OBJECTIVE A large number of studies have highlighted the important role of the gut microbiota in the pathophysiology of neurological disorders, suggesting that its manipulation might serve as a treatment strategy. We hypothesized that the gut microbiota participates in absence seizure development and maintenance in the WAG/Rij rat model and tested this hypothesis by evaluating potential gut microbiota and intestinal alterations in the model, as well as measuring the impact of microbiota manipulation using fecal microbiota transplantation (FMT). METHODS Initially, gut microbiota composition and intestinal histology of WAG/Rij rats (a well-recognized genetic model of absence epilepsy) were studied at 1, 4, and 8 months of age in comparison to nonepileptic Wistar rats. Subsequently, in a second set of experiments, at 6 months of age, untreated Wistar or WAG/Rij rats treated with ethosuximide (ETH) were used as gut microbiota donors for FMT in WAG/Rij rats, and electroencephalographic (EEG) recordings were obtained over 4 weeks. At the end of FMT, stool and gut samples were collected, absence seizures were measured on EEG recordings, and microbiota analysis and histopathological examinations were performed. RESULTS Gut microbiota analysis showed differences in beta diversity and specific phylotypes at all ages considered and significant variances in the Bacteroidetes/Firmicutes ratio between Wistar and WAG/Rij rats. FMT, from both Wistar and ETH-treated WAG/Rij donors to WAG/Rij rats, significantly decreased the number and duration of seizures. Histological results indicated that WAG/Rij rats were characterized by intestinal villi disruption and inflammatory infiltrates already at 1 month of age, before seizure occurrence; FMT partially restored intestinal morphology while also significantly modifying gut microbiota and concomitantly reducing absence seizures. SIGNIFICANCE Our results demonstrate for the first time that the gut microbiota is modified and contributes to seizure occurrence in a genetic animal model of absence epilepsy and that its manipulation may be a suitable therapeutic target for absence seizure management.

中文翻译：

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在遗传动物模型 WAG/Rij 大鼠中微生物群改变和肠道损伤及其与失神性癫痫的联系的第一个证据

目的 大量研究强调了肠道微生物群在神经系统疾病病理生理学中的重要作用，表明其操作可能作为一种治疗策略。我们假设肠道微生物群参与 WAG/Rij 大鼠模型中失神发作的发展和维持，并通过评估模型中潜在的肠道微生物群和肠道改变，以及使用粪便微生物群移植测量微生物群操纵的影响来验证这一假设。 FMT）。方法最初，与非癫痫 Wistar 大鼠相比，在 1、4 和 8 个月大时研究了 WAG/Rij 大鼠（一种公认的失神癫痫遗传模型）的肠道微生物群组成和肠道组织学。随后，在第二组实验中，在 6 个月大时，使用乙琥胺 (ETH) 治疗的未经治疗的 Wistar 或 WAG/Rij 大鼠作为 WAG/Rij 大鼠 FMT 的肠道微生物群供体，并在 4 周内获得脑电图 (EEG) 记录。在 FMT 结束时，收集粪便和肠道样本，根据 EEG 记录测量失神发作，并进行微生物群分析和组织病理学检查。结果肠道微生物群分析显示，所有年龄阶段的β多样性和特定系统发育型存在差异，Wistar 和 WAG/Rij 大鼠之间的拟杆菌/硬壁比率存在显着差异。FMT，从 Wistar 和 ETH 处理的 WAG/Rij 供体到 WAG/Rij 大鼠，显着减少了癫痫发作的次数和持续时间。组织学结果表明，WAG/Rij 大鼠在 1 月龄时即出现癫痫发作前的肠道绒毛破裂和炎症浸润；FMT 部分恢复了肠道形态，同时也显着改变了肠道微生物群并同时减少了失神发作。意义我们的研究结果首次证明肠道微生物群被改变并有助于失神癫痫遗传动物模型的癫痫发作，并且其操作可能是失神癫痫管理的合适治疗靶点。