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: 9923556
• 负责人: MARTIN J BLASER
• 金额: $ 34.67万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923556
• 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.

每年在美国的门诊护理机构开出的抗生素处方超过2.5亿个疗程