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

炎症性肠病肠道宿主微生物生态系统的网络模型

基本信息

批准号：
9315812
负责人：
RICHARD A BONNEAU
金额：
$ 63.61万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-25 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315812
关键词：
American Anti-Inflammatory Agents Anti-inflammatory Antibody Therapy Arthritis Autoimmune Diseases Autoimmune Process Bacteria Cell Differentiation process Cell physiology Cells Chromatin Chronic Colitis Colon Communities Data Data Collection Data Set Databases Defect Dendritic Cells Development Disease Disease Progression Ecological Change Ecology Ecosystem Elements Epithelial Epithelial Cells Etiology Event Evolution Experimental Designs FAIRE sequencing Flow Cytometry Follow-Up Studies Gene Expression Regulation Genes Genetic Genetic Transcription Genetic Variation Genetic study Genomics Helicobacter hepaticus Homeostasis Human Human Genetics Immune Immune response Immune signaling Immune system Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-10 Internet Intervention Intestines Lamina Propria Lead Learning Measurement Measures Microbe Modeling Molecular Molecular Models Mouse Strains Mucosal Immunity Multiple Sclerosis Mus Mutant Strains Mice Mutation Orthologous Gene Pathogenesis Pathology Pathway interactions Phenotype Play Population Positioning Attribute Recombinant DNA Regulation Regulatory T-Lymphocyte Resources Rheumatoid Arthritis Role Series Side Signal Pathway Signal Transduction Site Small Intestines Surveys Symbiosis Testing Time Tissues antimicrobial peptide cell type cost cytokine design experimental study genome wide association study germ free condition gut microbiome gut microbiota human disease immune function immunoregulation interleukin-23 intestinal epithelium microbial microbial community microbial host microbiome microbiota molecular modeling molecular scale mouse model network models public health relevance response tool transcriptome sequencing transcriptomics

项目摘要

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.

描述（由申请人提供）：最近的研究强调了肠道粘膜免疫在近肠自身免疫性疾病（炎症性肠病（IBD））和涉及肠外区室（类风湿性关节炎和多发性硬化症）的自身免疫性疾病中的关键作用。疾病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，免疫细胞和肠上皮协调肠道微生物。通过效应细胞因子、抗菌肽和其他分子的分泌实现稳态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，我们提出了一种结合 IBD 相关的宿主和微生物群扰动的实验设计。丰度（免疫细胞和微生物群，目标 1）和基因组测量（微生物和宿主细胞转录组学，目标 2）将被合并到一个集成的实验设计中，这将使我们能够为了将肠道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 RORt、IL-10 和 IL-23），并引入两种诱导 IBD 相关的微生物。表型（分段丝状细菌（SFB）和肝螺杆菌（Hh））转化为无特定病原体的小鼠（具有“正常”微生物组的小鼠）。共生 Hh 促进抗炎免疫反应，限制其自身肠道定植，并且仅诱导结肠炎样症状。免疫功能受损的小鼠品系的病理学与人类 IBD 相似，在人类 IBD 中，原本无害的肠道微生物扰动会导致遗传性免疫缺陷的慢性肠道菌群失调。 SFB 和 Hh 与 IL-23 和 IL-10 信号通路相互作用（两者均与 IBD 发病机制密切相关）。IL-23 信号通路的阻断有助于 IL-12p40 抗体治疗 IBD 的疗效，并且全基因组关联研究证实。 IL-23R 在结肠炎中发挥着重要作用。在人类中，IL10R 突变与 IBD 相关，而在小鼠中，IL-10 信号传导缺陷会导致 Hh 定植后自发性微生物组依赖性结肠炎。宿主和免疫扰动矩阵将使我们能够探索与 IBD 相关的独特的互补宿主反应，我们将通过将我们的结果与与 IBD 和自身免疫性疾病相关的人类遗传变异的现有数据库相结合来重点研究人类相关机制，以选择能够产生 IBD 的宿主基因。然后在小鼠模型中与相关细菌及其产物一起进行进一步研究（我们的宿主调节网络和与 IBD 关联的人类直系同源物集的交集，目标 3）。完成我们的研究将导致对 IBD 的新的定量理解。免疫系统和微生物组之间相互作用的大型网络，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。