肠道微生态与肠免疫自身调控网络研究

Gut immune system play a critical role in the development of colitis-associated tumorigenesis. Recent studies have also shown that gut mirobiota are necessary for gut immune responses and inflammation under normal physiological and pathological conditions. However, it is very little understood for how gut microbiota to regulate the gut immune system, especially autologous regulation among gut bacteria-killing substance, gut microbiota and gut immune system. Gut epithelial cells derived genetic factors such as bacteria-killing molecules may alter the composition of gut microbiota. Thus, our general objective is to establish the regulatory axis of gut bacterium killing substance /gut microbiota/gut immune cells/ colitis-associated tumorigenesis etc diseases. To realize this purpose, we have investigated the effects of gut epithelial molecules such as REG3α, REG3γ and LRRC19 on the composition of gut microbiota and gut immune cells. To further understand the effects of gut epithelial derived bacteria-killing substance on the gut immune system, we also prepared the REG4，complement factor D (CFD) and CXCL9 (both potentially kill bacteria) gut conditioned knockout mice. In this program, we will use these genetically modified mice to determine the effects of gut epithelial cells derived bacteria-killing substance on the composition of gut microbiota and gut immune cells, and then characterize these immune cells, especially novel gut immune cell populations or subsets. Meanwhile we will investigate the mechanism of gut bacteria-killing substance relative bacteria/ metabolites to regulate gut immune cells .These studies will establish gut autologous regulation networks among bacteria-killing substance, microbiota and immune system.. Recent studies show that epigenetic modification such as lncRNAs and histone modification plays a critical role in the differentiation of immune cell populations. However, the molecular basis, especially epigenetic modification of gut immune cell differentiation, expansion, activation to different effective cells after exposing to different gut microbiota/metabolites, are not yet understood. Thus, we will also investigate how gut microbiota and /or metabolistes to regulate the differentiation and function of gut immune cell populations and subpopulations, mainly focused on the epigenetic modification, especially normal mechanism of lncRNA, histone mechanism and transcription factor complexes. These data will potentially offer therapeutically target(s) for human diseases such as colitis and colitic cancer.

肠源性物质（如杀菌素）如何通过肠道微生态影响肠免疫是肠组织器官尚未解决的重要科学问题。肠道微生态对肠道免疫形成和稳定起关键作用，而肠上皮杀菌素能够影响肠道微生态的构成，这样在肠组织器官一定存在着肠道微生态与肠免疫自身调控网络。课题组已研究了肠上皮LRRC19、REG（REG3a，REG3γ）对肠免疫的调控。为了系统建立肠源性因素对肠免疫形成和稳定的调控，又制备了REG4、CFD和CXCL9等多个肠条件过表达和敲除鼠。项目将围绕这些肠条件过表达和肠条件敲除鼠，调查相关肠道细菌及其代谢产物对肠免疫细胞的调控作用；在确定肠免疫基本属性的基础上，解析对肠免疫的调控及相应的网络调控机制以及对肠炎癌等疾病的影响；并聚焦相关肠免疫细胞群或亚群，尤其是新免疫细胞亚群，解析肠道微生态对肠免疫细胞的遗传与表观遗传调控机理。目标是构建肠源性因素对肠免疫系统的调控网络，为人类重大疾病如肠炎癌提供治疗靶点。

肠源性物质（如杀菌素）是如何通过肠道微生态影响肠免疫是肠组织器官尚未解决的重要科学问题。肠道微生态对肠道免疫形成和稳定起关键作用，而肠上皮杀菌素能够影响肠道微生态的构成，这样在肠组织器官一定存在着肠道微生态与肠免疫自身调控网络。.课题组围绕上述科学问题，设计以下主要研究内容：通过构建的肠上皮LRRC19、REG（REG3，REG3γ和REG4）、CFD和CXCL9肠条件过表达和敲除鼠，调查相关肠道细菌及其代谢产物对肠免疫细胞的调控作用；在确定肠免疫基本属性的基础上，解析对肠免疫的调控及相应的网络调控机制以及对肠炎癌等疾病的影响；聚焦一些相关肠免疫细胞群或亚群，尤其是新免疫细胞亚群，解析肠道微生态对肠免疫细胞的遗传与表观遗传调控机理。.重要成果包括：确定了肠上皮杀菌物质对肠道微生态的影响，鉴定了与肠炎癌和肥胖等疾病的发生发展相关的肠道微生态菌株4株和3个代谢物；发现了肠道微生态起源的色氨酸代谢物IAA能够引导IL-35+B调节细胞，确定了IAA在保持肠和机体免疫稳态方面起关键的作用；发现了肠道微生态起源代谢产物SCFAs丁酸能够通过遗传修饰调节免疫抑制巨噬细胞的分化与功能，确定了SCFAs丁酸在保持肠和机体免疫稳态过程中发挥作用；发现了肠道微生态起源的胆汁酸代谢产物DCA能够通过遗传修饰调控免疫炎性和免疫抑制巨噬细胞的分化与功能，确定了DCA在保持肠和机体免疫稳态中发挥重要作用。此外，也发现肠道上皮潘氏细胞产生的FABP4能够调控肠道杀菌态的表达，能够重新编辑肠道微生态；也对临床肠炎癌病原体进行了研究，发现了一些新的与肠炎癌有关的病原体；同时在免疫调控细胞，发现了几个调控免疫抑制细胞的分子.通过这些研究初步构建了肠源性因素对肠免疫系统的调控网络，为人类重大疾病如肠炎癌提供治疗靶点。