刘星吟等:自闭症相关基因突变改变肠道免疫,经菌群影响果蝇行为
  • 果蝇中,去甲基化酶KDM5水平不足可导致肠道屏障功能损伤,并使果蝇呈现“自闭”样社会行为异常,伴随肠道菌群失调,植物乳杆菌减少、条件致病菌过度繁殖;
  • 补充植物乳杆菌或给予抗生素可改变肠道菌群,还可部分改善KDM5缺陷型果蝇的行为、寿命和肠道异常,并降低肠道和脑内过高的5-羟色胺水平;
  • KDM5以依赖于其去甲基化酶活性的方式,在转录水平上抑制IMD/Rel先天免疫通路的过度活化,促进宿主-菌群稳态,经肠脑轴影响果蝇社交行为。
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mildbreeze
KDM5家族蛋白是一种组蛋白去甲基化酶,参与基因的表观遗传调控。此前有研究表明,在智力残疾和自闭症患者中,存在KDM5功能丧失型基因突变。南京医科大学刘星吟团队主导的最新研究,发现肠道菌群在KDM5突变相关的社会行为异常中有重要介导作用。通过使用多种KDM5缺陷型果蝇模型,该研究揭示出,KDM5通过调控先天免疫通路,影响肠道屏障和菌群组成,经肠脑轴改变果蝇社会行为,并表明靶向肠道菌群的干预方法可在一定能程度上改善果蝇的社会行为异常。相关成果发表在Cell Host and Microbe上,对于研究宿主-菌群互作和菌群-肠-脑轴等都很有借鉴价值。
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Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance

果蝇组蛋白去甲基化酶KDM5通过免疫控制和维持肠道菌群调控社交行为

10.1016/j.chom.2019.02.003

2019-03-19, Article

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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 Drosophila melanogaster 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.

First Authors:
Kun Chen,Xiaoting Luan,Qisha Liu,Jianwei Wang,Xinxia Chang,Antoine M Snijders,Xingyin Liu

Correspondence Authors:
Xingyin Liu

All Authors:
Kun Chen,Xiaoting Luan,Qisha Liu,Jianwei Wang,Xinxia Chang,Antoine M Snijders,Jian-Hua Mao,Julie Secombe,Zhou Dan,Jian-Huan Chen,Zibin Wang,Xiao Dong,Chen Qiu,Xiaoai Chang,Dong Zhang,Susan E Celniker,Xingyin Liu

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