Faecalibacterium prausnitzii协同LFA-1在炎症性肠病发生中调控淋巴细胞分化及功能的作用机制

The inappropriate immune response to gut microbiota plays a key role in the development of inflammatory bowel disease(IBD). An important feature of gut dysbiosis in IBD patients is the decreasing of Faecalibacterium prausnitzii(F. prausnitzii). Our previous study results indicated that F. prausnitzii and lymphocyte function associated antigen-1(LFA-1) may be involved in the differentiation and function regulation of lymphocytes, but the cooperative effects and mechanism of F. prausnitzii and LFA-1 is still unclear. The study will be performed in patients with IBD and animal model with LFA-1 gene knockout mice induced by DSS to observe the relationship between IBD with F. prausnitzii and LFA-1. The subsets of CD4+ T lymphocytes and the realted protein of Toll-like receptors as well as cytokines will be detected in peripheral blood and lmphatic tissues in intstinal mucosa and mesenteric lymph nodes for investigating the effects of F. prausnitzii and LFA-1 on the CD4+ T lymphocyte differentiation and their relationship with clinicopathologic phenotypes. The intervention study in vitro on the differentiation and funtion regulation of T lymphocytes will be performed to illuminate the cooperative effects and mechanism of F. prausnitzii and LFA-1. The study results should be utilized to help to develop therapeutic strategies for IBD.

肠道菌群紊乱引起的免疫应答异常在IBD的发生中起重要作用，而肠道普拉梭菌（F. pransnitzii）减少是IBD肠道菌群紊乱的重要特征。我们前期研究发现，F. prausnitzii和淋巴细胞功能抗原-1（LFA-1）参与了淋巴细胞的分化和功能调节，但二者内在关联的协同效应和机制尚不清楚。本课题以LFA-1基因缺失鼠及IBD患者为研究对象，通过DSS诱导IBD模型观察F. prausnitzii及LFA-1与IBD发生的关系；通过检测外周血、肠粘膜及肠系膜淋巴结等组织内CD4+T细胞亚群数量及相关TLR相关调节蛋白和效应细胞因子的变化；分析F. pransnitzii、LFA-1调控CD4+T细胞分化特征及与IBD临床病理表型的关系；同时通过体外干预T细胞的分化与功能分析，探讨F. prausnitzii与LFA-1调控淋巴细胞分化的协同作用关系及机制，为IBD的治疗干预提供新的策略。

普拉梭菌(Faecalibacterium prausnitzii, F. pransnitzii)减少是IBD肠道菌群紊乱的重要特征。我们前期研究发现，F. prausnitzii和淋巴细胞功能抗原-1(LFA-1)参与了淋巴细胞的分化和功能调节，但二者内在关联的协同效应和机制尚不清楚。本课题以LFA-1基因缺失鼠及IBD患者为研究对象，通过DSS诱导IBD模型观察F. prausnitzii及LFA-1与IBD发生的关系; 通过检测外周血、肠粘膜及肠系膜淋巴结等组织内CD4+T细胞亚群数量及相关TLR相关调节蛋白和效应细胞因子的变化; 分析F. pransnitzii、LFA-1调控CD4+T细胞分化特征及与IBD临床病理表型的关系;同时通过体外干预T细胞的分化与功能分析，探讨F. prausnitzii与LFA-1调控淋巴细胞分化的协同作用关系及机制。结果发现，F. prausnitzii在LFA-1缺失情况下影响Treg细胞分化调控，能上调Treg细胞比例，促进Treg细胞分泌抗炎因子TGF-β1、IL-10; F. prausnitzii治疗野生鼠结肠炎疗效优于LFA-1缺失鼠，可能与LFA-1缺失对Treg细胞功能的发挥及细胞因子分泌受限有关。F. prausnitzii上清可预防和治疗DSS所致的小鼠结肠炎，在实验性结肠炎小鼠中发挥抗炎效应；其机制可能为抑制脾和肠道Th17细胞的生成，减少外周血和结肠组织炎性细胞因子IL-17A分泌; F. prausnitzii上清可通过下调TLR4/NF-kB信号通路，降低炎性因子及炎性介质的表达如IL-6水平来治疗结肠炎。而普拉梭菌上清液这种作用证实是通过分泌丁酸实现的，其分泌的丁酸能够抑制HDAC1来促进Foxp3并阻断IL-6/STAT3/IL-17信号通路，从而促进Treg抑制Th17细胞，发挥缓解IBD结肠炎症作用的。