肠道菌群代谢调控异氟烷暴露增强Fmr1-KO小鼠自闭症遗传易感性的作用及机制

自闭症（ASD）的高患病率（18.5‰）及其对家庭影响和社会带来的损失难以估量。幼年期接受异氟烷暴露对成年后神经功能影响的机制受到广泛关注。肠道菌群及代谢产物通过肠-脑轴参与各类脑病进展，但肠道菌群调节在异氟烷暴露加重ASD表现中的机制并不清楚。我们的预实验结果显示，幼年期异氟烷暴露会增加Fmr1-KO小鼠成年后出现ASD表型的几率和严重程度，体外培养神经元突触标志物Synapsin-1，PSD-95等表达发生改变。基于这一发现，我们提出假设，发育早期接受异氟烷暴露可以通过影响肠道菌群及其代谢产物，加重神经炎症，干扰神经生长，增强ASD样表现的遗传易感性。本项目将应用病毒转染、菌群移植、16S rDNA基因测序、GC-MS联用、免疫荧光神经元示踪三维重建等技术验证上述科学假说，完善异氟烷“二次打击”加重ASD遗传易感性的肠-脑轴机制研究，为寻找ASD合适治疗靶点的评估提供新思路。

The high prevalence of Autism Spectrum Disorders (ASD) (18.5‰), the family impact, and social losses it causes are incalculable. The mechanism of the effect of isoflurane exposure in childhood on long-term neurological function has received widespread attention. Intestinal flora and its metabolites participate in the progression of various types of encephalopathy through the gut-brain axis, but the mechanism of isoflurane exposure during the formation of ASD is still not clear. Our results show that isoflurane exposure in the juvenile period will increase the probability and severity of ASD phenotype in Fmr1-KO mice in adulthood. The expression of the synaptic markers for cultured neurons in vitro, Synapsin-1 and PSD-95 have changed. Based on this result, we hypothesized that exposure to isoflurane in the early stages of development can increase neuroinflammation and interfere with neurogenesis and synaptic plasticity by affecting the intestinal flora and its metabolites, thereby enhancing the genetic susceptibility to ASD-like manifestations. This project will apply virus transfection, bacterial colony transplantation, 16S rDNA gene sequencing, GC-MS combined use, immunofluorescence three-dimensional neuron tracing reconstruction, and other technologies to verify the above scientific hypotheses, and improve that isoflurane play a "second hit" role in aggravated ASD behavior. The study may provide new ideas for evaluating suitable targets for treatment.