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

• 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
• 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

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.

项目总结/摘要 急性呼吸窘迫综合征（ARDS）是急性肺损伤（ALI）的最严重形式， 自二零二零年三月以来，美国的死亡人数已超过100万人。严谨的工作 强调了免疫系统和微生物组在肺部疾病如ALI中的关键作用。这 包括促炎性辅助性T细胞17（Th 17）的重要作用，其扩增并增加其免疫应答。 在ALI期间肺组织中活化并导致肺液体积聚。虽然选择肠道细菌可以诱导 Th 17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。 双歧杆菌是一种肠道分离物，在任何人类肠道中具有最高的Th 17诱导能力 细菌。我自己的初步数据表明，无菌（GF）小鼠定植B。黑猩猩属 足以显着改变肺组织中许多基因的表达，包括数百个涉及 在ARDS。我的数据还表明，B.双歧杆菌和其他双歧杆菌分泌小分子， 激活Th 17细胞，提供了一种合理的机制，通过这种机制，双歧杆菌可能导致肺损伤。我 K 08应用将建立在一套基于我们实验室最近发现的工具上， β-羟基丁酸盐（βHB），独特地抑制双歧杆菌属的生长。 我假设双歧杆菌，这是由肠道上皮βHB抑制，分泌小分子 在ALI期间到达肺组织并激活Th 17细胞。该研究计划将提供多个 培训机会，导致一个独特的和可持续的研究计划。作为一个在特恩堡的临床研究员， 在加州大学旧金山分校的实验室，我学习了微生物组数据分析，厌氧微生物学和gnotobiotic小鼠 畜牧业这个项目，再加上肺部专家谢泼德博士和马泰（加州大学旧金山分校）的深入支持，将 帮助我发展一个独立的研究领域，建立在我过去的训练。我将发展量化技能 在两个ALI模型中评估ALI严重程度，并将这些ALI模型与微生物组研究中的最新工具配对。 这一建议在技术和概念上都是创新的。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常规饲养的小鼠中的定植水平， βHB。我提出的实验将有助于阐明肠道双歧杆菌产生的代谢产物， 肺Th 17表型，强调考虑细菌代谢对免疫的重要性 功能和肺生理损害。我们提出的研究将重点转移到远程通信 之间流行的人类肠道细菌和肺组织，由分泌的细菌代谢产物介导。患者 与ALI，这项工作将确定假定的机制，肠道微生物有助于破坏性 生理损伤，并提供一个概念基础，了解肠道的范围和分子影响 微生物组在健康和疾病中对肺功能的影响。