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: 10651895
• 负责人: STEVEN R. GILL
• 金额: $ 72.84万
• 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/10651895
• 关键词: 4 year old; Age; Anabolism; Anxiety; Area; Bacteria; Behavior; Biochemical; Biological; Birth; Blood specimen; Brain; Central Nervous System; 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; Pregnancy; Prevention strategy; Production; Reporting; Risk Factors; Role; Sampling; Shapes; Signal Transduction; Source; Taxonomy; Testing; Third Pregnancy Trimester; Umbilical Cord Blood; 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，孕产妇和婴儿肠道微生物组在婴儿早期大脑中的关键作用 神经发育。产后婴儿肠道微生物组发育的时间里程碑与变化 早期婴儿脑发育，表明这两个关键事件之间的功能关系。这 我们的提案的前提是基于大量研究和下面报告的新初步分析 产前焦虑症（PNA），一种显着的产前母子危险因素和儿童神经发育。我们 假设产前母体微生物组及其对新生神经发育的影响是形状的 通过PNA，早期婴儿的认知是由母亲到fant的微生物组转移确定的 微生物元素衍生的神经活性代谢产物（NAMS）的开发和生物合成。我们的研究是由 提出的发展模型，其中包括两个主要组成部分；产前动画和发展阶段 婴儿肠道微生物组的轨迹。提出的模型具有科学和实践优势 利用大量现有数据作为大型，前瞻性纵向和多元化的怀孕的一部分 从三个月到孩子的第四年，一直遵循的队列，并进行了广泛的纵向 产前暴露，儿童微生物组和其他关键生物样品的表征以及儿童 神经发育对纵向评估，这将使重要的和先前被忽视的研究 潜在的混淆。我们使用这些组件来检验神经发育的中心假设 依赖于NAM的年龄驱动的生物合成，这是婴儿肠肠球菌（IGM）的出生后期 发展。在AIM 1中，我们使用产前母体阴道微生物组（MVM）的宏基因组分析 确定与PNA相关的NAM的物种和功能性生物合成途径。我们还评估 通过焦虑的婴儿肠道微生物组的初始定植，孕产妇焦虑的潜在转移 “印迹” MVM。在AIM 2中，我们使用宏基因组和代谢组分析来确定关联 在第一年的IGM开发的关键阶段与NAM的差异合成之间 混淆和竞争暴露，最值得注意的是母子饮食和婴儿喂养。在AIM 3中，我们应用了这种富人 数据以预测1至4岁的神经认知评估以正式测试临时关系 在生命的第一年中，微生物组相和神经发育之间以及微生物群的耐用性 神经发育关系到4岁。该研究的科学影响将对高级 了解产前暴露的作用；个人间和个体之间的文档来源 在生命的头几年中，IgM的差异；识别NAM在 MGB轴；记录对神经发育的潜在广泛和持续的影响。