The role of the gut-brain axis and S-equol in the treatment of epilepsy

Infection with the Theiler mouse encephalomyelitis virus (TMEV) leads to a significant change in the gut microbiome, including the loss of S-equol-producing bacteria, highlighting the role of this metabolite and the gut-brain axis in virus-induced seizures, epilepsy according to published study results.

Previous studies suggested that the gut-brain axis could be a potential therapeutic target in patients with epilepsy. The current study focused on changes in the gut microbiome in TMEV-induced seizures and examined the role of S-equol, a metabolite formed solely by the metabolism of soy isoflavones by the gut microbiome and which has neuroprotective properties against glutamate excitotoxicity.

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

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

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

The investigation into which taxonomies were changed in TMEV-infected mice showed no difference in the Firmicutes / Bacteroidetes ratio in all test groups, but mice infected with TMEV showed a lower frequency of allobaculum regardless of the type of seizure.

An analysis to determine the relationship between seizure phenotype and changes in the intestinal microbiome showed that Lactobacillus of the class Bacilli and Streptococaceae bacterium RF32 may be potential biomarkers for the seizure phenotype after TMEV infection.

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

The exogenous application of high S-equol concentrations changed the action potential thresholds with indications of dose- and time-dependent changes in the neuronal physiological properties.

The excitability of neurons of the entorhinal cortex in TMEV-infected mice was increased compared to mice with injected phosphate-buffered saline solution. In addition, the exogenous application of the microbial metabolite S-Equol improved this TMEV-induced neuronal hyperexcitability of the entorhinal cortex.

One of the limitations of the current study was that no direct relationship could be drawn between TMEV-induced seizures and changes in the microbiome after 5 to 7 days of TMEV infection.

“Taken together, our results show a clear role for the gut-brain axis in TMEV-induced seizures. These data underscore 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, ”the study’s researchers concluded.


Gallucci A, Patel DC, Thai K. et al. The intestinal metabolite S-Equol improves the hyperexcitability in entorhinal cortical neurons after acute attacks induced by the Theiler mouse encephalomyelitis virus. Epilepsy. 2021; 62 (8): 1829-1841. Published online July 2, 2021. doi: 10.1111 / epi.16979

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