Population Genomic Analysis of Gut Microbial Colonization in Premature Infants

早产儿肠道微生物定植的群体基因组分析

• 批准号: 10298678
• 负责人: Jillian Banfield
• 金额: $ 78.67万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10298678
• 关键词: 16S ribosomal RNA sequencing; Adverse effects; Aerobic; Agreement; Ampicillin; Anaerobic Bacteria; Ancillary Study; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacterial Antibiotic Resistance; Bacterial Chromosomes; Bacterial Genes; Bacteriophages; Biology; Birth; Blinded; Cell Respiration; Cessation of life; Childhood; Clinical; Clinical Trials; Collection; Drug resistance; Early Diagnosis; Ecosystem; Elements; Enrollment; Equipment and supply inventories; Exposure to; Face; Funding; Genes; Genetic; Genomics; Gentamicins; Gestational Age; Grant; Health; Hospitals; Hour; Human; Human Milk; Incidence; Infant; Intestines; Intravenous; Knowledge; Length; Life; Link; Literature; Longitudinal Studies; Measures; Metabolism; Metagenomics; Mothers; Multicenter Trials; Mutation; Necrotizing Enterocolitis; Neonatal; Newborn Infant; Nitrogen; Organism; Outcome; Outcome Study; Oxidation-Reduction; Oxygen; Participant; Patients; Pattern; Perinatal; Placebo Control; Placebos; Plasmids; Population; Premature Infant; Process; Protocols documentation; Randomized; Research; Resistance; Resolution; Ribosomal RNA; Saline; Sampling; Sampling Studies; Sepsis; Study Subject; Swab; Testing; Time; Time Series Analysis; United States National Institutes of Health; Vagina; Variant; Vertical Disease Transmission; adverse outcome; antenatal; clinically relevant; early onset; fitness; gut health; gut microbiome; infant gut microbiome; inter-individual variation; knock-down; late onset sepsis; maternal microbiome; member; microbial; microbial colonization; microbiome; microbiome analysis; microbiome research; nano; novel; opportunistic pathogen; pathogen; placebo group; preterm newborn; primary endpoint; randomized placebo controlled trial; rectal microbiome; resistance gene; resistant strain; sex; standard of care; transcriptomics

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.

抽象的 现在大量文献表明，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被破坏而导致的儿童结局。对于早产儿，护理标准 几十年来，包括在生命的最初几个小时内给予广谱抗生素， 治疗早发性脓毒症的推定诊断。然而，几乎所有接受这些治疗的早产儿 抗生素实际上不会导致败血症。该拨款续展申请提出了一项辅助微生物组研究 与 NANO（NICU 抗生素和结果）试验相关，这是一项最近启动的临床试验，将挑战 这种立即给早产儿开抗生素处方的长期做法。 NANO 将测试 假设出生时使用抗生素会使临床稳定的早产儿的结局恶化。这个多中心 由我们研究团队成员领导的试验将随机抽取 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。该研究将衡量变量的影响，包括 分娩方式、胎龄、性别、母乳摄入以及产前管理 抗生素。 出生第一个月的婴儿粪便样本以及母亲粪便和阴道拭子将在 NANO 使用 16S rRNA 基因测序对抗生素组和安慰剂组进行基本微生物组分析。 在这里，我们建议使用新的菌株水平来增强 NANO 研究对象的微生物组分析 宏基因组策略并通过分析生命第一个月后的样本。通过这一策略，我们建议 目标 1. 检验经验性抗生素 (EA) 会破坏早产儿母婴菌株共享的假设。 目标 2. 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 延迟肠道生态系统由以下物质主导的转变的假设： 兼性厌氧菌转变为以专性厌氧菌为主的厌氧菌。因为 NANO 是一项史无前例的临床试验 在生命的最初几天评估抗生素治疗，这项辅助研究将提供一个难得的机会来询问 并回答一系列有关早期肠道细菌定植的生物学的独特问题。