Population Genomic Analysis of Gut Microbial Colonization in Premature Infants

摘要 大量文献表明，产前和新生儿接触抗生素与不良反应有关。 由于发育中的微生物群的破坏而导致的童年结局。对于早产儿，护理的标准是 几十年来一直包括在生命的最初几个小时使用广谱抗生素 推定诊断为早发性脓毒症的治疗。然而，几乎所有接受这些治疗的早产儿 抗生素实际上并不会导致败血症。这项拨款续期申请提出了一项辅助微生物组研究。 与NANO(NICU抗生素和结果)试验有关，这是一项最近启动的临床试验，将挑战 这是一种长期的做法，即立即给早产儿开抗生素。Nano将测试 假设出生时的抗生素会恶化临床稳定的早产儿的结局。这个多中心 由我们的研究团队成员领导的试验将随机选择802名早产儿接受静脉注射 氨苄西林和庆大霉素或生理盐水安慰剂对照。这项研究将衡量变量的影响，包括 分娩方式、胎龄、性别、接受母乳和孕妇产前管理 抗生素。 婴儿出生后第一个月的粪便样本，以及母亲的粪便和阴道拭子将在 使用16S rRNA基因测序，在抗生素组和安慰剂组中使用NANO进行基本微生物群谱分析。 在这里，我们建议使用新的应变水平来增强对纳米研究对象的微生物组分析 通过分析出生后第一个月以后的样本，研究元基因组学策略。通过这一战略，我们建议 目的1.验证经验性抗生素(EA)干扰早产儿母婴菌株共享的假说。 目的2.验证电针增加肠道细菌耐药基因丰度的假设 早产儿。目标3.测试这样一种假设，即EA延迟了从由 兼性厌氧菌到以专性厌氧菌为主的一种。因为Nano是首创的临床试验 评估生命最初几天的抗生素治疗，这项辅助研究将提供一个难得的机会来询问 并回答了一组关于早期肠道细菌定植生物学的独特问题。

Abstract A large body of literature now indicates that antenatal and neonatal antibiotic exposure is associated with adverse childhood outcomes due to disruption of the developing microbiome. In premature infants, the standard of care for many decades has included the administration of broad-spectrum antibiotics in the first hours of life as treatment for a presumptive diagnosis of early onset sepsis. However, nearly all preterm infants receiving these antibiotics do not actually have sepsis. This grant renewal application proposes an ancillary microbiome study linked to the NANO (NICU Antibiotics and Outcomes) Trial, a recently launched clinical trial that will challenge this longstanding practice of immediately prescribing antibiotics to newborn preterm infants. NANO will test the hypothesis that antibiotics at birth worsens outcomes in preterm infants that are clinically stable. This multicenter trial, which is led by members of our research team, will randomize 802 premature infants to receive intravenous ampicillin and gentamicin or a saline placebo control. The study will measure the impact of variables including mode of delivery, gestational age, sex, and receipt of maternal milk, and administration of maternal antepartum antibiotics. Infant fecal samples in the first month of life as well as maternal fecal and vaginal swabs will be collected in NANO for basic microbiome profiling in the antibiotics and placebo groups using 16S rRNA gene sequencing. Here, we propose to augment microbiome analyses of NANO study subjects using novel strain-level metagenomic strategies and by analyzing samples beyond the first month of life. With this strategy, we propose to Aim 1. Test the hypothesis that empiric antibiotics (EA) disrupts mother-infant strain sharing in preterm infants. Aim 2. Test the hypothesis that EA increases the abundance of gut bacterial antimicrobial resistance genes in preterm infants. Aim 3. Test the hypothesis that EA delays the transition from a gut ecosystem dominated by facultative anaerobes to one dominated by obligate anaerobes. Because NANO is a first-of-its-kind clinical trial evaluating antibiotic therapy during the first days of life, this ancillary study will provide a rare opportunity to ask and answer a unique set of questions about the biology of early gut bacterial colonization.