Gut Microbiomes and Early Human Neurodevelopment

摘要 令人兴奋的临床前研究支持肠道微生物（微生物组）在调节大脑功能和 行为动物研究中的一个重要观察结果是，发育中的大脑 比成熟的大脑更容易受到微生物组调节的影响，这支持了有一个想法， 微生物组对大脑发育编程的早期敏感期。海马体，一个大脑 负责学习和记忆的区域是成年小鼠中微生物组介导作用的靶点;然而， 人类早期微生物组与海马功能编程之间的关系尚未得到证实， 本文研究了在初步的实验中，我们发现，一个婴儿队列预测有破坏肠道， 微生物组（由于抗生素暴露）表现出异常的识别记忆反应（由 事件相关电位（ERP）），与未暴露的婴儿相比。鉴于这些发现， 我们假设，婴儿期微生物组特征的变化与以下因素的差异有关： 海马体功能，以及破坏微生物组的早期生命事件将导致发育 受影响婴儿学习和记忆功能的获得延迟。在拟议的研究中，我们利用 我们的研究小组的独特能力，以量化海马功能在非常年轻的婴儿，并比较这些 使用最先进的计算策略来发现微生物组 海马功能的决定因素。在目标1中，我们将使用微生物组组成的自然变化， 健康婴儿队列相对没有混淆变量来定义微生物组。在目标2中， 将比较两组在微生物组破坏（抗生素）方面不同的健康婴儿， 暴露）作为新生儿。对于这两个目标，我们将描述和比较人类海马功能， 其最快速的发展阶段，在非常年轻的婴儿微生物组队列中，使用尖端的婴儿 我们在明尼苏达大学神经行为发展中心的团队正在进行神经行为测试。 唯一有资格执行的人婴儿将使用既定的听觉（1个月大）和视觉（6个月大）进行比较。 年龄）识别ERP范例，以确定微生物变异是否调节海马功能 并进一步确定特定的“健康”微生物组特征（生物多样性，关键类群的丰度）， 定义最佳海马体功能这项R21研究的潜在高影响力收益是，它将提供 有证据表明，肠道微生物在出生后人类神经发育的早期影响大脑， 因此，塑造长期大脑健康的可能性。与遗传因素相反，肠道微生物可以被修饰。 因此，我们的研究结果将为未来的研究奠定基础，以开发用于早期干预的微生物组， 通过改善抗生素管理，在发展窗口期保护健康微生物组 高大脑可塑性，以改善高危人群的大脑发育。

Abstract Exciting pre-clinical research supports a role for gut microbes (microbiomes) in modulating brain function and behavior. An important observation stemming from studies in animals is that developing brains are more susceptible to the effects of microbiome modulation than mature brains, supporting the idea that there is an early-life sensitive period for brain developmental programming by the microbiome. The hippocampus, a brain region responsible for learning and memory, is a target of microbiome-mediated effects in adult mice; however a relationship between early-life microbiomes and programming of hippocampal function in humans has not been studied. In preliminary experiments, we have found that an infant cohort predicted to have disrupted gut microbiomes (due to antibiotic exposure) exhibited abnormal recognition memory responses (indexed by event-related potentials (ERPs)) at 1 month of age, as compared to unexposed infants. Given these findings, we hypothesize that variations in microbiome signatures during infancy correlate with differences in hippocampus function, and that early-life events that disrupt the microbiome will result in a developmental delay in acquisition of learning and memory functions in affected infants. In the proposed studies, we capitalize on our group’s unique abilities to quantify hippocampal function in very young infants and to compare these functions to microbiome features using state-of-the-art computational strategies to discover microbiome determinants of hippocampus function. In Aim 1, we will use natural variation in microbiome composition in a healthy infant cohort that is relatively free of confounding variables to define microbiome groups. In Aim 2, we will compare two groups of otherwise healthy infants that differ with respect to microbiome disruption (antibiotic exposure) as newborns. For both Aims, we will characterize and compare human hippocampus function during its most rapid phase of development, in very young infant microbiome cohorts, using cutting-edge infant neurobehavioral testing approaches that our team at the U of MN Center for Neurobehavioral Development is uniquely qualified to execute. Infants will be compared using established auditory (1 mo of age) and visual (6 mos of age) recognition ERP paradigms to determine if microbial variation modulates hippocampus function and, further, to identify specific "healthy" microbiome features (biodiversity, abundances of key taxa) that define optimum hippocampus function. The potential high-impact gain of this R21 research is that it will provide evidence that gut microbes affect the brain at very early times in postnatal human neurodevelopment with a likelihood, then, of shaping long-term brain health. In contrast to genetic factors, gut microbes can be modified. Thus, our results will lay the foundation for future studies to develop microbiomes for early interventions and for protection of healthy microbiomes via improved antibiotic stewardship, during the developmental window of high brain plasticity, to improve brain development in at-risk individuals.