Impact of gut bacterial metabolites on lung function and disease

肠道细菌代谢对肺功能和疾病的影响

基本信息

批准号：
10663755
负责人：
Vaibhav Upadhyay
金额：
$ 16.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663755
关键词：
Ablation Acute Lung Injury Acute Respiratory Distress Syndrome Advisory Committees Alveolar Area Bacteria Bifidobacterium Biology COVID-19 Cell physiology Cells Cessation of life Clinical Communication Coupled Data Data Analyses Disease Foundations Future Genes Germ-Free Gnotobiotic Grant Growth Health Human IL17 gene Immune system Impairment In Situ In Vitro Inflammation Inflammatory Injury Ketone Bodies Ketones Knowledge Laboratories Learning Link Liquid substance Lung Lung diseases Measurement Measures Mediating Mentors Microbiology Modeling Molecular Mus National Heart, Lung, and Blood Institute Organism Pathology Pathway interactions Patients Phenotype Physicians Physiological Play Pneumococcal Pneumonia Pneumonia Positioning Attribute Research Research Infrastructure Resources Role Scientist Serum Severities Strategic vision Structure of parenchyma of lung T-Lymphocyte Technology Testing Training Work bacterial metabolism beta-Hydroxybutyrate career career development experimental study gastrointestinal epithelium gut bacteria gut microbiome immune function in vivo innovation intestinal epithelium ketogentic lung injury microbiome microbiome research microorganism programs pulmonary function response skills small molecule tool training opportunity

项目摘要

Project Summary/Abstract Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), is common in COVID-19 and was a major driver of the now >1 million deaths in the USA since March 2020. Rigorous work has emphasized the key role the immune system and the microbiome plays in lung diseases like ALI. This includes an important role for pro-inflammatory T helper 17 (Th17) cells, which expand and increase their activation in lung tissue during ALI and lead to pulmonary fluid accumulation. While select gut bacteria can induce Th17 cells, the causal role of the microbiome in ALI and ARDS remains a major knowledge gap. Bifidobacterium adolescentis is a gut isolate with the highest Th17 inducing capacity of any human gut bacterium. My own preliminary data show that colonization of germ-free (GF) mice with B. adolescentis is sufficient to markedly alter the expression of many genes in lung tissue, including hundreds of genes implicated in ARDS. My data also indicates that B. adolescentis and other bifidobacteria secrete small molecules that activate Th17 cells, providing a plausible mechanism by which bifidobacteria could contribute to lung injury. My K08 application will build on a set of tools based on our laboratory’s recent discovery that the host ketone body, β-hydroxybuytrate (βHB), uniquely suppresses the growth of Bifidobacterium species. I hypothesize that Bifidobacterium, which are suppressed by gut epithelial βHB, secrete small molecules that reach lung tissue and activate Th17 cells during ALI. The proposed research plan will provide multiple training opportunities leading to a unique and sustainable research program. As a clinical fellow in the Turnbaugh lab (UCSF), I have learned microbiome data analysis, anaerobic microbiology, and gnotobiotic mouse husbandry. This project, coupled to in-depth support by lung experts Drs. Sheppard and Matthay (UCSF), will help me develop an independent research area that builds upon my past training. I will develop skills quantifying ALI severity in two ALI models and pair these ALI models with state-of-the-art tools in microbiome research. This proposal is both technologically and conceptually innovative. We will leverage resources available in our laboratory to selectively manipulate Bifidobacterium colonization levels in conventionally raised mice using βHB. My proposed experiments will help elucidate the metabolites produced by gut Bifidobacterium that induce pulmonary Th17 phenotypes, emphasizing the importance of considering bacterial metabolism for immune function and lung physiologic impairment. Our proposed studies will shift the focus to remote communication between prevalent human gut bacteria and lung tissues, mediated by secreted bacterial metabolites. For patients with ALI, this work will define putative mechanisms by which gut microorganisms contribute to devastating physiologic impairment and provide a conceptual basis to understand the scope and molecular impact of the gut microbiome on lung function in both health and disease.

项目概要/摘要急性呼吸窘迫综合征（ARDS）是最严重的急性肺损伤（ALI）形式，常见于自 2020 年 3 月以来，COVID-19 是导致美国目前超过 100 万人死亡的主要原因。强调了免疫系统和微生物组在 ALI 等肺部疾病中发挥的关键作用。包括促炎辅助性 T 细胞 17 (Th17) 细胞的重要作用，这些细胞会扩张并增加其 ALI 期间肺组织的激活并导致肺液积聚，而某些肠道细菌可以诱导。 Th17 细胞、微生物组在 ALI 和 ARDS 中的因果作用仍然是一个主要的知识空白。青春双歧杆菌是一种肠道分离株，在人类肠道中具有最高的 Th17 诱导能力我自己的初步数据表明，青春双歧杆菌在无菌（GF）小鼠中的定植是足以显着改变肺组织中许多基因的表达，包括数百个相关基因我的数据还表明，青春双歧杆菌和其他双歧杆菌分泌的小分子激活 Th17 细胞，为双歧杆菌导致肺损伤提供了一种合理的机制。 K08 应用程序将建立在一组工具的基础上，该工具基于我们实验室最近的发现，即宿主酮体， β-羟基丁酸 (βHB) 具有独特的抑制双歧杆菌生长的作用。我目睹了被肠上皮βHB抑制的双歧杆菌分泌小分子拟议的研究计划将提供多种方法，以在 ALI 期间到达肺组织并激活 Th17 细胞。作为 Turnbaugh 的临床研究员，我们获得了培训机会，从而获得独特且可持续的研究计划。实验室（UCSF），我学习了微生物组数据分析、厌氧微生物学和无菌小鼠该项目加上肺部专家 Sheppard 和 Matthay (UCSF) 博士的深入支持，将帮助我在过去的培训基础上开发一个独立的研究领域，我将培养量化技能。两个 ALI 模型中的 ALI 严重程度，并将这些 ALI 模型与微生物组研究中最先进的工具配对。该提案在技术和概念上都具有创新性，我们将利用现有资源。在我们的实验室中，选择性地操纵双歧杆菌在传统饲养的小鼠中的定植水平我提出的实验将有助于阐明肠道双歧杆菌产生的代谢物，从而诱导肺 Th17 表型，强调考虑细菌代谢对于免疫的重要性我们提出的研究将重点转向远程通信。常见的人类肠道细菌和肺组织之间，由分泌的细菌代谢物介导。通过 ALI，这项工作将定义肠道微生物导致毁灭性损伤的假定机制。生理损伤并为理解肠道的范围和分子影响提供概念基础微生物组对健康和疾病中肺功能的影响。