Miljanovic Nina, Potschka Heidrun
Institute of Pharmacology, Toxicology & Pharmacy, Ludwig-Maximilians-University (LMU), Munich, Germany; Graduate School of Systemic Neurosciences (GSN), Ludwig-Maximilians-University (LMU), Munich, Germany.
Institute of Pharmacology, Toxicology & Pharmacy, Ludwig-Maximilians-University (LMU), Munich, Germany.
Epilepsy Res. 2021 Dec;178:106826. doi: 10.1016/j.eplepsyres.2021.106826. Epub 2021 Nov 24.
The gut-brain axis has been discussed as a possible factor contributing to ictogenesis and epilepsy. While recent preclinical studies have proposed a link between the antiseizure effect of a ketogenic diet (KD) and alterations to the gut microbiota, there is a knowledge gap about microbial composition as a result of Scn1a genetic deficiency and how this is affected by KD in Dravet syndrome.
A large-scale microbiome analysis using 16S rRNA gene sequencing was performed in fecal samples collected from wildtype and Dravet mice fed either control diet (CD) or KD. Microbial alterations associated with the Dravet phenotype or triggered by KD exposure were identified.
The comprehensive microbial analysis revealed pronounced alterations in gut microbiota between wildtype and Dravet mice. The regulation of Chao index indicated a reduced species richness in Dravet mice when compared to wildtype controls. The ratio between Firmicutes and Bacteroidetes phyla was increased in mice with the Dravet genotype, therefore implying a microbial dysbiosis in these animals. Following the switch to CD or KD, several bacteria phyla and genera were regulated in Dravet mice. Interestingly, an increased abundance of the Clostridium genus and a decreased abundance of the Romboutsia genus showed a significant correlation with the severity of the phenotype in Dravet mice. KD increased the abundance of Firmicutes and reduced the abundance of Bacteroidetes phyla in Dravet mice. The degree of these microbial alterations correlated with the reduction in the frequency and duration of motor seizures in these animals.
In conclusion, the comprehensive microbial analysis demonstrated pronounced alterations in the gut microbiota with evidence of a gut dysbiosis as a consequence of the Scn1a genetic deficiency. Exposure to KD affected the gut microbiome in Dravet mice. Interestingly, abundance of selected genera correlated with the seizure phenotype of Dravet mice. Future studies investigating the functional relevance of disease-associated and KD-triggered changes would be essential to confirm the relevance of these findings.
肠-脑轴已被讨论为可能导致癫痫发作和癫痫的一个因素。虽然最近的临床前研究提出了生酮饮食（KD）的抗癫痫作用与肠道微生物群改变之间的联系，但关于Scn1a基因缺陷导致的微生物组成以及在德雷维特综合征中KD如何影响这种组成，仍存在知识空白。
对从喂食对照饮食（CD）或KD的野生型和德雷维特小鼠收集的粪便样本进行大规模微生物组分析，使用16S rRNA基因测序。确定与德雷维特表型相关或由KD暴露引发的微生物改变。
全面的微生物分析揭示了野生型和德雷维特小鼠肠道微生物群的明显改变。Chao指数的调节表明，与野生型对照相比，德雷维特小鼠的物种丰富度降低。具有德雷维特基因型的小鼠中厚壁菌门与拟杆菌门的比例增加，因此表明这些动物存在微生物失调。在切换到CD或KD后，德雷维特小鼠中的几种细菌门和属受到调节。有趣的是，梭菌属丰度增加和罗姆布茨菌属丰度降低与德雷维特小鼠表型的严重程度显著相关。KD增加了德雷维特小鼠中厚壁菌门的丰度并降低了拟杆菌门的丰度。这些微生物改变的程度与这些动物运动性癫痫发作的频率和持续时间的减少相关。
总之，全面的微生物分析表明，由于Scn1a基因缺陷，肠道微生物群发生了明显改变，有肠道失调的证据。暴露于KD影响了德雷维特小鼠的肠道微生物组。有趣的是，选定属的丰度与德雷维特小鼠的癫痫发作表型相关。未来研究疾病相关和KD引发变化的功能相关性对于证实这些发现的相关性至关重要。
