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

点击翻译按钮获取中文摘要

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.