Maternal and Infant Microbiome Determinants of Brain and Behavioral Development

母婴微生物群对大脑和行为发育的决定因素

基本信息

批准号：
8749960
负责人：
CHRISTOPHER L COE
金额：
$ 29.12万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8749960
关键词：
Address Affect Age-Months Age-Years Animals Bacteria Behavior Behavioral Biological Markers Biopsy Biopsy Specimen Blood Brain Brain region Brain scan Breeding Cerebrospinal Fluid Child health care Childhood Collection Communities Consumption Coupled Data Development Diet Diffusion Magnetic Resonance Imaging Discipline of Nursing Disease Emotional Endocrine Enteric Nervous System Environment Experimental Designs Exposure to Feces Food Gastrointestinal tract structure Goals Health Human Immune Immune response In Vitro Infant Infant Development Inflammatory Institution Intestines Life Macaca mulatta Magnetic Resonance Imaging Measurement Measures Mediating Mediator of activation protein Methods Modeling Molecular Biology Monitor Monkeys Mothers Neuraxis Neurophysiology - biologic function Neurosciences Neurotransmitters Normalcy Outcome Pathway interactions Pediatric Research Peer Group Performance Phase Phenotype Phylogeny Physiological Physiology Play Population Pregnancy Primates Production Rectum Research Resources Ribosomal RNA Role Running Sampling Signal Transduction Solid Specimen Staging Structure Swab Techniques Testing Tissue Banks Tissues Transplantation Weaning base behavior measurement cohort commensal microbes cytokine gamma-Aminobutyric Acid gray matter gut microbiota in vivo innovation liquid chromatography mass spectrometry metabolomics microbial community microbiome monoamine myelination neurochemistry neurodevelopment neuroimaging nonhuman primate novel peer public health relevance rectal relating to nervous system social group social skills white matter

项目摘要

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.

描述（由申请人提供）：通过暴露于母亲和早期饲养环境而获得的婴儿的肠道菌群，在建立功能性胃肠道和促进健康的健康中起着至关重要的作用，通过刺激免疫，内分泌和肠神经系统的成熟。我们的项目使用非人类灵长类动物模型来特异性确定婴儿的肠道微生物组在生命的第一年中影响大脑发育以及情绪和行为反应性的机械途径。母亲的微生物组将在怀孕和护理期间进行实验控制，从而使我们能够产生具有两个独特的微生物组特征的婴儿。微生物群落分析将在Illumina Miseq上进行，以获取高质量的16S rRNA数据，以便在与母亲在一起的同时跟踪婴儿的微生物群的发展，并在对肠道细菌群落进行了重新组织后，由于固体食品的消费和与同伴的暴露。基于初步结果，我们关注两组信号传导介质：1）肠道细菌（包括单胺神经递质和GABA）的神经化学物质的产生，以及2）血液和肠内障碍物中的炎症细胞因子活性。在一岁的时候，最新的神经影像学将用于对皮质大脑区域（灰质和白质体积）的结构分析，并通过扩散张量成像来量化髓鞘速度。在最初的R21阶段，我们将验证可以可靠地产生20个具有不同微生物组谱的婴儿猴子，并且人口差异持续存在，从而使我们能够创建由具有可比微生物群的婴儿组成的同伴社会群体。在R33阶段，将产生较大的40个婴儿队列，使我们还可以使用粪便移植方法系统地改变肠道菌群的组成，并测试行为和神经轨迹的假设，即行为和神经轨迹将转移到捐助动物。该项目利用了主要的灵长类动物繁殖设施的独特资源，使我们能够在受控的环境条件下评估大量婴儿猴子，以及4个机构的合作研究团队的多学科专业知识和资源。采用了创新方法，包括肠道组织标本的活检收集，以验证从定向更常规收集的直肠拭子中得出的定向代谢组面板的测序和神经化学结论。我们的项目直接解决了RFA的中心宗旨，这是为了调查孕产妇和婴儿的微生物组在行为和脑成熟度上，并确定微生物组失调是否与非典型发育有关。采用了多层，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翻译相关性，导致现存的发现表明异常微生物组在几种小儿疾病中很明显。我们准备验证新的生物标志物，以跟踪肠道微生物群对系统生理学的影响，并就肠道和肠神经系统与微生物组的接口如何影响中枢神经系统的正常功能和发育做出新颖的发现。