First evidence of altered microbiota and intestinal damage and their link to absence epilepsy in a genetic animal model, the WAG/Rij rat

Citraro, Rita; Lembo, Francesca; De, Carmen; Tallarico, Martina; Coretti, Lorena; Iannone, Luigi Francesco; Leo, Antonio; Palumbo, Domenico; Cuomo, Mariella; Buommino, Elisabetta; Nesci, Valentina; Marascio, Nadia; Iannone, Michelangelo; Quirino, Angela; Russo, Roberto; Calignano, Antonio; Constanti, Andrew; Russo, Emilio; Sarro, Giovambattista De

doi:10.1111/epi.16813

Cited by 45 publications

(58 citation statements)

References 51 publications

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“…Many rodent models of epilepsy, including TMEV, follow a similar disease progression 25 . Probiotics have been shown to be beneficial in rodent models during the initial insult phase of TLE, reducing the occurrence of acute seizures following pentylenetetrazole (PTZ)‐induced kindling 8 and 6‐Hz stimulation, 7 and in a genetic model of absence seizures 49 . Microbiota transplant is additionally protective in rodents against PTZ‐induced seizures following chronic stress 50 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…This study also described a significantly close association between probiotic administration after birth and reduction of rotavirus-associated neonatal seizures ( 177 ). Furthermore, a recent study also described how gut microbiota transfer by fecal microbiota transplantation (FMT) in rats was able to modulate the risk of seizure, supporting gut microbiota causality ( 178 ). This experimental finding was clinically supported by a case study where a patient with Crohn's disease, with a 17-year-long history of seizures, became seizure-free for at least 20 months, despite discontinuing antiepileptic drug treatment with sodium valproate, after a FMT ( 179 ).…”

Section: Gut Microbiota Diet and Epilepsymentioning

confidence: 94%

Towards Tailored Gut Microbiome-Based and Dietary Interventions for Promoting the Development and Maintenance of a Healthy Brain

et al. 2021

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Mental health is determined by a complex interplay between the Neurological Exposome and the Human Genome. Multiple genetic and non-genetic (exposome) factors interact early in life, modulating the risk of developing the most common complex neurodevelopmental disorders (NDDs), with potential long-term consequences on health. To date, the understating of the precise etiology underpinning these neurological alterations, and their clinical management pose a challenge. The crucial role played by diet and gut microbiota in brain development and functioning would indicate that modulating the gut-brain axis may help protect against the onset and progression of mental-health disorders. Some nutritional deficiencies and gut microbiota alterations have been linked to NDDs, suggesting their potential pathogenic implications. In addition, certain dietary interventions have emerged as promising alternatives or adjuvant strategies for improving the management of particular NDDs, at least in particular subsets of subjects. The gut microbiota can be a key to mediating the effects of other exposome factors such as diet on mental health, and ongoing research in Psychiatry and Neuropediatrics is developing Precision Nutrition Models to classify subjects according to a diet response prediction based on specific individual features, including microbiome signatures. Here, we review current scientific evidence for the impact of early life environmental factors, including diet, on gut microbiota and neuro-development, emphasizing the potential long-term consequences on health; and also summarize the state of the art regarding the mechanisms underlying diet and gut microbiota influence on the brain–gut axis. Furthermore, we describe the evidence supporting the key role played by gut microbiota, diet and nutrition in neurodevelopment, as well as the effectiveness of certain dietary and microbiome-based interventions aimed at preventing or treating NDDs. Finally, we emphasize the need for further research to gain greater insight into the complex interplay between diet, gut microbiome and brain development. Such knowledge would help towards achieving tailored integrative treatments, including personalized nutrition.

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“… 7 Recently, significant differences in the intestinal microbiota have been reported in patients with epilepsy compared to healthy volunteers, 8 as well as in WAG/Rij rats, a genetic model of absence epilepsy. 9 Moreover, the transplant of the intestinal microbiota from chronically stressed to naive rats has been demonstrated to facilitate kindling epileptogenesis. 10 However, to our knowledge, a direct proepileptogenic effect of gut microbiota collected from epileptic donors has yet to be demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota modulates seizure susceptibility

et al. 2021

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A bulk of data suggest that the gut microbiota plays a role in a broad range of diseases, including those affecting the central nervous system. Recently, significant differences in the intestinal microbiota of patients with epilepsy, compared to healthy volunteers, have been reported in an observational study. However, an active role of the intestinal microbiota in the pathogenesis of epilepsy, through the so‐called “gut–brain axis,” has yet to be demonstrated. In this study, we evaluated the direct impact of microbiota transplanted from epileptic animals to healthy recipient animals, to clarify whether the microbiota from animals with epilepsy can affect the excitability of the recipients’ brain by lowering seizure thresholds. Our results provide the first evidence that mice who received microbiota from epileptic animals are more prone to develop status epilepticus, compared to recipients of “healthy” microbiota, after a subclinical dose of pilocarpine, indicating a higher susceptibility to seizures. The lower thresholds for seizure activity found in this study support the hypothesis that the microbiota, through the gut–brain axis, is able to affect neuronal excitability in the brain.

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First evidence of altered microbiota and intestinal damage and their link to absence epilepsy in a genetic animal model, the WAG/Rij rat

Cited by 45 publications

References 51 publications

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

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

Towards Tailored Gut Microbiome-Based and Dietary Interventions for Promoting the Development and Maintenance of a Healthy Brain

Gut microbiota modulates seizure susceptibility

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