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bioRxiv · 10.1101/2025.05.23.655804

Impact of Dysbiosis and Antiseizure Medication on Seizure Pathophysiology in a Viral Infection-Induced Epilepsy Model

Shonka, S.·Erickson, I.·Park, H.·Barker-Haliski, M.
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Abstract

Viral encephalitis is a major worldwide cause of acquired epilepsy, yet the impact of environmental and non-neuronal factors on an individuals risk for epilepsy is understudied. For example, the gut microbiome influences immune system function yet the impact of the gut microbiome on seizure-associated neuropathology remains poorly understood. Using the Theilers murine encephalomyelitis virus (TMEV) mouse model of infection-induced acute symptomatic seizures (ASyS), we aimed to investigate how antibiotic (ABX)-induced gut dysbiosis during a brain viral infection could influence resulting hippocampal neuropathology. Further, we included co-administration of carbamazepine (CBZ) to assess the extent to which antiseizure medicines could also shift the neurological impact of ASyS and gut dysbiosis. Brain tissue from TMEV-infected mice with and without gut dysbiosis was assessed for neurodegeneration and glial response (astrocytes and microglia). TMEV infection primarily drove neuroinflammatory changes in CA1, including increased astrogliosis, microgliosis, and microglial activation. ABX-induced dysbiosis exacerbated neuroinflammation across hippocampal subregions, markedly increasing microgliosis in CA3 and DG, and elevating microglial and neuronal proliferation in CA1. TMEV infection-induced astrogliosis was impacted by dysbiosis in a region-dependent manner, being worsened in DG while being alleviated in CA3. CBZ was neuroprotective selectively within DG, reducing neurodegeneration and microglial immunoreactivity with dysbiosis. Astroglial proliferation occurred regardless of gut microbiome integrity. Altogether, gut dysbiosis shapes hippocampal neuroimmune responses following viral infection-induced ASyS in a region-dependent manner, and CBZ may confer a neuroprotective effect. Together this work highlights the acute neuroinflammatory impact of infection-induced ASyS and reveals an underappreciated contribution of the gut-brain-axis to seizure-related neuropathology.

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Shonka, S., Erickson, I., Park, H., Barker-Haliski, M.. 2025-05-28. Impact of Dysbiosis and Antiseizure Medication on Seizure Pathophysiology in a Viral Infection-Induced Epilepsy Model. https://doi.org/10.1101/2025.05.23.655804

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