Antibiotic-Brain Disorder of Prematurity:Prolonged Exposure of Antibiotics in Preterm Infant That Leads to Adverse Neurodevelopmental Outcome and Brain Connectivity Development Is Associated with Choroid Plexus Barrier Disruption and Neuroinflammation(2/3)

Delivering a preterm birth infant is a distressing process for parents and adapting to the world outside of the womb is another challenge for preterm infants. The prevalence of the neurodevelopmental disorder, namely autism spectrum disorder (ASD), in very preterm infant is the highest among other diseases. There are various risk factors associated with neurodevelopment impairment in very preterm infants. Prolonged exposure of antibiotics, which is a common practice used in the preterm infant, may relate to subsequent adverse outcomes. Exposure to antibiotics may disrupt the homeostasis of normal flora in multiple body sites, including the bacteria in the gut, trachea, mucosa, nasal, and oral cavity. The chronic use of antibiotics can lead to bacteria overgrowth that is resistant to antibiotics, which may further cause enhanced inflammation in our body. In addition, antibiotics may itself have a direct adverse effect on the brain. Choroid plexus has been demonstrated as a gatekeeper in the brain for immune molecules and also serves as a critical circadian component. Disruption of core circadian clock function has been associated with peripheral inflammation and neuroinflammation. Our preliminary data show that broad-spectrum antibiotic cocktail (ABX) treatment starting from the perinatal period drastically impairs social behavior development. Our clinical data suggests that early-life prolonged antibiotic exposure during hospitalization is associated with impaired cognition, motor, and language outcome in very-preterm birth children at 2 years of age. Herein, prolonged antibiotic use in preterm infants, so called “Antibiotic-Brain axis disorder of prematurity”, leads the adverse neurodevelopment is the key question we aim to investigate. Therefore, my central hypothesis for this subproject is that early-life prolonged antibiotic exposure in mice pups leads to altered brain connectivity development and long-term neurodevelopmental/neurobehavioral disorders in association with dysregulation of choroid plexus-inflammation loops. This subproject will determine whether antibiotic usage in mice at early-life stage could induce the negative influences to mouse brain and gut development. In order to examine this hypothesis, we have six specific aims: Aim 1: Characterize the neurodevelopmental/neurobehavioral outcome in mice after early-life prolonged antibiotic exposure. Aim 2: Delineate the alteration of brain structural and functional connectivity development by neuroimaging in mice and preterm birth children with early-life prolonged antibiotic exposure (Collaboration with Subproject 5). Aim 3: Illustrate the intestinal immune profiles and peripheral immunograms in mice pups after early-life prolonged antibiotic exposure. Aim 4: Examine the gut motility and barrier function in mice with early-life prolonged antibiotic exposure. Aim 5: Determine if the altered gut microbiota induced by early-life prolonged antibiotic exposure is the critical factor shaping neurobehavioral development. Aim 6: Determine whether prolonged antibiotic exposure induces dysregulation of the circadian, barrier, and inflammatory response in choroid plexus (collaboration with Subproject 4). With the completion of this study, we anticipate that we will not only reveal a potential mechanism by which early-life prolonged antibiotic exposure increases the risk for neurodevelopmental disorders but also show the adverse long-term brain connectivity impact of early-life prolonged antibiotics exposure in preterm infants.