Neurobiological and neurocognitive consequences of diverse microbiome functional trajectories

有令人信服的证据表明，母亲和婴儿肠道微生物组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 早期婴儿大脑发育，表明这两个关键事件之间的功能关系。的 我们的建议的前提是基于大量的研究和新的初步分析报告如下， 母亲产前焦虑（PNA），一个突出的产前母亲的危险因素，和儿童神经发育。我们 假设产前母体微生物组及其对新生儿神经发育的影响 婴儿早期认知是由母婴微生物组转移决定的， 微生物源性神经活性代谢物（NAM）的发育和生物合成。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 婴儿肠道微生物组的轨迹。所提出的模型具有科学性和实用性，因为它 利用大量的现有数据，作为大型、前瞻性纵向和多样化妊娠的一部分收集 队列，从第一个三个月到孩子的第四年，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以及儿童 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。我们使用这些成分来检验神经发育是一个重要的假设。 在婴儿肠道微生物组（IGM）的出生后阶段依赖于年龄驱动的NAM生物合成 发展在目标1中，我们使用产前母体阴道微生物组（MVM）的宏基因组分析， 鉴定与PNA相关的NAM的种类和功能性生物合成途径。我们还评估了 母亲焦虑通过焦虑对婴儿肠道微生物组的初始定殖的潜在转移 “印记”MVM。在目标2中，我们使用宏基因组学和代谢组学分析来确定 在第一年，在IGM开发的关键阶段和NAM的差异化综合之间， 混淆和竞争性暴露，最明显的是母亲饮食和婴儿喂养。在目标3中，我们应用这种丰富的 数据预测1至4岁的神经认知评估，以正式测试时间关系 微生物组阶段和生命第一年的神经发育之间的关系以及微生物组的持久性- 神经发育的关系，通过4岁。这项研究的科学影响将是先进的 了解产前暴露的作用;记录个体间和个体内暴露的来源 在生命的最初几年，IGM中的差异;确定NAM在IGM中可能发挥的机制作用， MGB轴;记录对神经发育的潜在广泛和持续影响。

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.