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.

项目摘要 特发性肺纤维化（IPF）是一种进行性肺部疾病，目前尚无治愈方法， 了解发病机制。IPF导致生活质量显著降低、复发性住院， 致命的我们和其他人已经表明，肺免疫在IPF中失调。细菌和宿主 人类肠道的环境-肠道微生物组-对人类免疫力有着深远的影响。肠道 微生物组是肺免疫的关键调节因子，这是几个国家的一致生物学观察结果。 实验模型在最近发表的一项关键发现中，我们已经表明，无菌（GF）小鼠- 缺乏微生物组的实验小鼠-被保护免于肺纤维化相关的死亡。人 在IPF患者中，肺部细菌负荷可预测死亡率，肺部细菌多样性与 肺部炎症虽然微生物组可以预测结果，但微生物之间的关键调控相互作用 宿主、肺和肠道微生物群仍然未知。 这一提议的中心假设是，关键肠道微生物群，即双歧杆菌属，作为主 肺纤维化中的肺免疫调节剂，形成宿主防御，相关炎症和 改变肺损伤后的实质修复。这项建议的理由是，这项工作将加强我们的 目前对IPF发病机制的了解，并进一步为基于微生物组的治疗奠定基础， 慢性肺病我们将通过以下实验目标来实现这一目标： 具体目标1：确定有助于治疗结果的关键双歧杆菌副产物和代谢产物， 使用益生元饮食改良、无菌（GF）和非益生菌（gnotobiotic）的肺纤维化临床前模型 小鼠，16 S 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， 使用肺纤维化临床前模型研究双歧杆菌改善肺纤维化的预后 常规和GF衍生的T细胞和IL-10转基因模型，T细胞过继转移和流式细胞术 流式细胞术介导的肺细胞免疫的表征。 具体目的3：确定IPF患者肠道微生物群的免疫原性和纤维化作用。 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 结果。GF小鼠将接受来自人类患者的样本的粪便微生物群移植 IPF。这些细菌将在体内进行研究，并在该临床前模型中与肺纤维化相关。 这种转化方法将使用先进的机械工具来1）提高我们对复杂性的理解 在肺纤维化临床前模型中发生的免疫-微生物群相互作用，2）鉴定可改变的宿主， 肺纤维化中的微生物群相关靶标，最后3）推进基于微生物群的治疗的基础 在慢性肺病中。