克罗恩病易感基因干扰素α-4突变型与特异微生物相互作用在肠炎发生中的作用和机制

克罗恩病（CD）的发生与遗传因素、肠道微生态失衡密切相关，但中国人群特异CD易感基因与肠道内特异微生物的相互作用参与其发病尚未见报道。本课题组已报道干扰素（IFN）α-4、10突变型为国人特异的CD易感基因并诱发IFNα亚型的功能缺损；在前期已构建的IFNα-4、IFNα-4-Mut条件性转基因小鼠DSS肠炎模型粪便中，病毒宏基因组等测序发现了与IFNα-4-Mut显著相关的Cellulophages等噬菌体病毒。因此本课题将：1、对前期测序发现的特异微生物，扩大DSS和TNBS肠炎模型小鼠粪便样本，进一步鉴定IFNα-4-Mut介导的肠道内特异微生物；2、在IFNα-4、10不同基因型患者粪便中，验证从动物实验发现的肠道特异微生物；3、探索IFNα-4突变型与特异微生物的失衡在肠道黏膜异常免疫应答中的发病机制。从而对不同基因型患者通过干预肠道特异微生物而对CD进行个体化治疗提供理论依据。

The pathogenesis of Crohn's disease (CD) is closely associated with genetic factors and imbalance of gut microecology. However, the involvement of specific intestinal microorganisms mediated by CD-specific susceptible gene in the pathogenesis of CD in Chinese population has not been reported. We reported that Interferon (IFN)α-4、10 mutations as susceptible gene and impaired function in Chinese CD patients. Then, we established the DSS induced colitis model on IFNα-4 and IFNα-4-Mut conditional transgenic mice, and viral metagenome sequencing from fecal samples revealed several specific bacteriophage viruses such as Cellulophages significantly associated with IFNα-4-Mut. Therefore, 1. We will expanding the mice fecal samples from DSS and TNBS colitis models and further identify specific microorganisms mediated by IFNα-4-Mut; 2. To validate the findings from animal experiments on fecal sample of CD patients with different genotypes of IFNα-4、10 mutations; 3. To explore the mechanism of IFNα-4 mutant as susceptible gene of CD with imbalanced specific microbiota during intestinal immune responses; and to provide theoretical basis for personalized treatment of CD by editing the specific intestinal microorganisms in patients with different genotypes.