Resilience in early development: How antibiotics shape infant microbiome assembly

早期发育的弹性：抗生素如何塑造婴儿微生物组组装

• 批准号: 8704976
• 负责人: Elizabeth Costello
• 金额: $ 10.46万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-25 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704976
• 关键词: Acute; Adult; Affect; Age; Age-Years; Amoxicillin; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Asthma; Bacteria; Bacteriophages; Bacteroides; Bifidobacterium; Birth; Child; Child health care; Childhood Asthma; Chronic; Clostridium difficile; Colitis; Collection; Communities; Complex; Contracts; DNA; Data; Development; Diarrhea; Disease; Distal; Elements; Environment; Exhibits; Feces; Fetal Development; Food; Gastrointestinal tract structure; Generations; Genes; Genetic; Genome; Genomics; Goals; High-Throughput Nucleotide Sequencing; Human; Human Development; Immigration; Immune system; In Situ; Indigenous; Individual; Infant; Infection; Inflammatory Bowel Diseases; Internet; Intestines; Klebsiella; Knowledge; Life; Link; Mediating; Metabolism; Metagenomics; Methods; Microbe; Mothers; Obesity; Oral; Oral cavity; Pattern; Phylogenetic Analysis; Plasmids; Population; Postpartum Period; Process; Recording of previous events; Recovery; Research; Resistance; Resolution; Sampling; Series; Shapes; Shotgun Sequencing; Site; Skin; Solid; Source; Structure; Surveys; Taxon; Testing; Time; Time Series Analysis; Tooth structure; Vagina; Variant; Vertical Disease Transmission; Work; base; cohort; early childhood; functional genomics; human disease; immune function; imprint; infant nutrition; metagenomic sequencing; microbial colonization; microbial community; microbiome; nutrition; obesity risk; pathogen; postnatal; predictive modeling; programs; public health relevance; rRNA Genes; resilience; response; transmission process

DESCRIPTION (provided by applicant): Fetal development generally takes place within a microbe-free environment. During delivery and rapidly thereafter, microbes from a variety of sources colonize the infant skin, mouth, and gastrointestinal tract until dense, complex communities are established. Successional changes in the structure and function of these communities are marked in early development and have important consequences for infant nutrition, pathogen resistance, gut maturation, and immune system programming. During this time, deviations from the normal development of the indigenous microbiota may affect child health. Antibiotic disruption of the native microbiota is implicated in a wide range of human disease, including Clostridium difficile colitis and other acute and chronic forms of diarrhea. Longer-term consequences, such as childhood asthma, obesity, and inflammatory bowel disease have also been linked to antibiotic use early in life. Surprisingly, we lack a clear understanding of the direct effects of antibiotics on the developing microbiota of infants. In part this is because until recently, methods capable of detecting the signature of disturbance within complex, dynamic microbial communities were unavailable. Albeit an integral and universal part of human development, the postnatal assembly of the indigenous microbiota, including its variability over time, sources of colonists, responses to disturbance, and the key factors affecting such patterns remains poorly understood. Our objective is to track microbiome assembly from birth until two years of age in a cohort of 20 healthy infants, by following baseline developmental patterns and responses to antibiotic perturbation using time series analysis of high-throughput phylogenetic marker gene and metagenomic sequencing surveys. We will also track the postpartum microbiomes of their mothers, and assess the evidence for direct transmission from mother to child. We hypothesize that the developing microbiomes of infants exhibit resilience in the wake of antibiotic therapy. Having examined this question, we will go on to test the specific hypothesis that the response of the developing microbiome to antibiotic exposure depends, in part, on the infant's mode of delivery. We will study this question in a larger cohort of amoxicillin-treated infants. The long-term goal of this research is to understand the ecological basis of microbiome resilience (or collapse) in the context of early childhood development. It will lay important groundwork for predictive models of antibiotic (or other) perturbation responses that will aid in the promotion of healthy microbiome transmission and assembly.

描述（由申请人提供）：胎儿发育通常在无微生物的环境中进行。在分娩过程中以及分娩后不久，来自各种来源的微生物在婴儿的皮肤、口腔和胃肠道中定植，直到形成密集、复杂的群落。这些群落的结构和功能的连续变化在早期发育中是显著的，并对婴儿营养、病原体抗性、肠道成熟和免疫系统编程具有重要影响。在此期间，偏离本土微生物群的正常发育可能会影响儿童健康。抗生素对天然微生物群的破坏涉及广泛的人类疾病，包括艰难梭菌结肠炎和其他急性和慢性形式的腹泻。长期后果，如儿童哮喘，肥胖和炎症性肠病也与生命早期的抗生素使用有关。令人惊讶的是，我们对抗生素对婴儿发育中的微生物群的直接影响缺乏明确的认识。部分原因是直到最近，还没有能够检测复杂动态微生物群落中干扰信号的方法。尽管是人类发展的一个组成部分和普遍的一部分，出生后组装的土著微生物群，包括其随时间的变化，殖民者的来源，对干扰的反应，以及影响这种模式的关键因素仍然知之甚少。我们的目标是跟踪20名健康婴儿从出生到两岁的微生物组组装， 使用高通量系统发育标记基因和宏基因组测序调查的时间序列分析的发展模式和抗生素干扰的反应。我们还将跟踪他们母亲的产后微生物组，并评估母婴直接传播的证据。我们假设婴儿的微生物组在抗生素治疗后表现出弹性。在研究了这个问题之后，我们将继续测试特定的假设，即发育中的微生物组对抗生素暴露的反应部分取决于婴儿的分娩方式。我们将在一个更大的阿莫西林治疗婴儿队列中研究这个问题。这项研究的长期目标是了解在儿童早期发育背景下微生物组恢复力（或崩溃）的生态基础。它将为抗生素（或其他）扰动反应的预测模型奠定重要基础，这将有助于促进健康的微生物组传播和组装。