Dust-Induced Microbiome Changes Alter Allergic Immune Responses

过敏性哮喘在西方国家很常见，其患病率在上个世纪大大增加。有趣的是，最近的研究表明，婴儿时期接触宠物与晚年患过敏和哮喘的风险较低有关。此外，PPG调查人员产生的数据表明，宠物可能与室内灰尘中微生物群的改变有关。众所周知，儿童会摄入土壤和灰尘，肠道微生物群的改变与过敏性哮喘发展的风险有关。为了进一步了解导致临床观察到的变化的机制，该项目建立并利用了暴露于有狗和没有宠物的家庭粉尘中的肺部疾病模型。使用两种不同的过敏性哮喘小鼠模型（蟑螂抗原和卵清蛋白），我们将研究口服暴露于室内灰尘后的肺部免疫反应，使用从有狗和没有宠物的家庭收集的样本。我们将测试一个整体假设，即有狗的家庭与没有宠物的家庭的灰尘微生物组的组成在过敏原暴露期间通过改变Gl微生物群或细菌群落组成（BCC）而改变肺部免疫反应，从而导致抗原呈递细胞和骨髓祖细胞编程和过敏结果的系统性改变。为了验证这一假设，我们将特别关注肺源性过敏原反应诱导Th2细胞因子、粘液高分泌、生理变化（AHR）以及局部和全身先天反应变化的临床相关机制。我们的研究将：1)确定小鼠暴露于有狗的家中粉尘与没有宠物的家中粉尘会导致Gl BCC的不同变化，2)证明狗粉尘改变的肠道微生物组改变了肺部过敏反应，3)确定狗粉尘诱导的变化改变了肺部树突状细胞反应，4)通过检查骨髓细胞反应确定先天反应的变化是一种全身效应。5)利用创新的小鼠模型来推导改变反应的细胞机制。BCC将使用G3 PhyloChip测量。因此，这些研究与PPG中的其他项目密切合作，将澄清许多以前未探索的问题，并将指导探索这一新的研究领域。

Allergic asthma is common in Westernized countries and its prevalence has increased greatly during the last century. Interestingly, recent research has shown that exposure to pets during infancy correlates with a lower risk of developing allergy and asthma in later life. In addition, data generated by the PPG investigators have demonstrated that pets can be associated with alterations to the microbiota in house dust. It is well known that soil and dust are ingested by children, and alterations in gut microbiome have been associated with risk for allergic asthma development. In order to further our understanding of the mechanisms that lead to the alterations observed clinically, this project has established and utilized models of pulmonary disease with exposure to dust from homes with dogs versus no pets. Using two different mouse models of allergic asthma (cockroach antigen and ovalbumin), we will study pulmonary immune responses after oral exposure to house dust using samples collected from homes with dogs and without pets. We will test the overall hypothesis that the composition of the dust microbiome from homes with dogs versus no pets differentially alters pulmonary immune responses during allergen exposure by changing the Gl microbiota or bacterial community composition (BCC), resulting in systemic changes in antigen presenting cell and bone marrow progenitor cell programming and allergic outcomes. To test this hypothesis, we will specifically focus on clinically relevant mechanisms involved in the ability of pulmonary-derived allergen responses to induce Th2 cytokines, mucus hypersecretion, physiologic changes (AHR), and changes in innate responses locally as well as systemically. Our studies will: 1) establish that exposure of mice to dust from homes with dogs versus no pets will result in differential changes in the Gl BCC, 2) demonstrate that the dog dust-altered gut microbiome alters pulmonary allergic responses, 3) establish that the dog dust-induced changes alter dendritic cell responses in the lung, 4) identify that changes in innate responses are a systemic effect by examining bone marrow cell responses, and 5) utilize innovative mouse models to derive the cellular mechanisms of the altered responses. BCC will be measured using the G3 PhyloChip. Thus, these studies, in close collaboration with the other projects in this PPG, will clarify a number of previously unexplored questions and will guide exploration into this novel area of research.