Journal
EPILEPSIA
Volume 62, Issue 8, Pages 1829-1841Publisher
WILEY
DOI: 10.1111/epi.16979
Keywords
electrophysiology; gut-brain axis; seizures; S-equol; TMEV
Categories
Funding
- College of Agricultural and Life Sciences at Virginia Tech
- School of Neuroscience at Virginia Tech
- Virginia Tech Insitute for Critical Technology and Applied Science (ICTAS)
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Our study reveals that the diversity of gut microbiota is significantly altered in TMEV-infected mice 5-7 days post-infection, showing a beta diversity separation in TMEV-infected mice depending on seizure phenotype, and a lower abundance of genus Allobaculum in TMEV-infected mice regardless of seizure phenotype. Conversely, a specific reduction in the S-equol-producing genus Adlercreutzia was identified as a microbial hallmark of seizure phenotype post-TMEV infection. Electrophysiological recordings indicated that exogenous S-equol modifies cortical neuronal physiology and ameliorates TMEV-induced hyperexcitability in entorhinal cortex neurons.
Objective A growing body of evidence indicates a potential role for the gut-brain axis as a novel therapeutic target in treating seizures. The present study sought to characterize the gut microbiome in Theiler murine encephalomyelitis virus (TMEV)-induced seizures, and to evaluate the effect of microbial metabolite S-equol on neuronal physiology as well as TMEV-induced neuronal hyperexcitability ex vivo. Methods We infected C57BL/6J mice with TMEV and monitored the development of acute behavioral seizures 0-7 days postinfection (dpi). Fecal samples were collected at 5-7 dpi and processed for 16S sequencing, and bioinformatics were performed with QIIME2. Finally, we conducted whole-cell patch-clamp recordings in cortical neurons to investigate the effect of exogenous S-equol on cell intrinsic properties and neuronal hyperexcitability. Results We demonstrated that gut microbiota diversity is significantly altered in TMEV-infected mice at 5-7 dpi, exhibiting separation in beta diversity in TMEV-infected mice dependent on seizure phenotype, and lower abundance of genus Allobaculum in TMEV-infected mice regardless of seizure phenotype. In contrast, we identified specific loss of S-equol-producing genus Adlercreutzia as a microbial hallmark of seizure phenotype following TMEV infection. Electrophysiological recordings indicated that exogenous S-equol alters cortical neuronal physiology. We found that entorhinal cortex neurons are hyperexcitable in TMEV-infected mice, and exogenous application of microbial-derived S-equol ameliorated this TMEV-induced hyperexcitability. Significance Our study presents the first evidence of microbial-derived metabolite S-equol as a potential mechanism for alteration of TMEV-induced neuronal excitability. These findings provide new insight for the novel role of S-equol and the gut-brain axis in epilepsy treatment.
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