Population Genomic Analysis of Gut Microbial Colonization in Premature Infants

摘要 大量文献表明，产前和新生儿抗生素暴露与不良反应有关。 由于发育中的微生物组的破坏，儿童的结果。在早产儿中， 几十年来，包括在生命的最初几个小时内给予广谱抗生素， 早期发病脓毒症的推定诊断的治疗。然而，几乎所有接受这些治疗的早产儿， 抗生素不会导致败血症这项资助更新申请提出了一项辅助微生物组研究 与NANO（NICU抗生素和结局）试验有关，这是一项最近启动的临床试验，将挑战 这是一种长期存在的做法，即立即给新生早产儿开抗生素。NANO将测试 假设出生时使用抗生素会影响临床稳定的早产儿的结局。这项多中心 一项由我们研究小组成员领导的试验将随机选择802名早产儿接受静脉注射， 氨苄青霉素和庆大霉素或盐水安慰剂对照。该研究将衡量变量的影响，包括 分娩方式、胎龄、性别、母乳的接受情况以及母亲产前给药情况 抗生素 出生后第一个月的婴儿粪便样本以及母体粪便和阴道拭子将在 NANO使用16S rRNA基因测序进行抗生素和安慰剂组的基本微生物组分析。 在这里，我们建议使用新的菌株水平来增强NANO研究受试者的微生物组分析。 宏基因组策略和分析超过第一个月的生命样本。根据这一战略，我们建议 目标1检验经验性抗生素（EA）破坏早产儿母婴菌株共享的假设。 目标二。检验EA增加肠道细菌抗菌素耐药基因丰度的假设， 早产儿目标3。检验EA延迟肠道生态系统从由以下因素主导的转变的假设： 从兼性厌氧菌到专性厌氧菌。因为NANO是第一个临床试验 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， 并回答了一系列关于早期肠道细菌定植的独特生物学问题。

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.