<b><i>Cntn4</i></b><b> Gene Deficiency Promotes Autism-like Phenotypes through Gut Microbiota Perturbations and Intestinal-Brain Axis Metabolomic Alterations in Mice</b>
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Autism spectrum disorder (ASD) has a pathogenesis that involves complex genetic-environmental interactions. To investigate whether the ASD risk gene <i>Cntn4</i> contributes to disease development <i>via</i> gut-brain axis mechanisms. In this study, a <i>Cntn4 </i>gene<i> </i>knockout mouse model was established. After behavioral tests, 16S rDNA sequencing was employed to evaluate microbial diversity and abundance in the gut contents, while metabolomic methods were applied to detect changes in metabolites in gut contents, serum and cerebral cortex. The results demonstrated that knockdown of the <i>Cntn4</i> gene induced autism-like behavioral changes in the mice. Significant differences were observed in both intestinal microbiota composition and metabolomic profiles compared to control mice. Arginine and proline metabolism, histidine metabolism, sphingolipid metabolism, tyrosine metabolism, and purine metabolism, were notably affected. Changes in the abundance of certain microbial taxa, such as <i>Adlercreutzia </i>and <i>Desulfovibrionaceae_unclassified</i>, were correlated with alterations in metabolites, particularly organic acids and their derivatives, across different sample types. These findings suggest that knockout of the <i>Cntn4</i> gene leads to autism-like changes in mice through mechanisms associated with alterations in gut microbiota and gut-brain axis metabolites. This study provides valuable insights into the mechanisms underlying ASD development and offers potential directions for the prevention and treatment of ASD.
自闭症谱系障碍（Autism Spectrum Disorder, ASD）的发病机制涉及复杂的遗传-环境交互作用。本研究旨在探讨自闭症风险基因Cntn4是否通过肠-脑轴（gut-brain axis）机制参与疾病发生发展。本研究构建了Cntn4基因敲除小鼠模型。行为学检测完成后，采用16S rDNA测序技术评估小鼠肠道内容物的微生物多样性与丰度，并通过代谢组学方法检测肠道内容物、血清及大脑皮层中的代谢物变化。结果显示，Cntn4基因敲除可诱导小鼠出现类自闭症行为学改变。与对照组小鼠相比，实验组小鼠的肠道菌群组成与代谢组谱均存在显著差异。精氨酸与脯氨酸代谢、组氨酸代谢、鞘脂代谢、酪氨酸代谢及嘌呤代谢均受到显著影响。部分微生物类群（如Adlercreutzia菌属及未分类脱硫弧菌科）的丰度变化，与不同样本类型中代谢物（尤其是有机酸及其衍生物）的改变呈显著相关性。上述结果表明，Cntn4基因敲除可通过改变肠道菌群及肠-脑轴代谢物的相关机制，诱导小鼠出现类自闭症表型改变。本研究为自闭症谱系障碍的发病机制提供了重要见解，同时为该病的防治提供了潜在方向。
