UC Davis School of Medicine, Department of Medical Microbiology and Immunology, Genome Center, MIND Institute, Davis, CA, USA.
Oregon State University, Corvallis, OR, USA.
Commun Biol. 2021 Dec 16;4(1):1408. doi: 10.1038/s42003-021-02915-3.
Rett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 deficient rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models.
雷特综合征（RTT）是一种发生于女童的进行性神经发育障碍，其特征为包括肠道菌群失调和代谢改变在内的多系统并发症。虽然已知 RTT 是由 X 连锁基因 MECP2 的突变引起的，但进行性疾病表型的中间分子途径尚不清楚。在大多数先前的研究中，用于模拟 RTT 病理生理学的 Mecp2 缺陷啮齿动物均为雄性。因此，我们利用与患者相关的 RTT 小鼠模型，在疾病进展的各个阶段对两性的肠道微生物组和代谢组进行纵向分析。在运动神经表型出现之前，Mecp2e1 突变型雌性的粪便代谢物发生改变，且与大脑中的脂质缺乏相关，而在雄性中未观察到这些变化。雌性还表现出改变的肠道微生物群落和炎症特征，与 RTT 患者更为一致，而雄性则不然。这些发现确定了 RTT 疾病进展的新分子途径，并证明了在雌性 Mecp2 动物模型中进一步研究的相关性。
