Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance
Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance
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果蝇组蛋白去甲基化酶 KDM5 通过免疫控制和肠道微生物群维护调节社会行为
DOI：
10.1016/j.chom.2019.02.003
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发表时间：
2019-04-10
影响因子：
30.3
通讯作者：
Liu, Xingyin
中科院分区：
文献类型：
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作者：
Chen, Kun;Luan, Xiaoting;Liu, Xingyin
组蛋白去甲基化酶KDM 5A、KDM 5 B或KDM 5C中的功能丧失突变在智力残疾（ID）和自闭症谱系障碍（ASD）患者中发现。在这里，我们使用模式生物果蝇黑腹描绘KDM 5如何有助于ID和ASD。我们发现，减少KDM 5会导致肠道屏障功能障碍和社会行为的变化，这些变化与肠道微生物群的组成变化相关。通过抗生素给药或用益生菌乳杆菌菌株喂养来治疗性改变生态失调的微生物群，部分挽救了在kdm 5缺陷型果蝇中观察到的行为、寿命和细胞表型。从机制上讲，KDM 5被发现转录调节免疫缺陷（IMD）信号通路的组成基因，并随后以脱甲基酶依赖性方式维持宿主-宿主细菌的稳态。总之，我们的研究使用遗传方法来剖析KDM 5在肠道-微生物组-脑轴中的作用，并表明修改肠道微生物组可能为ID和ASD患者提供治疗益处。
Loss-of-function mutations in the histone demethylases KDM5A, KDM5B, or KDM5C are found in intellectual disability (ID) and autism spectrum disorders (ASD) patients. Here, we use the model organism Drosophilamelanogaster to delineate how KDM5 contributes to ID and ASD. We show that reducing KDM5 causes intestinal barrier dysfunction and changes in social behavior that correlates with compositional changes in the gut microbiota. Therapeutic alteration of the dysbiotic microbiota through antibiotic administration or feeding with a probiotic Lactobacillus strain partially rescues the behavioral, lifespan, and cellular phenotypes observed in kdm5-deficient flies. Mechanistically, KDM5 was found to transcriptionally regulate component genes of the immune deficiency (IMD) signaling pathway and subsequent maintenance of host-commensal bacteria homeostasis in a demethylase-dependent manner. Together, our study uses a genetic approach to dissect the role of KDM5 in the gut-microbiome-brain axis and suggests that modifying the gut microbiome may provide therapeutic benefits for ID and ASD patients.