Neurobiological and neurocognitive consequences of diverse microbiome functional trajectories

有令人信服的证据表明母婴肠道微生物群在早期婴儿大脑中起着关键作用。 神经发育。出生后婴儿肠道微生物组发育的时间里程碑与 婴儿早期大脑发育，提示这两个关键事件之间的功能关系。这个 我们建议的前提是基于大量的研究和以下报告的新的初步分析链接 孕妇产前焦虑(PNA)是一个突出的产前孕妇风险因素，与儿童神经发育有关。我们 孕期母体微生物群及其对新生儿神经发育影响的假说 通过PNA，早期婴儿的认知是由母婴微生物组转移，出生后决定的 微生物源性神经活性代谢产物(NAMS)的开发和生物合成。我们的研究是由一个 提出的发展模型包括两个主要组成部分：产前焦虑和发展阶段 婴儿肠道微生物群的轨迹。所提出的模型具有科学和实用的优点，因为它 利用收集的大量现有数据作为大型、前瞻性、纵向和多样化怀孕的一部分 从怀孕前三个月到孩子第四年一直被跟踪的队列，具有广泛的纵向 产前暴露、儿童微生物组和其他关键生物样本的特征，以及儿童 对神经发育进行纵向评估，这将使重要的和以前被忽视的 潜在的混乱。我们使用这些组件来检验神经发育是 婴儿肠道微生物组(IGM)出生后依赖于年龄驱动的NAMS生物合成 发展。在目标1中，我们使用产前母体阴道微生物组(MVM)的元基因组分析来 确定与PNA相关的NAMS的种类和功能生物合成途径。我们还评估了 焦虑通过婴儿肠道微生物群的初始定植转移母亲焦虑的可能性 “印记”的MVM。在目标2中，我们使用元基因组学和代谢组学分析来确定这种关联 在免疫球蛋白发育的关键阶段和第一年的NAMS的差异合成之间，关注 混淆和相互竞争的暴露，最明显的是母亲的饮食和婴儿喂养。在目标3中，我们应用了这一丰富的 预测1至4岁儿童神经认知评估的数据，以正式测试时间关系 在微生物组阶段和生命第一年的神经发育和微生物区系的持久性之间- 4岁以下儿童的神经发育关系。这项研究的科学影响将对高级 了解产前暴露的作用；记录个人之间和内部的来源 在生命的最初几年中，政府间机制的差异；确定非政府组织可能在 MGB轴；记录了对神经发育的潜在的广泛和持久的影响。

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.