Abstract Body: Introduction: The neurovascular unit (NVU) has been shown to be influenced by the gut microbiome ecology along the gut-brain axis. However, the precise mechanisms underlying the interaction between the gut microbiome and the NVU remains unclear. The NVU can be stressed by multiple pathologies which can manifest as loss of blood brain barrier (BBB) integrity. Understanding the regulation of the gut-brain axis on the cells of the NVU presents a unique opportunity to regulate the BBB or explain variability within diseases such as adverse radiation effects (ARE), traumatic brain injury, aneurysmal subarachnoid hemorrhage and ischemic stroke.
Objective: To elucidate the mechanism by which the gut microbiota impacts NVU permeability and associate these findings to patients experiencing NVU insults.
Methods: Using a radiation-induced neurovascular dysfunction model established by our group, we investigated the impact of gut microbiota modulation on NVU function. C57BL/6 mice were given either an oral antibiotic cocktail or sterilized water to alter their gut microbiome. After three weeks of treatment, stereotactic irradiation (40 Gy at the 50% isodose line) was administered to a 5mm brain target. Six weeks post-radiation, contrast-enhancing ARE were measured using CT imaging. Differentially expressed circulating plasma metabolites were identified, and brains were collected for histological evaluation and spatial transcriptomic analysis. In an association study, a prospective cohort of age- and sex-matched acute brain injury patients with NVU dysfunction (n=73) underwent untargeted serum metabolomic analysis to identify prognostic biomarkers for favorable (mRS 0-3, n=45) and unfavorable (mRS 4-6, n=28) outcomes.
Results: Mice treated with antibiotics exhibited a reduction in ARE volume and histological evidence of decreased radiation damage. Metabolomic and transcriptomic analyses revealed differential expression of microbial metabolites and associated biological pathways. In a validation experiment, a second group of mice was gavaged with microbial metabolites, resulting in a significant reduction in AREs. In patients with brain injury, the same metabolites and pathways were associated with favorable outcomes (p<0.0001, FDR-corrected).
Conclusions: Microbiome-derived metabolites may play a crucial role in restoring blood-brain barrier function and improving patient outcomes following NVU injury.