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

• 批准号: 9306197
• 负责人: CHRISTOPHER L COE
• 金额: $ 76.03万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306197
• 关键词: 1 year old; Address; Affect; Age-Months; 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; MRI Scans; 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; Nurses; 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; Structure; Swab; Techniques; Testing; Tissue Banks; Tissues; Weaning; base; behavior measurement; cohort; commensal microbes; cytokine; fecal transplantation; gamma-Aminobutyric Acid; gray matter; gut microbiome; gut microbiota; in vivo; innovation; liquid chromatography mass spectrometry; metabolomics; microbial community; microbiome; microbiota; monoamine; multidisciplinary; myelination; neurochemistry; neurodevelopment; neuroimaging; nonhuman primate; novel; peer; power analysis; public health relevance; rectal; relating to nervous system; sample collection; social group; social skills; white matter

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（由申请方提供）：通过暴露于母亲和早期养育环境获得的婴儿肠道微生物群在建立功能性胃肠道和通过刺激免疫、内分泌和肠神经系统的成熟促进健康方面发挥关键作用。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的机制途径，以及生命第一年的情绪和行为反应。母亲的微生物组将在怀孕和哺乳期间进行实验控制，使我们能够产生具有两种不同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的微生物群的发育，以及随后断奶后肠道细菌群落重组时，由于固体食物的消耗和与同龄人的接触。基于初步结果，我们专注于两组信号介质：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。在1岁时，将使用最先进的神经成像技术对大脑皮质区域（灰色和白色物质体积）进行结构分析，并通过扩散张量成像量化髓鞘形成的速度。在R21初始阶段，我们将验证 可以可靠地产生20只具有不同微生物群特征的婴儿猴子，并且群体差异持续存在，使我们能够创建由具有可比微生物群的婴儿组成的同龄社会群体。在R33阶段，将产生一个更大的40名婴儿的队列，使我们能够使用粪便移植方法来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移到 捐赠动物的数量。该项目利用了一个主要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的幼猴，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学面板的测序和神经化学结论。我们的项目直接解决了RFA的一个中心原则，即调查 研究的目的是确定母亲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相关。采用多层次的分子生物学和发育神经科学方法。这项研究对儿童健康有明确的翻译相关性，有助于现存的发现，表明一种异常的 微生物组在几种儿科疾病中是明显的。我们准备验证新的生物标志物，以跟踪肠道微生物群对全身生理学的影响，并在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方面取得新的发现。