The Role of the Gut-Brain Axis and S-equol in Epilepsy Treatment

Human intestinal pain, computer illustration.
A team of researchers sought to determine role of the gut-brain axis as a possible therapeutic target for Theiler murine encephalomyelitis (TMEV) linked seizures.

Theiler murine encephalomyelitis virus (TMEV) infection leads to significant alteration in gut microbiome, including loss of S-equol-producing bacteria, highlighting the role of this metabolite and the gut-brain axis in virus-induced seizures, according to study results published in Epilepsia.

Previous studies suggested the gut-brain axis may be a potential therapeutic target in patients with epilepsy. The current study focused on gut microbiome alterations in TMEV-induced seizures and investigated the role of S-equol, a metabolite produced exclusively by the metabolism of soy isoflavones by the gut microbiome and has neuroprotective features against glutamate excitotoxicity.

Study researchers infected C57BL/6J mice with TMEV. They then conducted acute behavioral seizure monitoring for 7 days and fecal collection for 16S sequencing. Study researchers conducted whole-cell patch-clamp recordings in cortical neurons to determine the impact of exogenous S-equol on cell intrinsic properties and neuronal hyperexcitability.

The study included 3 separate groups of mice, TMEV-infected mice with seizures, TMEV-infected mice without seizures, and phosphate-buffered saline-injected mice.

While there was no difference between the groups in gut microbiome alpha diversity richness, TMEV infection was associated with significant beta diversity after 5 to 7 days postinfection.

Assessment of which taxonomies were altered in TMEV-infected mice revealed there was no difference in Firmicutes/Bacteroidetes ratio across any experimental group, but mice infected with TMEV displayed lower abundances of Allobaculum, regardless of seizure type.

Analysis to determine the association between seizure phenotype and gut microbiome alterations revealed that Lactobacillus in class Bacilli and Streptococcaceae bacterium RF32 may be potential biomarkers of seizure phenotype following TMEV infection.

In contrast, study researchers identified phyla Tenericutes, classes Bacteroidia and Mollicutes, and genera Roseburia, Anaeroplasma, Ruminococcus, and Adlercreutzia as biomarkers of TMEV-infected mice that did not develop acute seizures.

Exogenous application of high S-equol concentration altered the action potential thresholds with evidence to suggest dose- and time-dependent alterations in neuronal physiologic properties.

The excitability of entorhinal cortex neurons in TMEV-infected mice was increased, compared with phosphate-buffered saline-injected mice. Additionally, exogenous application of the microbial metabolite S-equol ameliorated this TMEV-induced entorhinal cortex neuronal hyperexcitability.

One of the limitations of the current study was that no directional link could be drawn between TMEV-induced seizures and the microbiome alterations shown after 5 to 7 days of TMEV infection.

“Taken together, our results demonstrate a clear role of the gut-brain axis in TMEV-induced seizures. These data highlight the role of S-equol and the gut-brain axis in virus-induced seizures and identify a new target in the study of gut-brain axis therapeutics in epilepsy,” concluded the study researchers.


Gallucci A, Patel DC, Thai K, et al. Gut metabolite S-equol ameliorates hyperexcitability in entorhinal cortex neurons following Theiler murine encephalomyelitis virus-induced acute seizures. Epilepsia. 2021;62(8):1829-1841. Published online July 2, 2021. doi:10.1111/epi.16979