Gut metabolite S‐equol ameliorates hyperexcitability in entorhinal cortex neurons following Theiler murine encephalomyelitis virus‐induced acute seizures

Abstract

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.

A six-month prospective, randomised, double-blinded, placebo-controlled, crossover, dietary trial design to investigate the potential of psychobiotics on seizure semiology and comorbidities in canine epilepsy: study protocol

“…In recent years, there has been an increasing interest in the research field of neurogastroenterology. Evidence from human and animal cases suggests that specific changes in the intestinal flora cause neurodegenerative diseases, modify host behaviour and seizure semiology [13][14][15][16][17]. A bidirectional crosstalk between the intestinal flora and the brain is mediated via the microbiome-gutbrain axis [18] (Fig.…”

GW4064 Alters Gut Microbiota Composition and Counteracts Autism-Associated Behaviors in BTBR T+tf/J Mice

“…Allobaculum is a mouse commensal and associated with 5-hydroxytryptamine levels and short-chain fatty acid production ( Wu et al., 2020 ; Wang et al., 2020 ; Li et al., 2020 ). Several lines of studies have found that the reduction of genus Allobaculum is involved in behavior deficits and neurological disease ( Davis et al., 2017 ; Gubert et al., 2020 ; Xie et al., 2020 ; Gallucci et al., 2021 ). Correlation analysis found a positive association between decreased genus Allobaculum and decreased social deficits in BTBR mice.…”

The microbiota‐gut‐brain axis and epilepsy from a multidisciplinary perspective: Clinical evidence and technological solutions for improvement of in vitro preclinical models

“…The attention has been mainly focused on dietary modification, microbiome supplementations, or manipulation of gut microbiota from mouse models, to evaluate pathological outcomes such as a reduction in seizures' frequency 16 . On the other hand, the number of studies demonstrating a link between gut microbiota alterations and increased neuronal excitability and seizures is constantly increasing, shedding light on the potential mechanisms, pharmacological targets, and treatments 31–34 . It is worth noting that literature studies can be divided into those demonstrating a direct or an indirect impact of microbiota manipulation on epilepsy features.…”

“…16 On the other hand, the number of studies demonstrating a link between gut microbiota alterations and increased neuronal excitability and seizures is constantly increasing, shedding light on the potential mechanisms, pharmacological targets, and treatments. [31][32][33][34] It is worth noting that literature studies can be divided into those demonstrating a direct or an indirect impact of microbiota manipulation on epilepsy features. Among those included in the first group, some studies reported an increased susceptibility to seizures that could be transferred by fecal microbiota transplantation as well as this latter can confer seizure protection and even be used to identify molecules (microbiota metabolites) as potential treatments.…”