Role of gut microbiota in susceptibility of preterm infants to hypoxic brain injury

早产儿在其发育过程中通常缺乏正常的微生物群落或微生物群。 这些肠子本来应该是母亲的婴儿也会接触到非自然的 在医院环境中的微生物导致异常肠道定植。过早 婴儿经常处于围产期缺氧缺血性脑损伤的风险中，被认为是 导致运动、感觉和认知缺陷的主要因素。 肠道微生物群以多种方式影响身体，其中最明显的影响之一是 影响婴儿的免疫系统因此，我们假设新生儿肠道微生物群可以 调节新生儿脑对缺氧性脑损伤的免疫反应。我们建议研究 利用小鼠模型研究肠道微生物群对缺氧诱导的新生儿脑损伤的影响。 新生小鼠幼仔在肠道中没有微生物群（无菌）或具有常规微生物群， 暴露于空气中的低氧（间歇性缺氧），模仿呼吸暂停发作 在早产儿中。间歇性缺氧导致神经炎症和弥漫性白色物质 可以通过最先进的MRI方法和组织分析来量化的脑损伤。 在具体目标1中，我们将首先确定异常肠道微生物定植的影响 通过使用先进的MRI技术（目的1a）和运动， 使用行为测试的认知缺陷（目标1b）。此外，我们将评估 微生物群对神经炎症因子（aim 1c）的影响，并与脑组织的改变相关 成像和行为测试。第二个具体目标将扩大结果在临床上 相关的场景，其中肠道微生物群将以受控的方式被修改。具体地说， 将无菌小鼠幼仔暴露于已知的致病或有益细菌菌株， 研究其耐缺氧能力。 了解肠道微生物群对神经系统反应的保护或有害作用 围产期缺氧缺血可能导致新的治疗策略，因为操纵 通过有针对性益生菌补充和其他方法， 新兴技术。

Premature infants are often lacking normal microbial community, or microbiota, in their intestines that naturally should have come from mothers. Infants are also exposed to unnatural microbiota in the hospital environment that results in abnormal intestinal colonization. Premature infants are often at risk of perinatal hypoxic-ischemic brain injury, considered as one of the major factors leading to motor, sensory and cognitive deficits. Gut microbiota affects the body in numerous ways and one of the most pronounced effects is on the infant’s immune system. Therefore we hypothesize that neonatal gut microbiota can regulate immune reaction of the neonatal brain to hypoxic brain injury. We propose to examine the effect of gut microbiota on hypoxia-induced neonatal brain injury utilizing a mouse model. Neonatal mouse pups without microbiota in guts (germ free) or with conventional microbiota will be exposed to periods of low oxygen in air (intermittent hypoxia), mimicking episodes of apnea in premature infants. Intermittent hypoxias results in neuroinflammation and diffuse white matter brain injury that can be quantified by state-of-the-art MRI methodology and tissue analysis. In the Specific Aim 1 we will first determine the effect of abnormal gut microbial colonization on hypoxia-induced brain injury by using advanced MRI techniques (aim 1a) and motor and cognitive deficits using behavioral tests (aim 1b). In addition, we will evaluate the effect of microbiota on neuroinflammatory factors (aim 1c), and correlate with the alterations on brain imaging and behavioral tests. The second specific aim will expand the results in a clinically relevant scenario in which gut microbiota will be modified in a controlled manner. Specifically, germ free mouse pups will be exposed to known pathogenic or beneficial bacteria strains and studied for resistance to hypoxia. Understanding the protective or deleterious role of gut microbiota on neurologic responses to perinatal hypoxia-ischemia may lead to novel therapeutic strategies since manipulation of intestinal microbiota is easily achievable through targeted probiotic supplementation and other emerging technologies.