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

项目摘要 肠道微生物群在宿主免疫系统的发展和稳定中起着重要作用。 系统某些细菌，甚至个别物种的定植，可以改变 许多传染性和炎症性疾病。我们对免疫后果的理解 肠道微生物群成员的定殖主要基于实验室小鼠模型。 虽然这种传统的方法已经能够对免疫系统进行详细的机制研究， 系统，实验室小鼠可能无法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，我们提出了一个独特的户外设施， 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，引入实验室C57 BL/6小鼠到我们的设施， 增加与微生物组一致的关键免疫细胞群的存在和功能 变化循环中性粒细胞和CD 4 +/CD 8+记忆细胞的增加，幼稚细胞的减少， T细胞，以及抗原呈递细胞上共刺激分子表达的增加，所有这些都是 在没有病毒、细菌或寄生病原体暴露的情况下发生。详细的机理 关于天然微生物群如何改变粘膜免疫力并导致疾病风险的研究还没有 接受调查因此，我们认为肠道野生微生物群增强了局部先天免疫 激活并促进宿主免疫应答朝向促炎状态。为了验证这一 假设，我们提出了三个目标：1）确定野生菌群对T细胞极化的影响 2）确定炎性小体在由免疫调节剂介导的增强免疫中的作用， 野生微生物群，和3）确定Nod 2 −/−小鼠是否显示免疫失调， 暴露在野生微生物中总之，这些研究将阐明新的宿主微生物 相互作用，并可能提供创新的见解，如何遗传易感性可以有助于 疾病的发展和维持。

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.