2025 Proffered Presentations
S063: A NOVEL MECHANISM WITHIN THE GUT-BRAIN AXIS THAT MODULATES STEREOTACTIC RADIOSURGERY DAMAGE.
Roberto J Alcazar; Sean P Polster; University of Chicago
Introduction: Stereotactic radiosurgery (SRS) is a key tool within neurosurgery for the treatment of skull base tumors, neurovascular diseases, and functional disorders. However, up to 20% of patients treated with SRS develop adverse radiation effects (AREs) identified with contrast-enhanced imaging, a marker of blood brain barrier leakage. Emerging research has suggested that the gut microbiome plays a crucial role in modulating brain permeability. However, the precise mechanisms through which the gut microbiome influences these changes in the neurovascular unit (NVU) remain elusive. A crucial gap remains in the understanding of the gut-brain axis which represent a unique opportunity for the development of targeted therapeutic interventions for AREs.
Objective: To elucidate the mechanisms through which the gut microbiome affects the NVU permeability.
Methods: To study the effect of gut microbiome modulation on the NVU, C57BL/6 mice were assigned and maintained on an oral antibiotic cocktail treatment or autoclaved water only. Three weeks after treatment allocation, mice were stereotactically irradiated using a 5mm beam-wide collimator. A total dose of 40Gy at the 50% isodose line was delivered to the left hemisphere using a parallel-opposed beam configuration. At 6 weeks post-SRS, cone-beam brain CT imaging was used to assess for AREs. Additionally, blood was collected for metabolomics study and brains were harvested for histological and spatial transcriptomic analysis for astrocytes, microglia, and endothelial cells. BBB permeability was assessed using Evan’s blue dye and optical imaging.
Results: Adverse radiation effects were observed as soon as 4 weeks post-SRS on contrast-enhanced CT scan imaging. Compared to control, antibiotic treatment significantly reduced contrast-enhancing lesion volumes at 4 and 6 weeks post-SRS. On histology, antibiotic treated mice showed reduced radiation necrosis changes compared to control. The antibiotic effect on radiation was found to be mainly driven by genomic signature changes in astrocyte and microglial cells but not vascular endothelium. Antibiotic treated mice had increased concentration of microbiome-derived tryptophan metabolites. To determine whether decreased AREs were associated with tryptophan metabolites, another set of mice were gavaged tryptophan metabolites during SRS treatment. Tryptophan metabolites significantly reduced ARE lesion volumes compared to control.
Conclusion: We have shown that radiation damage to the NVU can be altered by the gut-brain axis. This mechanism of radioprotection from gut-derived metabolites acting on the NVU can prevent AREs and possibly allow for more efficient administration of SRS. This novel mechanism defines a new level of physiologic control of the BBB that has implications to multiple diseases of the head and neck.