The Gut Microbiome Brain Axis and Preterm Infants

项目总结 婴儿期越来越被认为是微生物组建立的关键时间点，它会影响 新生儿健康以及以后的结局。肠道微生物组特别牵涉到 通过肠道-脑轴的神经学结果。然而，肠道微生物群可以通过哪些方式 人们对大脑的影响知之甚少。早产儿是这些未知因素的结合点。早产 婴儿是一个脆弱的患者群体，面临着严重不良的长期神经发育结果的风险。 早产儿的大脑发育与肠道微生物群的发育是平行的，因此发生了改变 肠道微生物组的研究是改善神经发育结果的潜在手段。在这份提案中， 我们将检验这样一种假设，即在关键时间点，不同的肠道微生物类群和代谢物有所改善 学龄期早产儿神经发育结局。 我们在灵知生菌小鼠模型中的初步和发表的数据表明，不同的早期 早产儿微生物区系影响神经元数量、髓鞘形成和行为。这项提案将使用我们正在进行的 Mind(新生儿发育中的微生物组)早产儿队列如何确定肠道微生物组 影响NICU的神经发育潜力，以及它可能如何改变神经发育轨迹 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抽样，以监测肠道 微生物组以及粪便和血清代谢物。我们还将在治疗期间进行神经发育测试 NICU课程，直到学龄前/学龄(3.5-5岁)。入学准备情况，它描述了 在课堂上学习时，孩子们的优势、挑战和对支持的需求是一个功能性的 结果不同于单一的智力摘要测量(IQ)，将作为结果衡量标准。 16S rRNA基因测序、元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被用来开发新的模型 以时间为关键因素的早产儿肠道微生物群落演替。血清细胞因子分析和 代谢组学将提供对肠道微生物群如何影响的机械性洞察 神经发育。我们已经建立了体内互补的GnotoBiotic小鼠模型，在该模型中，无菌 小鼠会感染早产儿的微生物区系。这种最先进的实验模型将允许 对临床相关微生物区系对大脑发育的影响的具体研究 人类婴儿。这项提议的目标是发现与学校有关的肠道微生物群模式。 准备情况，确定代表微生物组优化机会窗口的关键时间点，以及 确定肠道微生物群影响大脑发育和行为的机制。这是一项新的 知识将加强我们对肠道-脑轴的了解，并为以微生物为基础的 改善婴儿神经发育轨迹的治疗。

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.