Abstract：
The extra copy of the methyl-CpG-binding protein 2 (MeCp2) gene causes MeCP2 duplication syndrome (MDS), a neurodevelopmental disorder characterized by intellectual disability and autistic phenotypes. However, the disturbed microbiome and metabolic profiling underlying the autistic-like behavioral deficits of MDS are rarely investigated. Here we aimed to understand the contributions of microbiome disruption and associated metabolic alterations, especially the disturbed neurotransmitters in MDS employing a transgenic mouse model with MeCP2 overexpression. We analyzed metabolic profiles of plasma, urine, and cecum content and microbiome profiles by both 16 s RNA and shotgun metagenomics sequence technology. We found the decreased levels of Firmicutes and increased levels of Bacteroides in the single MeCP2 gene mutation autism-like mouse model, demonstrating the importance of the host genome in a selection of microbiome, leading to the heterogeneity characteristics of microbiome in MDS. Furthermore, the changed levels of several neurotransmitters (such as dopamine, taurine, and glutamate) implied the excitatory-inhibitory imbalance caused by the single gene mutation. Concurrently, a range of microbial metabolisms of aromatic amino acids (such as tryptophan and phenylalanine) were identified in different biological matrices obtained from MeCP2 transgenic mice. Our investigation revealed the importance of genetic variation in accounting for the differences in microbiomes and confirmed the bidirectional regulatory axis of microbiota-gut-brain in studying the role of microbiome on MDS, which could be useful in deeply understanding the microbiome-based treatment in this autistic-like disease.
摘要：
甲基CpG结合蛋白2（MeCp2）基因的额外拷贝导致MeCP2重复综合征（MDS），一种以智力障碍和自闭症表型为特征的神经发育障碍。然而,作为MDS孤独症样行为缺陷的基础的紊乱的微生物组和代谢谱很少被研究.在这里，我们旨在了解微生物组破坏和相关代谢改变的贡献，特别是使用MeCP2过表达的转基因小鼠模型的MDS中的神经递质受到干扰。我们分析了血浆的代谢谱,尿液,通过16sRNA和shot弹枪宏基因组学序列技术，以及盲肠含量和微生物组谱。我们发现在单MeCP2基因突变孤独症样小鼠模型中Firmicutes的水平降低和拟杆菌的水平升高,证明宿主基因组在选择微生物组中的重要性，导致MDS中微生物组的异质性特征。此外，几种神经递质(如多巴胺，牛磺酸,和谷氨酸）暗示由单基因突变引起的兴奋性抑制失衡。同时,在从MeCP2转基因小鼠获得的不同生物基质中鉴定了一系列芳香族氨基酸(如色氨酸和苯丙氨酸)的微生物代谢。我们的调查揭示了遗传变异在解释微生物组差异中的重要性，并证实了微生物群-肠-脑的双向调节轴在研究微生物组对MDS的作用中。这可能有助于深入了解这种自闭症样疾病中基于微生物组的治疗方法。
