Early life antibiotics, gut microbiome development, and risk of childhood obesity

 描述（由申请人提供）：美国三分之一的新生儿暴露于抗生素，从托儿所出院后，抗生素是幼儿最常见的处方药。此外，这些围产期和婴儿抗生素暴露的很大一部分是不必要的。虽然抗生素的副作用，如抗生素耐药性的发展已得到充分描述，但抗生素的患者特异性作用， 对儿童长期健康的影响仍不清楚。人类婴儿的形成微生物组在生命早期非常容易受到破坏和肠道细菌种类的改变 在正常定植的关键时期，可能会产生长期影响。早期抗生素暴露与肥胖、过敏和哮喘的风险增加有关。然而，各种早期抗生素暴露，微生物组功能或成熟的改变以及健康结果之间的潜在联系通常仍然未知。为了解决这些知识差距，我们将纵向收集和跟踪一个大型的、多样化的出生队列，以确定（1）抗生素暴露与肠道微生物组发育之间的关系;（2）抗生素暴露与体重增加/肥胖;（3）微生物组发育与体重增加/肥胖。我们将检查常规分娩期，新生儿和婴儿抗生素暴露;使用细菌分类标志物基因测序，元转录组学和代谢组学来测量微生物组分类携带，生物多样性和婴儿肠道微生物组成熟率的代谢相关变化;并进行一系列人体测量以评估生命前24个月的体重增加和肥胖。该项目利用了宾夕法尼亚大学、费城儿童医院（CHOP）和明尼苏达大学研究人员在流行病学、儿科学、泌尿学、传染病、肥胖研究、临床生物信息学和微生物组分析方面的互补优势。我们之前的工作表明，（1）研究人员在定义抗菌药物使用的流行病学和结果方面具有丰富的经验;围产期母婴二元组的研究;人类肠道微生物组数据的收集，处理和分析;以及评估和表征婴儿和幼儿生长; 2）在这个人群中抗生素的使用是频繁和可变的，这是一个理想的环境，以评估所提出的假设;和3）纵向早期生命人体测量的队列从出生开始是可行的。通过CHOP，我们可以使用通用的电子健康记录访问一个大型分娩中心，为美国最大的儿科医疗保健网络之一提供服务。这个庞大的异质性队列是我们提案的关键优势之一，将使我们能够真实的招募、跟踪和监测所有队列成员的健康记录。建立一个大型出生队列，其中定义微生物组并前瞻性记录患者健康信息，将为未来提供独特的机会，将发育中微生物组的结构和功能变化与额外的健康结果直接联系起来。

 DESCRIPTION (provided by applicant): One third of newborn babies in the US are exposed to antibiotics and, after discharge from the nursery, antibiotics are the most common prescription medication given to young children. Moreover, a large proportion of these perinatal and infant antibiotic exposures are unnecessary. While adverse effects of antibiotics such as the development of antibiotic resistance are well described, the patient-specific effects of antibiotic use on the long-term health of children remains unclear. The forming microbiome of the human infant is highly susceptible to disruptions, and alterations in gut bacterial species in early life during a critical period of normal colonization can have long-term effects. Early life antibiotic exposures have been associated with increased risks of obesity, allergy, and asthma. However, the potential links between varied early life antibiotic exposures, alterations in microbiome function or maturation, and health outcomes generally remain unknown. To address these knowledge gaps, we will assemble and follow longitudinally a large, diverse birth cohort to determine the relationship between (1) antibiotic exposure and gut microbiome development; (2) antibiotic exposure and weight gain/adiposity; (3) and microbiome development and weight gain/adiposity. We will examine routine intrapartum, neonatal, and infant antibiotic exposures; use bacterial taxonomic marker gene sequencing, metatranscriptomics, and metabolomics to measure antibiotic-related shifts in microbiome taxonomic carriage, biodiversity, and rate of maturation of the infant gut microbiome; and perform serial anthropometric measurements to assess weight gain and adiposity over the first 24 months of life. This project leverages complementary strengths in epidemiology, pediatrics, neonatology, infectious diseases, obesity research, clinical bioinformatics, and microbiome analysis from investigators at the University of Pennsylvania, the Children's Hospital of Philadelphia (CHOP), and the University of Minnesota. Our prior work demonstrates that (1) the investigators have extensive experience with defining the epidemiology and outcomes of antimicrobial use; the study of the mother-infant dyad in the perinatal period; the collection, processing, and analysis of human gut microbiome data; and assessing and characterizing infant and early childhood growth; 2) that antibiotic use across this population is both frequent and variable-an ideal environment to evaluate the proposed hypothesis; and 3) longitudinal early life anthropometric measurements of a cohort enrolled from birth is feasible. Through CHOP we have access to a large birthing center feeding one of the largest pediatric healthcare networks in the US using a common electronic health record. This large heterogeneous cohort is one of the key strengths of our proposal, and will enable us to recruit, follow, and monitor health records of all cohort members in real time. The establishment of a large birth cohort in which the microbiome is defined and patient health information is prospectively recorded will lead to unique future opportunities to directly link changes in the structure and function of the developing microbiome with additional health outcomes.