Microbial-mediated blood-brain barrier development at the intersection of the gut-brain axis

微生物介导的肠脑轴交叉点的血脑屏障发育

• 批准号: 10373631
• 负责人: Jing Lu
• 金额: $ 24.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373631
• 关键词: 16S ribosomal RNA sequencing; Adolescent; Adult; Age; Astrocytes; Behavior; Bifidobacterium; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Breeding; Bypass; Cells; Cerebral Palsy; Characteristics; Communication; Communities; Complex; Development; Embryo; Exposure to; Female; Functional disorder; Germ-Free; Gnotobiotic; Growth; Health; Healthcare; Human; Immune; Infant; Intervention; Knowledge; Lactobacillus acidophilus; Life; Link; Long-Term Effects; Maternal Exposure; Mediating; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Mothers; Mus; Necrotizing Enterocolitis; Neonatal; Neonatal Brain Injury; Nerve; Nervous System Physiology; Neuraxis; Neurodevelopmental Deficit; Neurodevelopmental Impairment; Neurologic; Neurological outcome; Neurotransmitters; Oral; Outcome; Pathway interactions; Pattern; Pericytes; Perinatal Brain Injury; Population; Predisposition; Pregnancy; Premature Birth; Premature Infant; Probiotics; Property; Proteins; Publishing; Research; Risk Factors; Sampling; Sepsis; Signal Transduction; Site; Societies; Stream; System; Testing; Therapeutic; Tight Junctions; Time; Vascular Endothelium; Weaning; autism spectrum disorder; bacterial community; base; behavioral outcome; blood-brain barrier function; clinically relevant; commensal microbes; cytokine; dysbiosis; efficacy testing; fecal microbiome; germ free condition; gut microbiome; gut microbiota; gut-brain axis; high risk; immunoregulation; improved; intraamniotic infection; microbial; microbial colonization; microbial community; microbiome; microbiome alteration; microbiota; neonatal stroke; neonate; nervous system disorder; neuroinflammation; neuron development; novel; offspring; patient population; phenotypic biomarker; postnatal; postnatal period; pregnant; premature; prenatal; probiotic supplementation; response; seal; systemic inflammatory response; therapeutic target; therapy development; white matter

PROJECT SUMMARY/ABSTRACT The blood-brain barrier (BBB) is the direct interface that governs the interaction between the circulating blood and central nervous system (CNS). Current gut-brain axis research has made the association between the gut microbiome and CNS functions but largely bypasses the BBB which determines whether or what microbial mediators will enter CNS to have impacts on brain functions. Another aspect of the potential impacts of these circulating microbial factors is the direct impact on BBB components. Preterm birth represents an increasing burden for healthcare and society due to long term prematurity-associated neurodevelopmental deficits. Morbidities such as sepsis, necrotizing enterocolitis, and perinatal brain injuries are all associated with high risk for poor neurodevelopmental outcomes and have been associated with dysbiosis thus making the neonatal microbiome a target to improve developmental outcomes. In this proposal, we aim to test the overall hypothesis that early dysbiosis associated with preterm birth contributes to compromised blood-brain barrier development and functions, and has long term effects on brain development and neurological outcomes. We will utilize an established gnotobiotic mouse transfaunation method as the experimental platform. Three clinically relevant microbial communities will be utilized to evaluate BBB development under the influence of gut microbiota from prenatal stages to the early postnatal period: 1) Communities from preterm infants with low postnatal growth; 2) Communities from preterm infants born to a mother with confirmed chorioamnionitis; 3) Communities from full term healthy infants. In addition, the combination of Lactobacillus acidophilus and Bifidobacterium infantis will be maternally administrated as a strategy to optimize BBB development and function. BBB integrity, temporal development of BBB tight junction, components and transporter systems with phenotypical markers will be examined. Furthermore, neuronal development and white matter maturation at different developmental stages will be investigated as well as behaviors at a juvenile age. 16S rRNA gene sequencing of fecal samples of human donors, the transfaunated dams and offspring will be used to characterize the microbial communities to determine the distinct microbial species/pattern associated with BBB functional changes. The novel knowledge from this study will be 1) demonstrating that preterm microbial communities can influence BBB development and neurological outcomes from the embryonic stage to the postnatal period; 2) identifying the target(s) within the BBB components where microbial mediators have specific effects; 3) identifying microbial markers associated with BBB development and functions. Furthermore, by testing the efficacy of probiotics in improving microbiome characteristics, BBB function and neurological outcomes, we will identify a microbiome-based therapeutic option that can be used as a potential effective strategy to reduce neurodevelopmental deficits in preterm infants.

项目概要/摘要 血脑屏障（BBB）是控制循环血液之间相互作用的直接界面 和中枢神经系统（CNS）。目前的肠-脑轴研究已经将肠道与大脑之间的联系联系起来。 微生物组和中枢神经系统发挥功能，但很大程度上绕过了血脑屏障，血脑屏障决定是否或什么微生物 介质会进入中枢神经系统对大脑功能产生影响。这些潜在影响的另一个方面 循环微生物因素是直接影响BBB的成分。早产现象日益增多 由于长期早产相关的神经发育缺陷，给医疗保健和社会带来负担。 败血症、坏死性小肠结肠炎和围产期脑损伤等疾病都与高风险相关 神经发育结果不佳，并与生态失调有关，从而使新生儿 微生物组是改善发育结果的目标。在这个提案中，我们的目标是测试整体 与早产相关的早期生态失调会导致血脑屏障受损的假设 发育和功能，并对大脑发育和神经系统结果产生长期影响。我们 将利用已建立的无菌小鼠动物区系转移方法作为实验平台。三 临床相关微生物群落将用于评估 BBB 的影响下的发育 从产前阶段到产后早期的肠道菌群：1）早产儿的肠道菌群低 产后生长； 2) 确诊绒毛膜羊膜炎母亲所生早产儿的社区； 3） 来自足月健康婴儿的社区。此外，嗜酸乳杆菌和 婴儿双歧杆菌将通过母体给药，作为优化 BBB 发育和 功能。 BBB 完整性、BBB 紧密连接、组件和转运系统的时间发展 将检查表型标记。此外，神经元发育和白质成熟 将调查不同的发展阶段以及青少年时期的行为。 16S rRNA基因 对人类捐赠者、动物转移的母鼠和后代的粪便样本进行测序将用于 表征微生物群落以确定与 BBB 相关的不同微生物物种/模式 功能变化。这项研究的新知识将是 1) 证明早产儿微生物 社区可以影响从胚胎阶段到成年的 BBB 发育和神经系统结果 产后时期； 2) 识别 BBB 成分中微生物介体所具有的目标 具体效果； 3) 鉴定与 BBB 发育和功能相关的微生物标记。此外， 通过测试益生菌在改善微生物组特征、血脑屏障功能和神经功能方面的功效 结果，我们将确定一种基于微生物组的治疗方案，可用作潜在的有效方法 减少早产儿神经发育缺陷的策略。