Resilience in early development: How antibiotics shape infant microbiome 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。在分娩期间和分娩后，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，直到建立密集、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，并且对婴儿营养、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，偏离本地微生物群的正常发育可能会影响儿童的健康。抗生素对天然微生物群的破坏与多种人类疾病有关，包括艰难梭菌结肠炎和其他急性和慢性腹泻。儿童哮喘、肥胖和炎症性肠病等长期后果也与生命早期使用抗生素有关。令人惊讶的是，我们对抗生素对婴儿微生物群发育的直接影响缺乏清晰的认识。在某种程度上，这是因为直到最近，还没有能够检测复杂、动态微生物群落中干扰特征的方法。尽管是人类发展的一个整体和普遍的部分，本地微生物群的出生后组装，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。我们的目标是通过遵循基线，跟踪20名健康婴儿从出生到两岁的微生物组组装

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.