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

描述（由申请人提供）：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））和涉及肠外隔室的疾病（类风湿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组的协调。在宿主侧，免疫细胞和肠上皮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稳态。微生物群也是免疫反应的重要调节剂，影响免疫细胞群的分化和功能。我们提出了一个结合ibd相关的宿主和微生物群扰动的实验设计。细胞丰度（免疫细胞和微生物群，Aim 1）和基因组测量（微生物和宿主细胞转录组学，Aim 2）将结合成一个综合实验设计，这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的潜在分子事件联系起来。我们将结合三种宿主扰动（抑制ROR¿t， IL-10和IL- 23）和引入两种诱导ibd相关表型的微生物（分段丝状细菌（SFB）和肝螺杆菌（Hh））到特定的无病原体小鼠（具有“正常”微生物组的小鼠）。SFB粘附在小肠上皮上，引起固有层Th17细胞群的扩增，影响结肠炎、关节炎和ms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，并且仅在免疫功能受损的小鼠品系中诱导结肠炎样病理。依赖hh的小鼠结肠炎反映了人类IBD，在这种情况下，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发病机制密切相关）。阻断IL-23信号有助于IL-12p40抗体治疗IBD的疗效，全基因组关联研究证实了IL-23R在结肠炎中的核心作用。在人类中，IL10R突变与IBD有关，小鼠中IL-10信号缺乏导致Hh定植后自发的微生物组依赖性结肠炎。我们的宿主和免疫扰动矩阵将使我们能够探索不同的互补ibd相关宿主反应。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，选择宿主基因，然后在小鼠模型中与相关细菌及其产物进一步研究（我们的宿主调控网络和与IBD相关的人类同源物集的交集，Aim 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，并将确定与设计人类炎症性肠病新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.