System and Applied Pharmacology@University Magna Grecia (FAS@UMG) Research Center, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.
Department of Pharmacy, Federico II University of Naples, Naples, Italy.
Epilepsia. 2021 Feb;62(2):529-541. doi: 10.1111/epi.16813. Epub 2021 Jan 11.
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).
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.
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.
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.
大量研究强调了肠道微生物群在神经障碍病理生理学中的重要作用，提示其干预可能成为一种治疗策略。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，以及测量粪便微生物群移植（FMT）对微生物群的影响来验证这一假设。
首先，在 1、4 和 8 个月大时比较无癫痫 Wag/Rij 大鼠和无癫痫 Wistar 大鼠，研究 Wag/Rij 大鼠（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，未治疗的 Wistar 或 Wag/Rij 大鼠用乙琥胺（ETH）治疗作为 FMT 的肠道微生物群供体用于 Wag/Rij 大鼠，并进行 4 周的脑电图（EEG）记录。在 FMT 结束时，收集粪便和肠道样本，在 EEG 记录上测量失神发作，进行微生物群分析和组织病理学检查。
肠道微生物群分析显示，在所有考虑的年龄都存在β多样性和特定菌属的差异，并且在 Wistar 和 Wag/Rij 大鼠之间存在细菌/厚壁菌比值的显著差异。来自 Wistar 和 ETH 治疗的 Wag/Rij 供体的 FMT，显著减少 Wag/Rij 大鼠的发作次数和持续时间。组织学结果表明， Wag/Rij 大鼠在 1 个月大时，即在发作发生之前，就表现出肠道绒毛破坏和炎症浸润；FMT 部分恢复了肠道形态，同时显著改变了肠道微生物群，并相应减少了失神发作。
我们的研究结果首次证明，肠道微生物群在失神癫痫的遗传动物模型中发生改变，并有助于癫痫发作，其干预可能是失神发作管理的合适治疗靶点。
