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.

Rett 综合征 (RTT) 是一种 X 连锁神经发育障碍，主要由甲基-CpG 结合蛋白 2 (MECP2) 基因的改变引起。疾病严重程度和胃肠道​​不适等合并症的存在在受影响的个体中差异很大。肠道微生物群与自闭症谱系障碍 (ASD) 等神经发育障碍有关，是疾病严重程度和胃肠道​​合并症的调节因子。尽管与健康对照组相比，先前已在患有 RTT 的人类中对肠道微生物组进行了表征，但在可以通过实验控制宿主和饮食的动物模型中，MECP2 突变对肠道微生物组组成的影响仍有待阐明。随着行为症状的出现和进展，通过评估出生后发育过程中的微生物群落，我们已经确定了与 WT 相比，在 RTT 的锌指核酸酶大鼠模型中不同发育时间点的微生物分类群。我们还确定 p105 是一个关键的翻译时间点。最后，我们已经证明，与发育过程中的 WT 大鼠相比，RTT 大鼠的粪便 SCFA 水平没有改变。总体而言，这些结果代表了转化 RTT 研究的重要一步。