Gao Fengjie, Wang Chuyao, Cao Zhen, Zhang Xinyu, Xi Wenyu, Liu Yixin, Zhan Xianyan, Jia Min, Gou Ningzhi, Yu Lu, Zhang Yudan, Guo Yijie, Wang Wei, Zhu Feng, Ma Xiancang, Gao Yuan
Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China; Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.
Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China; Shaanxi Provincial Key Laboratory of Biological Psychiatry, Xi'an 710061, China.
Brain Behav Immun. 2025 Oct;129:126-142. doi: 10.1016/j.bbi.2025.05.030. Epub 2025 May 31.
Schizophrenia is a severe mental disorder with a complex etiopathogenesis involving both genetic and environmental risk factors. Evidence suggests that immune dysregulation plays a key role in its development, with maternal immune activation (MIA) during pregnancy identified as a significant environmental contributor. However, not all maternal infections result in schizophrenia-like outcomes, indicating that genetic susceptibility may render some individuals more vulnerable to MIA. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular receptor, plays a crucial role in maintaining the balance between intestinal microbiota and immune responses, but its precise role in gut-brain interactions during neurodevelopment remain unclear.
To investigate the interaction between MIA and Nod2 deficiency, we evaluated behavioral and physiological phenotypes in Nod2 mice exposed to poly(I:C)-induced MIA. In addition to immune responses, we analyzed maternal gut microbiota and the transmission of microbiota between mothers and offspring. Given the role of the gut-brain axis in schizophrenia, we conducted intestinal immunofluorescence staining, organoid cultures, and RNA sequencing of fetal brains to assess gut injury and neuroimmune changes in the brain. Male and female offspring were analyzed separately.
Dual exposure led to schizophrenia-like behaviors in a sex-specific manner, as well as brain development disruptions, compromised gut integrity, reduced intestinal organoid-forming capacity, and altered gut microbiota composition. Importantly, maternal gut microbiota disturbances, coupled with microbial transmission to offspring, appear to increase schizophrenia risk with potential long-term behavioral consequences.
This study underscores the intricate interplay of genetic, environmental, and microbiome factors, offering a valuable model for investigating the complex pathophysiology of neurodevelopmental disorders.
精神分裂症是一种严重的精神障碍，其病因发病机制复杂，涉及遗传和环境风险因素。有证据表明，免疫失调在其发展中起关键作用，孕期母体免疫激活（MIA）被确定为一个重要的环境因素。然而，并非所有母体感染都会导致类似精神分裂症的结果，这表明遗传易感性可能使一些个体更容易受到MIA的影响。含核苷酸结合寡聚化结构域蛋白2（NOD2）是一种细胞内受体，在维持肠道微生物群与免疫反应之间的平衡中起关键作用，但其在神经发育过程中肠道与大脑相互作用的确切作用仍不清楚。
为了研究MIA与Nod2缺陷之间的相互作用，我们评估了暴露于聚肌胞苷酸诱导的MIA的Nod2小鼠的行为和生理表型。除了免疫反应，我们还分析了母体肠道微生物群以及母体与后代之间微生物群的传递。鉴于肠道-脑轴在精神分裂症中的作用，我们进行了肠道免疫荧光染色、类器官培养以及胎儿大脑的RNA测序，以评估肠道损伤和大脑中的神经免疫变化。对雄性和雌性后代分别进行分析。
双重暴露以性别特异性方式导致类似精神分裂症的行为，以及大脑发育紊乱、肠道完整性受损、肠道类器官形成能力降低和肠道微生物群组成改变。重要的是，母体肠道微生物群紊乱，加上微生物向后代的传递，似乎会增加精神分裂症风险，并可能产生长期行为后果。
本研究强调了遗传、环境和微生物组因素之间的复杂相互作用，为研究神经发育障碍的复杂病理生理学提供了一个有价值的模型。
