A network model of the gut host-microbe ecosystem in Inflammatory Bowel Disease

描述(申请人提供)：最近的研究强调了肠道粘膜免疫在肠道近端自身免疫性疾病(炎症性肠病(IBD))和涉及肠外间隔(类风湿性关节炎和多发性硬化症)中的关键作用。自身免疫性疾病的发展涉及多种肠道驻留细胞类型和肠道微生物群的协调。在宿主方面，免疫细胞和肠道上皮细胞通过分泌效应细胞因子、抗菌肽和其他分子来协调肠道微生物的动态平衡。微生物区系也是免疫反应的重要调节器，影响免疫细胞群体的分化和功能。我们提出了一个实验设计，结合了与IBD相关的宿主和微生物区系的扰动。细胞丰度(免疫细胞和微生物区系，AIM 1)和基因组测量(微生物和宿主细胞转录，AIM 2)将被结合到一个综合实验设计中，该设计将使我们能够将肠道中的生态变化与细菌和宿主免疫细胞中潜在的分子事件联系起来。我们将结合三种宿主扰动(抑制RoR�t、IL-10和IL-23)，并将两种诱导IBD相关表型的微生物(节段性丝状细菌和肝螺杆菌)引入无特定病原体的小鼠(具有“正常”微生物群的小鼠)。SFB附着于小肠上皮，导致固有层中Th17细胞群的扩张，影响结肠炎、关节炎和多发性硬化症相关表型。共生HH促进抗炎免疫反应，以限制其自身的肠道定植，并仅在免疫功能紊乱的小鼠品系中诱导结肠炎样病理。HH依赖型小鼠结肠炎反映了人类IBD，否则无害的肠道微生物扰动会导致遗传免疫缺陷宿主的慢性肠道生态失调。SFB和HH与IL-23和IL-10信号通路相互作用(两者都与IBD的发病密切相关)。阻断IL-23信号转导有助于IL-12p40抗体治疗IBD的疗效，全基因组关联研究证实了IL-23R在结肠炎中的中心作用。在人类中，IL10R的突变与IBD和IL-10信号缺陷有关，小鼠的IL-10信号缺陷会导致HH定植后的自发性微生物群依赖型结肠炎。我们的宿主和免疫扰动矩阵将使我们能够探索与IBD相关的不同互补宿主反应。我们将把我们的结果与现有的与IBD和自身免疫性疾病相关的人类遗传变异数据库结合起来，专注于人类相关的机制，以选择宿主基因，然后可以在小鼠模型中与相关细菌及其产物一起进一步研究这些宿主基因(我们的宿主调控网络和一组与IBD相关的人类同源基因的交集，目标3)。我们研究的完成将导致对免疫系统和微生物组之间相互作用的大型网络的新的定量理解，并将确定与设计新的人类炎症性肠病干预措施相关的分子机制。

DESCRIPTION (provided by applicant): Recent studies highlight a crucial role for gut mucosal immunity in both gut-proximal autoimmune diseases (Inflammatory Bowel Disease (IBD)) and in those involving extraintestinal compartments (rheumatoid arthritis and multiple sclerosis). The development of autoimmune disease involves the coordination of multiple gut- resident cell types and the gut microbiome. On the host side, immune cells and intestinal epithelium orchestrate gut microbial homeostasis via secretion of effector cytokines, antimicrobial peptides, and other molecules. Microbiota are also important modulators of immune responses, influencing the differentiation and function of immune cell populations. We propose an experimental design that combines IBD-relevant perturbations of host and microbiota. Cell abundance (immune cell and microbiota, Aim 1) and genomic measurements (microbial and host cell transcriptomics, Aim 2) will be combined into an integrated experimental design that will allow us to connect ecological changes in the gut to underlying molecular events in bacteria and host immune cells. We will combine three host perturbations (inhibition of ROR�t, IL-10 and IL- 23) with the introduction of two microbes that induce IBD-relevant phenotypes (Segmented Filamentous Bacteria (SFB) and Helicobacter hepaticus (Hh)) into specific pathogen free mice (mice with "normal" microbiomes). SFB adheres to the small intestinal epithelium and causes the expansion of Th17 cell populations in the lamina propria, influencing colitis, arthritis- and MS-relevant phenotypes. The commensal Hh promotes an anti-inflammatory immune response to limit its own gut colonization and only induces colitis-like pathologies in mouse strains with disrupted immune function. Hh-dependent murine colitis mirrors human IBD, where otherwise harmless gut microbial perturbations lead to chronic intestinal dysbiosis in genetically immune-deficient hosts. SFB and Hh interact with IL-23 and IL-10 signaling pathways (both strongly implicated in IBD pathogenesis). Blockade of IL-23 signaling contributes to the efficacy of IL-12p40 antibody therapy for IBD and genome-wide association studies confirm a central role for IL-23R in colitis. In humans mutations in IL10R are associated with IBD and IL-10 signaling deficiency in mice leads to spontaneous microbiome- dependent colitis upon Hh colonization. Our matrix of host and immune perturbations will allow us to explore distinct complementary IBD-relevant host responses. We will focus on human-relevant mechanisms by combining our results with existing databases of human genetic variations associated with IBD and autoimmune disease to select host genes that can then be further studied in mouse models along with relevant bacteria and their products (the intersection of our host regulatory network and the set of human orthologs with IBD association, Aim 3). Completion of our study will result in a new quantitative understanding of the large network of interactions between the immune system and the microbiome and will identify molecular mechanisms relevant for designing new interventions for human inflammatory bowel disease.