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

早产儿的体内通常缺乏正常的微生物群落或微生物区系。 自然应该来自母亲的肠道。婴儿也暴露在不自然的环境中 医院环境中导致肠道非正常定植的微生物区系。过早 婴儿经常面临围产期缺氧缺血性脑损伤的风险，被认为是 导致运动、感觉和认知缺陷的主要因素。 肠道微生物区系以多种方式影响身体，其中最显著的影响之一 对婴儿的免疫系统有影响。因此，我们假设新生儿肠道微生物区系可以 调节新生儿大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区系对缺氧所致新生儿脑损伤的影响。 没有肠道微生物区系(无菌)或有常规微生物区系的新生小鼠将 暴露在空气中的低氧期(间歇性低氧)，模仿呼吸暂停发作 在早产儿身上。间歇性低氧导致神经炎症和弥漫性脑白质 脑损伤可以通过最先进的磁共振成像方法和组织分析进行量化。 在具体目标1中，我们将首先确定肠道微生物异常定植的影响 应用先进的磁共振成像技术(AIM 1a)和运动功能检测对缺氧脑损伤的研究 使用行为测试的认知缺陷(目标1b)。此外，我们还将评估 微生物区系对神经炎性因子(Aim 1c)的影响，并与脑内的变化相关 成像和行为测试。第二个具体目标将在临床上扩大结果 肠道微生物区系将以受控方式进行修改的相关情景。具体来说， 无菌小鼠幼鼠将接触到已知的致病或有益细菌菌株和 研究耐低氧能力。 了解肠道微生物区系对神经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，因为操作 肠道微生物区系很容易通过有针对性的益生菌补充剂和其他 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.