Neurobiological and neurocognitive consequences of diverse microbiome functional trajectories

不同微生物组功能轨迹的神经生物学和神经认知后果

• 批准号: 10443912
• 负责人: STEVEN R. GILL
• 金额: $ 72.32万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443912
• 关键词: 4 year old; Age; Anabolism; Anxiety; Area; Bacteria; Behavior; Biochemical; Biological; Birth; Blood specimen; Brain; Chemicals; Child; Clinical; Clinical Research; Cognition; Collection; Communication; Data; Development; Enteric Nervous System; Event; Exposure to; First Pregnancy Trimester; Future; Goals; Human Milk; Immune; Individual Differences; Infant; Intervention; Intestines; Life; Link; Maternal Exposure; Measures; Metagenomics; Modeling; Molecular; Mothers; Neurobiology; Neurocognitive; Neurotransmitters; Newborn Infant; Outcome; Participant; Pathway interactions; Peripheral; Phase; Placenta; Play; Pregnancy; Prevention strategy; Production; Reporting; Risk Factors; Role; Sampling; Shapes; Signal Transduction; Source; Taxonomy; Testing; Third Pregnancy Trimester; Umbilical Cord Blood; base; cohort; design; early onset; endophenotype; feeding; gut bacteria; gut colonization; gut microbiome; gut microbiota; gut-brain axis; imprint; improved; indexing; infant gut microbiome; maternal anxiety; maternal imprint; maternal microbiome; maternal microbiota; maternal risk; metabolomics; metagenome; microbiome; microbiome composition; microbiota; mother nutrition; neglect; neurodevelopment; neuroimaging; nutrition; offspring; parent grant; postnatal; postnatal development; postnatal period; pre-clinical; prenatal; prenatal exposure; prenatal influence; prospective; vaginal fluid; vaginal microbiome

There is compelling evidence for a critical role of the maternal and infant gut microbiome in early infant brain neurodevelopment. Temporal milestones in postnatal infant gut microbiome development align with changes in early infant brain development, suggesting functional relationships between these two pivotal events. The premise of our proposal is based on a wealth of studies and new preliminary analyses reported below linking maternal prenatal anxiety (PNA), a prominent prenatal maternal risk factor, and child neurodevelopment. We hypothesize that the prenatal maternal microbiome and its influence on newborn neurodevelopment is shaped by PNA, and that early infant cognition is determined by mother-to-infant microbiome transfer, postnatal development and biosynthesis of microbiota-derived neuroactive metabolites (NAMs). Our study is framed by a proposed developmental model that includes two major components; prenatal anxiety and developmental phase trajectories of the infant gut microbiome. The proposed model has scientific as well as practical strengths, as it leverages a wealth of existing data collected as part of a large, prospective longitudinal and diverse pregnancy cohort that has been followed from the first trimester through the child’s 4th year, with extensive longitudinal characterization of prenatal exposures, child microbiome and other key biological samples, and child neurodevelopment assessed longitudinally that will enable important and previously neglected incorporation of potential confounds. We use these components to test the central hypothesis that neurodevelopment is dependent on age-driven biosynthesis of NAMs through the postnatal period of infant gut-microbiome (IGM) development. In Aim 1, we use metagenomic analysis of the prenatal maternal vaginal microbiome (MVM) to identify species and functional biosynthetic pathways for NAMs associated with PNA. We also assess the potential transfer of maternal anxiety through the initial colonization of the infant gut microbiome by an anxiety “imprinted” MVM. In Aim 2, we use metagenomic and metabolomic analyses to determine the association between key stages of IGM development and differential synthesis of NAMs over the first year, attending to confounds and competing exposures, most notably, maternal diet and infant feeding. In Aim 3, we apply this rich data to predict neurocognitive assessments from age 1 to 4 years to formally test the temporal relationship between microbiome phase and neurodevelopment in the first year of life and durability of the microbiota- neurodevelopment relationship through 4 years of age. The scientific impact of the study will be on advanced understanding of the role of prenatal exposures; documenting sources of between- and within-individual differences in the IGM through the first years of life; identifying NAMs with a possible mechanistic role in the MGB axis; documenting a potentially broad and persistent impact on neurodevelopment.

有令人信服的证据表明母婴肠道微生物组在婴儿早期大脑中发挥着关键作用 神经发育。产后婴儿肠道微生物组发育的时间里程碑与 早期婴儿大脑发育表明这两个关键事件之间的功能关系。这 我们建议的前提是基于大量的研究和新的初步分析，如下所示链接 母亲产前焦虑（PNA）是一个重要的产前母亲危险因素，与儿童神经发育有关。我们 假设产前母体微生物组及其对新生儿神经发育的影响已形成 由 PNA 得出，早期婴儿认知是由母婴微生物组转移、产后决定的 微生物群衍生的神经活性代谢物（NAM）的发育和生物合成。我们的研究框架是 拟议的发展模型包括两个主要组成部分；产前焦虑和发育阶段 婴儿肠道微生物组的轨迹。所提出的模型具有科学性和实用性，因为它 利用作为大型、前瞻性纵向和多样化妊娠的一部分收集的大量现有数据 该队列从妊娠早期一直跟踪到孩子的第四年，具有广泛的纵向研究 产前暴露、儿童微生物组和其他关键生物样本以及儿童的特征 纵向评估神经发育，这将使重要的和以前被忽视的纳入 潜在的混淆。我们使用这些组件来检验神经发育是 婴儿肠道微生物群 (IGM) 的产后阶段依赖于年龄驱动的 NAM 生物合成 发展。在目标 1 中，我们利用产前母亲阴道微生物组 (MVM) 的宏基因组分析来 确定与 PNA 相关的 NAM 的种类和功能生物合成途径。我们还评估了 母亲的焦虑可能通过婴儿肠道微生物组的初始定植而转移 “印记”MVM。在目标 2 中，我们使用宏基因组和代谢组分析来确定关联性 在 IGM 开发的关键阶段和第一年 NAM 的差异合成之间，关注 混淆和竞争暴露，最显着的是母亲饮食和婴儿喂养。在目标 3 中，我们应用了这种丰富的 用于预测 1 至 4 岁神经认知评估的数据，以正式测试时间关系 生命第一年的微生物组阶段和神经发育之间以及微生物组的持久性之间 4 岁之前的神经发育关系。该研究的科学影响将是先进的 了解产前暴露的作用；记录个人之间和个人内部的来源 生命最初几年 IGM 的差异；识别 NAM 在以下方面可能具有的机械作用 MGB轴；记录了对神经发育的潜在广泛和持久的影响。