MICROBIOME-BASED STRATEGIES TO MODIFY NEURODEGENERATIVE SIGNATURES AFTER BRAIN INJURY

Traumatic brain injury (TBI) accelerates neurodegenerative trajectories and can unmask or intensify Alzheimer’s disease (AD)-like pathology, in part through systemic inflammation coupled to rapid gut microbiome disruption. How microbiome-directed interventions shape these responses across injury burden and sex remains unclear. We tested three microbiome-modulating strategies in mouse models spanning wild-type injury and AD-relevant pathology. In male C57BL/6 mice subjected to controlled cortical impact (CCI), a brief oral antibiotic (ABX) cocktail reduced fecal bacterial DNA and robustly remodeled community structure, with larger shifts after injury. Despite reduced serum levels of short-chain fatty acids (SCFAs), ABX-treated TBI mice showed smaller cortical lesions, attenuated peripheral immune infiltration, microglia/macrophage activation, and astrogliosis. Consistent with the microbiome's dependence, germ-free mice exhibited larger lesions and greater gliosis after TBI. Long-read metagenomics identified ABX-resilient taxa, including Parasutterella excrementihominis and Lactobacillus johnsonii, as candidates linked to post-injury resilience. To test whether microbiota transfer blunts TBI-driven AD acceleration, we performed sex-matched fecal microbiota transplantation (FMT) 24 h post-CCI in male and female 5xFAD mice. FMT modestly shifted TBI-associated beta-diversity trajectories and altered plaque features in sham animals, but did not prevent TBI-amplified amyloid burden, neuroinflammation, or motor deficits; females were more vulnerable. Finally, a defined multi-strain probiotic administered pre- and post-injury reduced lesion burden and microgliosis and improved sex-specific behavioral outcomes. Overall, TBI rapidly engages a gut-brain inflammatory axis that accelerates neurodegeneration and AD-like pathology, and microbiome manipulation yields intervention-specific, sex-dependent effects: ABX provides SCFA-independent neuroprotection, FMT shows limited efficacy, and defined probiotics offer translational promise.