457 Restoration of the Neurovascular Unit Permeability Through Gut Microbiome Modulation

INTRODUCTION: Emerging research has suggested that the gut microbiome plays a crucial role in modulating multiple disease phenotypes, however without a clear mechanism. Recent data has suggested that gut metabolites exert an effect on the neurovascular unit’s junctional integrity. METHODS: Using a stereotactic mouse brain radiation damage model, C57BL/6 mice were radiated to a single hemisphere with 40Gy. The gut microbiome was altered via oral antibiotics to decontaminate specific flora. In vivo, serial, cone beam computed tomography scans were obtained every 2 weeks after irradiation to quantify contrast-enhancing lesion volumes. Following euthanasia, mouse brains underwent adverse radiation effects histological scoring and cell specific spatial transcriptomic analysis for astrocytes, microglia, and endothelial cells. RESULTS: At 4 weeks post radiation, oral antibiotic regimen significantly attenuated radiation-induced neurovascular damage, as evidenced by both imaging and histological assessments. Spatial transcriptomic analysis revealed critical regulators of the neurovascular unit and blood-brain barrier (BBB) integrity in the setting of brain-gut-axis radiation damage modulation. Array analysis showed cell-cell communication regulatory changes involved in endothelial junctional integrity. CONCLUSIONS: We have demonstrated that manipulation of the brain-gut-axis can modulate the integrity and function of the neurovascular unit and BBB permeability in the setting of radiation damage. We propose a novel framework for cellular signaling that influence the neurovascular unit along the brain-gut-axis.