Graduate Program in Translational Biology Medicine and Health, Virginia Tech, Roanoke, VA 24014, United States of America; Animal and Poultry Sciences, Virginia Polytechnic and State University, Blacksburg, VA 24061, United States of America.
Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, 1918 University Blvd., Birmingham, AL 35294, United States of America.
Prog Neuropsychopharmacol Biol Psychiatry. 2021 Jul 13;109:110259. doi: 10.1016/j.pnpbp.2021.110259. Epub 2021 Feb 4.
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is predominantly caused by alterations of the methyl-CpG-binding protein 2 (MECP2) gene. Disease severity and the presence of comorbidities such as gastrointestinal distress vary widely across affected individuals. The gut microbiome has been implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) as a regulator of disease severity and gastrointestinal comorbidities. Although the gut microbiome has been previously characterized in humans with RTT compared to healthy controls, the impact of MECP2 mutation on the composition of the gut microbiome in animal models where the host and diet can be experimentally controlled remains to be elucidated. By evaluating the microbial community across postnatal development as behavioral symptoms appear and progress, we have identified microbial taxa that are differentially abundant across developmental timepoints in a zinc-finger nuclease rat model of RTT compared to WT. We have additionally identified p105 as a key translational timepoint. Lastly, we have demonstrated that fecal SCFA levels are not altered in RTT rats compared to WT rats across development. Overall, these results represent an important step in translational RTT research.
雷特综合征（RTT）是一种 X 连锁的神经发育障碍，主要由甲基-CpG 结合蛋白 2（MECP2）基因的改变引起。受影响个体的疾病严重程度和伴发疾病（如胃肠道不适）的存在差异很大。肠道微生物组已被认为与神经发育障碍有关，如自闭症谱系障碍（ASD），是疾病严重程度和胃肠道伴发疾病的调节剂。尽管与健康对照组相比，已经在 RTT 患者中对肠道微生物组进行了描述，但在宿主和饮食可以进行实验控制的动物模型中，MECP2 突变对肠道微生物组组成的影响仍有待阐明。通过评估微生物群落在出现和进展的行为症状后的发育过程中，我们在锌指核酸酶 RTT 大鼠模型中发现了与 WT 相比在发育时间点上差异丰度的微生物分类群。我们还确定了 p105 是一个关键的翻译时间点。最后，我们证明了 RTT 大鼠与 WT 大鼠相比，粪便短链脂肪酸（SCFA）水平在整个发育过程中没有改变。总的来说，这些结果代表了 RTT 转化研究的重要一步。
