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.
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越来越多的证据表明，肠道-脑轴作为治疗癫痫的新靶点具有潜在的作用。本研究旨在研究泰勒氏小鼠脑脊髓炎病毒(TMEV)致痫过程中肠道微生物组的特征，并评价微生物代谢物S对神经元生理学和体外TMEV诱导的神经元超兴奋性的影响。我们用TMEV感染C57BL/6J小鼠，并监测感染后0-7天(Dpi)急性行为惊厥的发展。在5-7dpi时采集粪便样本，进行16S测序，并用QIIME2进行生物信息学分析。最后，我们在大脑皮层神经元上进行了全细胞膜片钳记录，以观察外源性S对细胞固有特性和神经元超兴奋性的影响。我们证明，在TMEV感染的小鼠中，肠道微生物区系多样性在5-7dpi时显著改变，在TMEV感染的小鼠中表现出依赖于癫痫表型的β多样性的分离，在TMEV感染的小鼠中，Allobaculum属的丰度较低，而与癫痫的表型无关。相反，我们确定了S马匹产生属Adlercreutzia的特异性丢失是TMEV感染后癫痫表型的微生物标志。电生理记录表明，外源性S-马酚改变了大脑皮层神经元的生理。我们发现，在TMEV感染的小鼠内嗅皮层神经元是过度兴奋的，外源性应用微生物衍生的S-QUOL改善了这种由TMEV诱导的过度兴奋。我们的研究首次证明微生物衍生的代谢物S-马酚是改变TMEV诱导的神经元兴奋性的潜在机制。这些发现为S-马兜铃和肠脑轴在癫痫治疗中的新作用提供了新的见解。
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. 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. 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. 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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影响因子：
2
作者：
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2.2
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3.9
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