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.
