Resilience in early development: How antibiotics shape infant microbiome assembly

描述(申请人提供)：胎儿发育一般在无微生物的环境中进行。在分娩期间和分娩后迅速，来自各种来源的微生物在婴儿的皮肤、口腔和胃肠道中定居，直到形成密集、复杂的群落。这些群落的结构和功能的演进性变化在早期发育时是显著的，并对婴儿营养、病原体抵抗力、肠道成熟和免疫系统编程产生重要影响。在此期间，偏离土著微生物区系的正常发育可能会影响儿童健康。抗生素对当地微生物区系的破坏与一系列人类疾病有关，包括艰难梭菌结肠炎和其他急性和慢性形式的腹泻。儿童哮喘、肥胖和炎症性肠病等较长期的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发育中的微生物区系的直接影响缺乏明确的了解。这在一定程度上是因为，直到最近，还没有能够检测复杂、动态微生物群落内干扰特征的方法。尽管土著微生物区系是人类发展不可或缺的普遍组成部分，但其出生后的组装情况，包括其随时间的变异性、殖民者的来源、对干扰的反应以及影响这些模式的关键因素，仍然知之甚少。我们的目标是通过跟踪基线，跟踪20名健康婴儿从出生到两岁的微生物组组装。 利用高通量系统发育标记基因的时间序列分析和元基因组测序调查的发育模式和对抗生素扰动的响应。我们还将跟踪他们母亲产后的微生物群，并评估母亲直接传播给孩子的证据。我们假设婴儿发育中的微生物群在抗生素治疗后表现出韧性。在研究了这个问题后，我们将继续测试特定的假设，即发育中的微生物群对抗生素暴露的反应部分取决于婴儿的分娩方式。我们将在接受阿莫西林治疗的更大的婴儿队列中研究这个问题。这项研究的长期目标是在儿童早期发展的背景下理解微生物组恢复(或崩溃)的生态学基础。这将为抗生素(或其他)扰动反应的预测模型奠定重要的基础，这将有助于促进健康的微生物群的传播和组装。

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.