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

• 批准号: 10294291
• 负责人: David Noel O'Dwyer
• 金额: $ 47.7万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294291
• 关键词: 16S ribosomal RNA sequencing; Adoptive Transfer; Animal Model; Antibiotics; Antigen-Antibody Complex; Attenuated; Bacteria; Bifidobacterium; Biological; Biological Response Modifiers; Blood; Cells; Cellular Immunity; Cessation of life; Chronic lung disease; Cicatrix; Clinical; Clinical Trials; DNA sequencing; Data; Diet Modification; Disease Progression; Enrollment; Environment; Experimental Models; Fibrosis; Flow Cytometry; Foundations; Future; Genes; Germ-Free; Gnotobiotic; Goals; Health; Hospitalization; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Inflammation; Interleukin-10; Intervention Trial; Knowledge; Link; Literature; Lung; Lung diseases; Mediating; Metagenomics; Modeling; Molecular; Mus; Oral; Outcome; Pathogenesis; Patients; Play; Pre-Clinical Model; Proteins; Publishing; Pulmonary Fibrosis; Pulmonary Inflammation; Quality of life; Recurrence; Regulatory T-Lymphocyte; Reporting; Research; Respiratory Failure; Role; Sampling; Severity of illness; Shapes; Structure of parenchyma of lung; Swab; T cell therapy; T-Lymphocyte; Transgenic Model; Transgenic Organisms; Work; base; dysbiosis; fecal transplantation; germ free condition; gut dysbiosis; gut microbiome; gut microbiota; host microbiota; idiopathic pulmonary fibrosis; immunogenic; improved; in vivo; lung injury; lung microbiota; metabolomics; microbiome; microbiota; mortality; mucosal microbiota; outcome prediction; recruit; repaired; tool; transcriptome sequencing; transcriptomics; translational approach

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 and IL-10 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. GF mice will undergo fecal microbiota transplantation with samples derived from human patients with IPF. These bacteria will be studied in vivo and correlated with lung fibrosis in this pre-clinical model. 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.

项目概要 特发性肺纤维化（IPF）是一种进行性肺部疾病，目前尚无已知的治愈方法，且治疗效果不佳 了解发病机制。 IPF 导致生活质量显着下降、反复住院，并且 致命的。我们和其他人已经证明 IPF 中肺部免疫失调。细菌和宿主 人体肠道环境——肠道微生物组——对人体免疫力有着深远的影响。肠道 微生物组是肺部免疫的关键调节因子，多项生物学观察结果一致 实验模型。在最近发表的一项重要发现中，我们表明无菌 (GF) 小鼠 – 缺乏微生物组的实验小鼠可以避免肺纤维化相关的死亡。在人类 对于 IPF 患者，肺部细菌负荷可预测死亡率，并且肺部细菌多样性与之相关 伴有肺部炎症。虽然微生物组可以预测结果，但之间的关键监管相互作用 宿主、肺和肠道微生物群仍然未知。 该提案的中心假设是关键的肠道微生物群，即双歧杆菌，充当主人 肺纤维化中肺免疫的调节因子，塑造宿主防御，相关炎症和 改变肺损伤后的实质修复。该提案的基本原理是这项工作将增强我们的能力 目前对 IPF 发病机制的了解，并进一步奠定基于微生物组的治疗的基础 慢性肺部疾病。我们将通过以下实验目标来实现这一目标： 具体目标 1：确定有助于结果的关键双歧杆菌副产物和代谢物 使用益生元饮食改良、无菌 (GF) 和限生素的肺纤维化临床前模型 小鼠、16S rRNA 基因测序、功能宏基因组学和代谢组学。 具体目标 2：确定宿主相关的细胞和分子机制 双歧杆菌属利用肺纤维化的临床前模型改变肺纤维化的结果 传统和 GF 衍生的 T 细胞和 IL-10 转基因模型、T 细胞过继转移和多色流 细胞计数介导的肺细胞免疫特征。 具体目标 3：确定 IPF 患者肠道微生物群的免疫原性和纤维形成作用。 将鉴定 IPF 患者的肠道微生物群，并将其与疾病严重程度和临床相关联 结果。 GF 小鼠将使用来自人类患者的样本进行粪便微生物群移植 与IPF。这些细菌将在该临床前模型中进行体内研究并与肺纤维化相关。 这种转化方法将使用先进的机械工具来 1）提高我们对复杂的理解 肺纤维化临床前模型中发生的免疫-微生物相互作用，2) 识别可修改的宿主和 肺纤维化中微生物群相关的靶标，最后 3) 为基于微生物组的治疗奠定基础 在慢性肺部疾病中。