炎症性肠病（IBD）是严重影响人类生存质量的一类常见的胃肠道慢性炎症性疾病。目前研究认为肠道菌群失调及宿主遗传易感基因是促进疾病发生的重要因素。多项GWAS研究报道CARD9 S12N变异是IBD的易感因素，我们的前期研究发现其在IBD中发生频率高且高于健康人群中的频率；采用CARD9 S12N点突变（KI）小鼠构建肠炎模型，发现KI小鼠对肠炎易感，肠道清除致病菌免疫应答缺陷，Treg功能缺陷，且KI小鼠对肠炎易感依赖于肠道菌群和肠道免疫功能失衡。.本项目将从携带CARD9 S12N变异的病人肠道菌群改变入手，寻找此类病人肠道潜在致病菌，阐明致病菌的致病作用，及致病菌与宿主肠道免疫系统的相互作用及分子机制，为临床治疗此类病人提供新的潜在靶点。这些问题的解决将有助于阐明肠道免疫稳态的重要生理及病理意义、肠道微生物与宿主免疫系统的相互作用，为日益严峻的IBD疾病诊治提供新的分子靶标和治疗策略。

Inflammatory bowel diseases (IBD) are common chronic gastrointestinal inflammatory diseases that severely affect human health. Intestinal microbial dysbiosis and genetic susceptibility genes are considered as important factors for IBD pathogensis. Several GWAS studies have revealed a single nucleotide polymorphism (SNP) at rs4077515 in human genome, which results in a single amino acid substitution of CARD9, pSer12Asn, CARD9 S12N, is associated with IBD. Our previous studies showed that CARD9 S12N occurred frequently in IBD patients and the frequency was higher than that in healthy people. We also established several colitis models in WT and CARD9 S12N KI mice, and found S12N KI mice were more susceptible to colitis with decreased anti-pathogen immune responses and deficient Treg function in intestinal lamina propria, and its function in colitis was microbiota-dependent..In this project, we will investigate the change of intestinal flora in patients carrying the CARD9 S12N mutation to find potential pathogenic commensal intestinal bacteria or fungi, and clarify the pathogenic role of the potential pathogens, their interactions with host intestinal immune system and the molecular mechanisms, thus providing new potential targets for clinical treatment. These lines of investigation will help us to understand the important physiological and pathological significance of intestinal immune homeostasis, the interaction between intestinal microflora and the host intestinal immune system, and provide the molecular basis of potential therapeutic targets for the treatment of IBD patients.