The effects of a wild gut microbiome on mucosal immunity and disease

野生肠道微生物组对粘膜免疫和疾病的影响

• 批准号: 10158471
• 负责人: Frank Yeung
• 金额: $ 5.1万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-14 至 2022-06-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158471
• 关键词: Address; Adult; Affect; Antibodies; Antigen-Presenting Cells; Bacteria; Blood; C57BL/6 Mouse; CD8B1 gene; Cell Differentiation process; Cells; Characteristics; Communicable Diseases; Complex; Data; Development; Disease; Disease Outcome; Disease susceptibility; Environment; Environmental Risk Factor; Equilibrium; Exposure to; Gastrointestinal tract structure; Genes; Genetic Predisposition to Disease; Germ-Free; Goals; Homeostasis; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunological Models; Inbreeding; Individual; Infection; Infectious Agent; Inflammasome; Inflammatory; Inflammatory Bowel Diseases; Intestines; Invaded; Knockout Mice; Laboratories; Laboratory Finding; Laboratory mice; Leukocytes; Lymphocyte Subset; Maintenance; Mammals; Mediating; Memory; Microbe; Mucosal Immunity; Mus; Nature; Neutrophilia; Pathology; Population; Research; Role; Salmonella typhimurium; Signal Pathway; System; T cell differentiation; T memory cell; T-Lymphocyte; Testing; Translations; Viral; Wild Type Mouse; animal facility; base; commensal bacteria; disorder risk; dysbiosis; gut bacteria; gut microbiome; gut microbiota; host microbiota; host-microbe interactions; human disease; immune activation; improved; inflammatory disease of the intestine; innovation; insight; member; mesenteric lymph node; microbiome; microbiota; mouse model; neutrophil; novel; novel strategies; pathogen; pathogen exposure; polarized cell; preservation; response

Project Summary The gut microbiota has a fundamental role in the development and stability of the host immune system. Colonization by certain bacteria, and even individual species, can alter the course of many infectious and inflammatory diseases. Our understanding of the immune consequences of colonization by members of the gut microbiota is based primarily on laboratory mouse models. Although this conventional approach has enabled detailed mechanistic studies on the immune system, laboratory mice may not reflect the more complex diseases of humans and free-living mammals in a natural environment. Here we present the use of a unique outdoor facility that allows us to adapt established mouse models to study disease risk in a more natural environment. Our preliminary data suggests that introduction of laboratory C57BL/6 mice to our facility increases the presence and function of key immune cell populations coincident with microbiome changes. The increase in circulating neutrophils and CD4+/CD8+ memory cells, reduction in naive T cells, and increased expression of costimulatory molecules on antigen presenting cells, all occurs in the absence of viral, bacterial or parasitic pathogen exposure. Detailed mechanistic study of how a natural microbiota alters mucosal immunity and contributes to disease risk has yet to be investigated. We therefore propose that gut wild microbiota enhances local innate immune activation and promotes the host immune response towards a proinflammatory state. To test this hypothesis, we propose three aims: 1) define the effect of the wild microbiota on T cell polarization in the gut, 2) determine the role of the inflammasome in the enhanced immunity mediated by the wild microbiota, and 3) determine whether Nod2−/− mice display immune dysregulation when exposed to wild microbiome. Altogether, these studies would elucidate novel host-microbe interactions and may provide innovative insight into how genetic susceptibility can contribute to the development and maintenance of disease.

项目摘要 肠道微生物区系在宿主免疫的发展和稳定中起着基础性作用。 系统。某些细菌的定居，甚至个别物种的定居，可以改变 许多传染病和炎症性疾病。我们对猪瘟免疫后果的理解 肠道微生物区系成员的定植主要基于实验室小鼠模型。 尽管这种传统的方法使得对免疫的详细机制研究成为可能 系统中，实验室小鼠可能不会反映人类和自由生活的更复杂的疾病 自然环境中的哺乳动物。在这里，我们展示了一种独特的户外设施的使用 使我们能够调整已建立的小鼠模型，以在更自然的环境中研究疾病风险。 我们的初步数据表明，将实验室的C57BL/6小鼠引入我们的设施 增加与微生物群一致的关键免疫细胞群的存在和功能 改变。循环中中性粒细胞和CD4+/CD8+记忆细胞增加，幼稚细胞减少 T细胞和抗原提呈细胞表面共刺激分子的表达增加，ALL 在没有接触病毒、细菌或寄生虫的情况下发生。详细机械论 关于天然微生物区系如何改变粘膜免疫并增加疾病风险的研究尚未完成 接受调查。因此，我们认为肠道野生微生物区系可增强局部先天免疫。 激活并促进宿主免疫反应进入促炎状态。为了测试这一点 假设，我们提出三个目标：1)确定野生微生物区系对T细胞极化的影响 在肠道中，2)确定炎症小体在介导的免疫增强中的作用 以及3)确定NOD2−/−小鼠在以下情况下是否表现出免疫失调 暴露在野生微生物群中。总之，这些研究将阐明新的宿主微生物 并可能提供对遗传易感性如何有助于 疾病的发展和维持。