Tim3-DC-ILC3调控轴在IBS肠道菌群-低度炎症循环中作用的研究

Irritable bowel syndrome (IBS) is a common functional bowel disease in which the etiology and pathophysiology are not completely understood. Previous studies by the applicant and other researchers have found that low grade inflammation and intestinal microflora disorders are widely present in IBS patients, suggesting that the alterations of local immune function might be a critical push for the development of IBS and the intervention targeting this inflammatory state might be a new therapeutic strategy. Our preliminary study found that the expression of Tim3 in colonic tissue increased in the IBS animal model, and the number of Tim3-positive DCs significantly increased in the FCM analysis, indicating that Tim3 might play an important role in the maintenance of IBS. However, both the detailed mechanisms and downstream pathway remain to be investigated. In this study, we aim to establish the correlation between Tim3-DC-ILC3 axis and intestinal microflora disorders –IBS symptoms by clinical studies. Then we plan to combine in-vitro experiments, such as over-expression or knocking down Tim3 and co-culture experiments, with in-vivo experiments, such as IBS animal model study, DC transfusion and probiotics treatment. Therefore, by multiple models and from multiple aspects, this study will clarify the role and mechanism of Tim3-DC-ILC3 regulatory axis in the cycle of intestinal microflora- chronic low grade inflammation in IBS, making it a prospective diagnostic biomarker and therapeutic target of IBS.

肠易激综合征（IBS）是一种常见的功能性肠病，申请者前期研究及其他多项研究证实IBS存在持续性低度炎症状态及肠道菌群紊乱，提示局部免疫系统功能的改变有可能是推动IBS发生发展的重要机制，对该种炎症状态的干预是IBS治疗的又一新方向。我们的前期研究发现，在IBS动物模型中结肠组织免疫检查点分子Tim3表达增高，分离免疫细胞进行流式细胞分析发现Tim3阳性DC细胞数量显著升高，提示Tim3在IBS低度炎症状态的维持中发挥作用，但其具体机制、下游信号通路不清。本研究拟通过临床病例初步建立Tim3-DC-ILC3与肠道菌群紊乱、IBS症状间的相关关系，并通过体外过表达与干扰Tim3、共培养实验，体内IBS模型研究、DC回输实验和益生菌干预等，多模型、多角度阐释Tim3-DC-ILC3调控轴对IBS肠道菌群-低度炎症循环的作用及机制，并有望使其成为IBS诊断和治疗的有价值的生物标志和靶点。

肠易激综合征（IBS）是一种病因尚不明确的功能性肠病，既往研究证实IBS存在持续性低度炎症状态及肠道菌群紊乱，提示了“菌群-免疫-炎症”的交互在IBS发病中的重要作用。本研究围绕IBS黏膜低度炎症状态、免疫调节机制及益生菌在IBS疾病干预中的作用开展了系列研究，主要发现如下：1. IBS存在分子水平的低度炎症表型，促炎免疫细胞比例和炎症性细胞因子水平存在升高；2.树突状细胞（DC）作为沟通肠道固有免疫和适应性免疫的重要桥梁，在IBS低度炎症中发挥重要作用，DC通过Tim3-DC-ILC3调控轴影响IBS疾病进程；3. 对不同时程合并肠道炎症表型宿主的菌群观察分析发现，炎症进程显著影响肠道菌群构成，并对黏膜免疫微环境发挥重塑作用；4. 益生菌酪酸梭菌和罗伊氏乳杆菌对IBS相关内脏表现具有保护作用，通过其调控分子Tim3改善分子水平低度炎症状态。从而，本研究从宏观角度探讨了菌群与肠道免疫及炎症的交互作用关系，并从细胞分子水平深入阐明了肠道DC通过其重要免疫监控点分子Tim3调控下游炎症因子的作用，益生菌干预重塑DC免疫表型从而改善黏膜炎症及内脏高敏感状态，对IBS的个体化治疗具有重要指导意义。