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



Infection with Theiler’s Murine Encephalomyelitis Virus (TMEV) results in significant alteration of 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, according to the results of a study published in Epilepsy.

Previous studies have suggested that the gut-brain axis could be a potential therapeutic target in patients with epilepsy. The current study focused on alterations to the gut microbiome 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 characteristics neuroprotective against the excitotoxicity of glutamate.

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

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

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

Evaluation of the altered taxonomies in mice infected with TMEV revealed that there was no difference in the Firmicutes / Bacteroidetes ratio in any experimental group, but mice infected with TMEV had lower abundances of Alloculum, regardless of the type of crisis.

Analysis to determine the association between seizure phenotype and alterations in the gut microbiome revealed that Lactobacilli in the Bacilli and Streptococcaceae class, the RF32 bacterium may be a potential biomarker of the epileptic phenotype following infection with TMEV.

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

Exogenous application of a high concentration of S-equol altered action potential thresholds with evidence suggesting dose and time dependent alterations in neuronal physiological properties.

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

One of the limitations of the present study was that no directional relationship could be established between the seizures induced by TMEV and the alterations in the microbiome shown after 5 to 7 days of infection with TMEV.

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


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


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