The role of the gut microbiome in susceptibility to Mycobacterium tuberculosis

项目摘要 结核病是一种致命的传染病，每年造成170多万人死亡。的 大多数个体能够控制结核分枝杆菌（Mtb）感染，但其他个体 极其脆弱危及生命的疾病症状，包括极度体重减轻或恶病质， 在个体之间也是异质的。免疫力低下的人特别容易受到 结核病和免疫系统功能的不太极端的变化也可能导致易感性。的 哺乳动物肠道微生物组是一个复杂的微生物群落， 个体肠道微生物组组成影响免疫功能和对各种疾病的易感性 病原体我们的试验数据表明，具有不同肠道微生物组的遗传相同的小鼠， 改变控制结核分枝杆菌感染的能力。在这项提案中，我们将询问微生物组在以下方面的作用： 结核病控制和恶病质。首先，我们将扩大我们的比较小鼠从不同的住房 确定结核菌负担变化程度的条件。为了证实微生物组在 MTB感染控制，我们将把感兴趣的粪便微生物组移植到无菌小鼠中， 结核病感染。我们还将分析每种情况下对感染的免疫反应。二是 通过测量肠道微生物在结核病相关恶病质中的作用， 以及在具有不同微生物组的遗传相同的小鼠中随时间推移的代谢变化。在后续行动中， 我们将从这些微生物群中分离出感兴趣的肠道细菌， 新陈代谢可能影响免疫功能。这一建议将开辟一个新的研究领域进行探讨 肠道微生物组在结核病发病机制中的作用。这项研究有可能确定 用于结核病预防和治疗的新的微生物和宿主定向治疗靶点。

PROJECT SUMMARY Tuberculosis (TB) is a deadly infectious disease that kills over 1.7 million people per year. The majority of individuals are able to control Mycobacterium tuberculosis (Mtb) infection, yet others are extremely vulnerable. Life-threatening disease symptoms, including extreme weight loss or cachexia, are also heterogenous across individuals. Immunocompromised people are particularly susceptible to TB, and less extreme variations in immune system function may also contribute to susceptibility. The mammalian gut microbiome is a complex community of microbes with extreme variation across individuals. Gut microbiome composition impacts immune function and susceptibility to a variety of pathogens. Our pilot data suggests that genetically identical mice with distinct gut microbiomes have altered ability to control Mtb infection. In this proposal we will interrogate the role of the microbiome in Mtb control and cachexia. First, we will expand our comparison of mice from different housing conditions to determine the extent of variation in Mtb burden. To confirm the role of the microbiome in Mtb infection control, we will transplant fecal microbiomes of interest into germ-free mice and repeat Mtb infection. We will also profile the immune response to infection in each case. Second, we will explore the role of the gut microbiome in mediating TB associated cachexia by measuring microbial and metabolic changes over time in genetically identical mice with diverse microbiomes. In follow up, we will isolate gut bacteria of interest from these microbiomes to investigate how microbial metabolism may impact immune function. This proposal will open up a new area of research to probe the role of the gut microbiome in the pathogenesis of TB. This research has the potential to identify new microbial and host directed therapeutic targets for TB prophylaxis and treatment.