群和宿主之间的关系。这个项目是一个全面和综合执行的机会 每年对数千万人进行的药理药物评估。仔细的分析和 开发综合模型以了解扰动的病理生理学可以识别 那些一直没有引起注意的问题的指纹。 相关性(请参阅说明)： 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人类健康的构成方面发挥了作用 通常生活在人体内和身体上的细菌，以及不断变化的组成可能会 改变免疫反应，以及导致新陈代谢后果。在临床试验中，我们将测试 健康成人志愿者服用短程抗生素是否会影响微生物群 组成和扰动代谢和免疫，我们将评估的大小和特异性 扰动，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.