Maternal and Infant Microbiome Determinants of Brain and Behavioral Development

描述（由申请人提供）：婴儿的肠道微生物群是通过接触母亲和早期养育环境获得的，通过刺激免疫、内分泌和肠道神经系统的成熟，在建立功能性胃肠道和促进健康方面发挥着关键作用。我们的项目使用非人类灵长类动物模型来专门确定婴儿肠道微生物组影响大脑发育以及生命第一年情绪和行为反应的机制途径。母亲的微生物组将在怀孕和哺乳期间通过实验进行控制，使我们能够培育出具有两种独特微生物组特征的婴儿。微生物群落分析将在 Illumina MiSeq 上运行，以获取高质量的 16S rRNA 数据，以便跟踪婴儿与母亲在一起时以及随后断奶后肠道细菌群落因食用固体食物和与同龄人接触而重组时微生物群的发育。根据初步结果，我们重点关注两组信号传导介质：1）肠道细菌产生神经化学物质，包括单胺神经递质和 GABA，2）血液和鞘内隔室中的炎症细胞因子活性。一岁时，最先进的神经成像将用于皮质脑区域（灰质和白质体积）的结构分析，并通过扩散张量成像量化髓鞘形成的速度。在最初的 R21 阶段，我们将验证 可以可靠地生成 20 只具有不同微生物组特征的幼猴，并且种群差异持续存在，使我们能够创建由具有可比微生物组的婴儿组成的同伴社会群体。在 R33 阶段，将产生 40 名婴儿的更大队列，使我们能够使用粪便移植方法系统地改变肠道微生物群的组成，并测试行为和神经轨迹将转变为 供体动物的。该项目利用了大型灵长类动物繁育设施的独特资源，使我们能够在受控环境条件下评估大量幼猴，以及 4 个机构合作研究团队的多学科专业知识和资源。采用创新方法，包括肠道组织标本的活检收集，以验证来自更常规收集的直肠拭子的定向代谢组组的测序和神经化学结论。我们的项目直接涉及 RFA 的核心原则，即调查 母体和婴儿微生物组对行为和大脑成熟的影响，并确定失调的微生物组是否与非典型发育有关。采用多层分子生物学和发育神经科学方法。这项研究对儿童健康具有明显的转化相关性，有助于现有的发现表明异常 微生物组在多种儿科疾病中很明显。我们准备验证新的生物标志物，用于追踪肠道微生物群对全身生理学的影响，并就肠道和肠神经系统如何与微生物组相互作用以影响中枢神经系统的正常功能和发育做出新的发现。

DESCRIPTION (provided by applicant): The gut microbiota of the infant, acquired by exposure to the mother and the early rearing environment, plays a critical role in establishing a functional gastrointestinal tract and promoting health via stimulating the maturation of the immune, endocrine, and enteric nervous systems. Our project uses a nonhuman primate model to specifically determine the mechanistic pathways through which the infant's gut microbiome affects brain development, as well as emotional and behavioral responsiveness during the first year of life. The mother's microbiome will be experimentally controlled during the pregnancy and nursing periods, enabling us to generate infants with two distinctive microbiome profiles. Microbial community analyses will be run on Illumina MiSeq to acquire high quality 16S rRNA data in order to track the development of the infant's microbiota while it is with the mother, and subsequently after weaning when the gut bacterial community is reorganized, due to the consumption of solid foods and exposure to peers. Based on preliminary results, we focus on two sets of signaling mediators: 1) the production of neurochemicals by gut bacteria, including monoamine neurotransmitters and GABA, and 2) inflammatory cytokine activity in the blood and intrathecal compartments. At one year of age, state-of-the-art neuroimaging will be used for structural analyses of cortical brain regions (gray and white matter volumes), and for quantifying the pace of myelination with diffusion tensor imaging. During the initial R21 phase, we will verify that 20 infant monkeys with distinct microbiome profiles can be reliably generated, and that population differences persist, allowing us to create peer social groups comprised of infants with comparable microbiota. During the R33 phase, a larger cohort of 40 infants will be generated, enabling us to also use fecal transplant methods to systematically change the composition of the gut microbiota and to test the hypothesis that behavioral and neural trajectories will shift to that of the donor animal. This project takes advantage of the unique resources of a major primate breeding facility, permitting us to evaluate a large number of infant monkeys under controlled environmental conditions, and the multi-disciplinary expertise and resources of the collaborating research team at 4 institutions. Innovative methods are employed, including the biopsy collection of gut tissue specimens to validate sequencing and neurochemical conclusions from directed metabolomic panels derived from the more routinely collected rectal swabs. Our project directly addresses a central tenet of the RFA, which is to investigate the influence of the maternal and infant microbiome on behavioral and brain maturation, and to determine if a dysregulated microbiome is associated with atypical development. Multi-tiered, molecular biology and developmental neuroscience approaches are employed. This research has a clear translational relevance for child health, contributing to extant findings that indicate an abnormal microbiome is evident in several pediatric disorders. We are poised to validate new biomarkers for tracking the influence of the gut microbiota on systemic physiology and to make novel discoveries on how the gut and enteric nervous system interface with the microbiome to influence the normal functioning and development of the central nervous system.