The Gut Microbiome Brain Axis and Preterm Infants

项目摘要 婴儿越来越被认为是微生物组建立的关键时间点， 新生儿健康以及以后的结果。肠道微生物组特别与 通过肠-脑轴的神经学结果。然而，肠道微生物组可以具有 对大脑的影响知之甚少。早产儿是这些未知因素的联系点。早产 婴儿是处于显著不良长期神经发育结果风险中的脆弱患者群体。 早产儿大脑发育与肠道微生物组发育平行发生，从而改变了 是改善神经发育结果的潜在手段。在这一提议中， 我们将检验不同的肠道微生物类群和代谢物在关键时间点改善肠道微生物的假设， 学龄期早产儿神经发育结果。 我们在gnotobiotic小鼠模型中的初步和已发表的数据表明， 早产儿微生物群影响神经元数量、髓鞘形成和行为。该提案将利用我们正在进行的 MIND（新生儿发育中的微生物组）早产儿队列，以确定肠道微生物组如何 影响NICU的神经发育潜力，以及它如何改变NICU后的神经发育轨迹。 新生儿重症监护室出院。我们将对参与者的粪便和血液样本进行纵向采样，以监测肠道 微生物组以及粪便和血清代谢物。我们还将进行神经发育测试， 新生儿重症监护室课程，直到学前/学龄（3.5-5岁）。入学准备，描述了 孩子们在课堂上学习时的优势，挑战和支持需求，是一个功能性的 结果不同于智力（IQ）的单一汇总测量，并将作为结果测量。 16 S rRNA基因测序、宏基因组学和代谢组学的组合将应用于 收集粪便样本。复杂的机器学习策略将用于开发新的模型， 早产儿肠道微生物组的演替与时间作为一个关键因素。血清细胞因子分析和 代谢组学将为肠道微生物组如何影响 神经发育我们已经建立了互补的体内致菌小鼠模型，其中无菌 用早产儿微生物群对小鼠进行动物群转移。这个最先进的实验模型将允许 具体调查临床相关微生物群对大脑发育的影响，这是不可能的， 人类婴儿该提案的目标是发现与学校相关的肠道微生物组模式 准备就绪，确定代表微生物组优化机会窗口的关键时间点，以及 确定肠道微生物组影响大脑发育和行为的机制。这个新 知识将提高我们对肠-脑轴的理解，并为基于微生物的 改善婴儿神经发育轨迹的疗法。

PROJECT SUMMARY Infancy is increasingly being recognized as a key time point of microbiome establishment that impacts neonatal health as well as later outcomes. The intestinal microbiome has specifically been implicated in neurologic outcomes via the gut-brain axis. However, means by which the intestinal microbiome can have influence on the brain are poorly understood. The preterm infant is at the nexus of these unknowns. Preterm infants are a vulnerable patient population at risk for significant poor long-term neurodevelopmental outcomes. Preterm infant brain development occurs in parallel with intestinal microbiome development, thus modification of the intestinal microbiome is a potential means of improving neurodevelopmental outcomes. In this proposal, we will test the hypothesis that distinct gut microbiome taxa and metabolites at key time points improve preterm infant neurodevelopmental outcomes at school age. Our preliminary and published data in gnotobiotic mouse models demonstrates that different early preterm infant microbiota impact neuron number, myelination, and behavior. This proposal will use our ongoing MIND (Microbiome In Neonatal Development) preterm infant cohort to determine how the gut microbiome impacts neurodevelopmental potential in the NICU, and how it may alter neurodevelopmental trajectories post- NICU discharge. We will conduct longitudinal sampling of participant fecal and blood samples to monitor gut microbiome as well as fecal and serum metabolites. We will also perform neurodevelopmental testing during the NICU course and up until preschool/school age (3.5-5 years old). School readiness, which describes children's strengths, challenges, and needs for supports when learning in the classroom, is a functional outcome that differs from single summary measures of intelligence (IQ) and will be the outcome measure. A combination of 16S rRNA gene sequencing, metagenomics and metabonomics will be applied to the collected fecal samples. Sophisticated machine learning strategies will be used to develop novel models of preterm infant gut microbiome succession with time as a critical element. Serum cytokine analysis and metabonomics will provide mechanistic insight into how the gut microbiome may be impacting neurodevelopment. We have established complementary in vivo gnotobiotic mouse models, in which germ-free mice are transfaunated with preterm infant microbiota. This state-of-the-art experimental model will allow specific investigation of the impact of clinically relevant microbiota on brain development that is not possible in human infants. The goal of this proposal is to discover intestinal microbiome patterns associated with school readiness, identify the key time points that represent windows of opportunity for microbiome optimization, and identify mechanisms by which the intestinal microbiome impacts brain development and behavior. This new knowledge will enhance our understanding of the gut-brain axis and lay the foundation for microbial based therapeutics to improve infant neurodevelopmental trajectories.