Intestinal dysbiosis alters acute seizure burden and antiseizure medicine activity in Theiler's virus model of encephalitis.

Abstract

Objective: Brain infection with Theiler's murine encephalomyelitis virus (TMEV) in C57BL/6J mice produces an etiologically relevant model of acquired seizures. Dietary changes can modify 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.

Methods: Male C57BL/6J mice (4-5 weeks old) received oral ABX or saline (SAL) once daily beginning on arrival through day 7 after TMEV infection (postinfection [p.i.]). Mice were infected with TMEV or phosphate-buffered saline on day 0. Mice received intraperitoneal (20 mg/kg) CBZ or vehicle (VEH) twice daily on 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 after CBZ administration for bioanalysis.

Results: TMEV 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 × ASM interaction (p = .0001), with differences in seizure burden in SAL- versus ABX-pretreated mice (p = .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.

Significance: ABX-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 underrecognized contributor to TMEV infection-induced seizures, ASM activity, and disease burden.