Gut Microbiota and Host Regulatory Cross-Talk in Pulmonary Fibrosis

肺纤维化中的肠道微生物群和宿主调节相互作用

基本信息

批准号：
10414838
负责人：
David Noel O'Dwyer
金额：
$ 51.09万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414838
关键词：
16S ribosomal RNA sequencing Adoptive Transfer Age Anaerobic Bacteria Animal Model Antigen-Antibody Complex Attenuated Bacteria Bifidobacterium Biological Cells Cellular Immunity Cessation of life Chronic lung disease Clinical Clinical Research Clinical Trials Data Diet Modification Disease Disease Progression Environment Experimental Models FOXP3 gene Fibrosis Flow Cytometry Foundations Future Genes Genetic Transcription Germ-Free Gnotobiotic Hospitalization Host Defense Human Immune Immune system Immunity In Vitro Inflammation Interleukin-10 Interleukin-17 Intervention Trial Knowledge Life Link Lung Lung diseases Machine Learning Mediating Metagenomics Modeling Molecular Mus Outcome Participant Pathogenesis Patients Phenotype Play Pre-Clinical Model Precision therapeutics Production Publishing Pulmonary Fibrosis Pulmonary Inflammation Quality of life Rag1 Mouse Recording of previous events Recurrence Regulation Regulatory T-Lymphocyte Reproducibility Research Research Personnel Respiratory Failure Role Sampling Sampling Studies Severity of illness Shapes Statistical Models Survivors T cell response T cell therapy T-Lymphocyte Testing Transgenic Model Transgenic Organisms Translational Research United States National Institutes of Health Work base cytokine fecal transplantation fibrotic lung gut microbiome gut microbiota host microbiota idiopathic pulmonary fibrosis immunogenic immunoregulation improved lung injury lung microbiome lung microbiota metabolomics microbiome microbiota mortality mouse model mucosal microbiota novel outcome prediction repaired response tool transcriptional reprogramming transcriptome sequencing translational approach translational study treatment strategy

项目摘要

Project Summary Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disorder with no known cure and poorly understood pathogenesis. IPF results in significant reductions in quality of life, recurrent hospitalizations and is fatal. We and others have shown that pulmonary immunity is dysregulated in IPF. The bacteria and host environment of the human gut - the gut microbiome - has a profound impact on human immunity. The gut microbiome is a key regulator of pulmonary immunity, a consistent biological observation across several experimental models. In a key finding, recently published, we have shown that germ free (GF) mice – experimental mice devoid of a microbiome – are protected from pulmonary fibrosis related mortality. In human patients with IPF, the bacterial burden of the lung predicts mortality and the lungs bacterial diversity correlates with pulmonary inflammation. While the microbiome predicts outcomes, key regulatory interactions between the host, lung and gut microbiota remain unknown. The central hypothesis of this proposal is that key gut microbiota, namely Bifidobacterium spp, act as master regulators of pulmonary immunity in lung fibrosis, shaping host defense, associated inflammation and modifying parenchymal repair after lung injury. The rationale for this proposal is that this work will augment our current knowledge of IPF pathogenesis and further the foundational basis for microbiome based therapies in chronic lung disease. We will accomplish this through the following experimental aims: Specific Aim 1: To determine key Bifidobacteria by-products and metabolites that contribute to outcomes in pre-clinical models of pulmonary fibrosis using pre-biotic diet modifications, germ free (GF) and gnotobiotic mice, 16S rRNA gene sequencing, functional metagenomics and metabolomics. Specific Aim 2: To determine the host related cellular and molecular mechanisms through which Bifidobacterium spp modify outcomes in pulmonary fibrosis using pre-clinical models of pulmonary fibrosis in conventional and GF derived T cell, IL-10 and IL-17 transgenic models, T cell adoptive transfer and multicolor flow cytometry mediated characterization of lung cellular immunity. Specific Aim 3: To determine the immunogenic and fibrogenic effects of gut microbiota from patients with IPF. Gut microbiota from patients with IPF will be identified and correlated with disease severity and clinical outcomes. Regulatory T cell phenotype from patients with IPF will be correlated with gut diversity and taxa. This translational approach will use advanced mechanistic tools to 1) improve our understanding of complex immune-microbiota interactions that occur in pre-clinical models of lung fibrosis, 2) identify modifiable host and microbiota related targets in lung fibrosis and finally 3) advance the foundation for microbiome based therapies in chronic lung disease.

项目摘要特发性肺纤维化（IPF）是一种进行性肺部疾病，没有已知的治愈方法了解发病机理。 IPF导致生活质量，复发性住院质量的大幅降低，并且是致命的。我们和其他人表明，IPF中的肺免疫。细菌和宿主人类肠道的环境 - 肠道微生物组 - 对人类免疫有深远的影响。肠道微生物组是肺免疫组织化学的关键调节剂，这是几个一致的生物学观察结果实验模型。在最近出版的关键发现中，我们表明了无细菌（GF）小鼠 - 没有微生物组的实验小鼠受到保护免受肺纤维化相关死亡率的保护。在人类中 IPF患者，肺预测死亡率的细菌燃烧和肺细菌多样性相关肺部炎症。尽管微生物组预测结果，但关键的调节性相互作用宿主，肺和肠道菌群仍然未知。该提议的中心假设是关键的肠道微生物群，即双歧杆菌属，充当主人肺纤维化中肺免疫的调节剂，塑造宿主防御，相关感染和肺损伤后修饰副群修复。该提议的理由是，这项工作将增加我们的当前对IPF发病机理的知识以及基于微生物组疗法的基础基础慢性肺部病。我们将通过以下实验目标来实现这一目标：特定目的1：确定有助于结果的关键双歧杆菌副产品和代谢产物肺纤维化的临床前模型，使用益生元饮食修饰，无细菌（GF）和gnotobiotic 小鼠，16S rRNA基因测序，功能性宏基因组学和代谢组学。特定目标2：确定宿主相关的细胞和分子机制双歧杆菌SPP使用肺纤维化的临床前模型在肺纤维化中修饰结果常规和GF衍生的T细胞，IL-10和IL-17转基因模型，T细胞产物转移和多色流式细胞仪介导的肺细胞免疫表征。特定目标3：确定IPF患者肠道菌群的免疫原性和纤维纤维效应。 IPF患者的肠道菌群将被鉴定出来并与疾病的严重程度和临床相关结果。 IPF患者的调节性T细胞表型将与肠道多样性和分类单元相关。这种翻译方法将使用先进的机械工具到1）提高我们对复杂的理解在肺纤维化前临床模型中发生的免疫微生物群相互作用，2）确定可修改的宿主和肺纤维化中的微生物群相关靶标，最后3）提高基于微生物组疗法的基础在慢性肺部疾病中。