Role of gut microbiome modulation in the attenuation of aging-related neuroinflammation in early brain injury after subarachnoid hemorrhage.

Early brain injury (EBI) critically determines post-subarachnoid hemorrhage (SAH) outcome, with worse prognosis in older patients. Aging confers exaggerated inflammation, possibly via gut microbiome (GM) alterations. We investigated whether GM alterations contribute to aging-related worsening of post-SAH EBI and whether GM modulation can reduce this inflammatory vulnerability. Young (8-12 weeks) and aged (17-20 months) male C57BL/6 mice underwent experimental SAH. Neurological scores, brain water content, neuronal degeneration, blood-brain barrier permeability, and inflammation were assessed. A combined GM modulation protocol consisting of antibiotic pretreatment, fecal microbiota gavage from young donors, and subsequent co-housing with young mice was performed in aged recipient mice. Compared to young mice, aged mice exhibited higher mortality, worse neurological scores, increased neuronal degeneration, and enhanced neutrophil infiltration, neutrophil extracellular trap (NET) formation, and microglial TNF-α expression. Absolute brain water content was lower in aged mice than in young mice, with a similar age-related difference also observed in sham animals. GM analysis revealed reduced diversity, decreasedFirmicutes, and increasedProteobacteriain aged mice. The GM modulation intervention shifted the GM composition toward that of young mice and was associated with reduced neuronal injury, neutrophil infiltration, NET formation, and microglial inflammation; however, neurological scores and brain water content did not improve at 24 h. These findings indicate that aging is associated with greater post-SAH vulnerability and enhanced neuroinflammation, while GM modulation reduces specific neuroinflammatory and neurodegenerative components of EBI without demonstrating improvement in overall functional outcome at 24 h. The gut-brain axis constitutes a potential therapeutic target for improved SAH outcomes in older adults.