Erickson, I. | bioRxiv Science

bioRxiv2025

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

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.

neuroscience↗

bioRxiv2024

Intestinal Dysbiosis Alters Acute Seizure Burden and Antiseizure Medicine Activity in the Theiler's Virus Model of Encephalitis

ObjectiveBrain infection with Theilers virus (TMEV) in C57BL/6J mice produces an etiologically relevant model of acquired seizures. Dietary changes can modify acute seizure presentation following TMEV brain infection and influence intestinal microbiome diversity and composition. Intestinal dysbiosis may thus similarly affect seizure burden and antiseizure medicine (ASM) activity in this model, independent of pharmacokinetic effects. We thus sought to define the influence of antibiotic (ABX)-induced gut dysbiosis on acute seizure presentation, anticonvulsant activity of carbamazepine (CBZ), and CBZ pharmacokinetics with TMEV infection. MethodsMale C57BL/6J mice (4-5 weeks) received oral (p.o.) ABX or saline (SAL) once daily beginning on arrival through Day 7 post-TMEV infection (p.i.). Mice were infected with TMEV or PBS on Day 0. Mice received intraperitoneal (i.p.; 20 mg/kg) CBZ or vehicle (VEH) twice daily Days 3-7 p.i. and were assessed for handling-induced seizures 30 min after treatment. Plasma was collected on Day 7 p.i. at 15 and 60 min post-CBZ administration for bioanalysis. ResultsTMEV infection induced acute seizures, but ABX-induced gut dysbiosis altered seizure presentation. There were 75% SAL-VEH, 35% SAL-CBZ, 35% ABX-VEH, and 72% ABX- CBZ mice with seizures during the 7-day monitoring period. There was a significant pretreatment x ASM interaction (p=0.0001), with differences in seizure burden in SAL- versus ABX-pretreated mice (p=0.004). CBZ significantly increased latency to seizure presentation; an effect absent in ABX-CBZ mice. Plasma CBZ concentrations did not differ between SAL and ABX pretreatment groups, suggesting that ABX did not influence CBZ pharmacokinetics. SignificanceABX-induced gut dysbiosis markedly altered acute disease trajectory with TMEV- induced encephalitis, reflecting a novel contribution of the gut microbiome to seizure presentation. ABX-induced gut dysbiosis also significantly changed acute seizure control by CBZ, but did not influence plasma CBZ concentrations. The gut-brain axis is thus an under- recognized contributor to TMEV infection-induced seizures, ASM activity, and disease burden. Key PointsO_LITheilers virus infection in mice models encephalitis that exhibits differential disease trajectory with gut microbiome modulation. C_LIO_LIExperimentally evoked gut dysbiosis, i.e. a disrupted gut microbiome, dramatically shifts the anticonvulsant activity of carbamazepine. C_LIO_LIThere is no concomitant shift in circulating carbamazepine concentrations in TMEV- infected mice with and without a dysbiotic microbiome. C_LIO_LIThe gut microbiome is an under-recognized driver of seizure risk and antiseizure medicine activity in the Theilers virus mouse model. C_LI

neuroscience↗