The Gut-Lung Axis: Immunometabolism Linking the Gut Microbiome and Lung Imunity

项目摘要/摘要 肠道-肺轴是肠道微生物群和肠外的许多通信轴之一。 系统、器官和组织。这一轴已被证明强烈影响肺免疫和炎症。 反应，主要是过敏性哮喘、炎症和肺部感染。实现这一目标的机制 推测通信是免疫细胞重新编程和/或因子的直接移位， 包括微生物配体。本课题的重点是后一种机制，即肠道的直接作用。 通过肺组织进入循环的微生物群产品。这项提议的目标是 严格研究1)肠-肺轴，重点是代谢物，如短链脂肪酸(SCFA)， 和共生相关分子模式(CAMP)，2)整合这些肠道来源的肺细胞 信号，以及3)这些信号对肺部对无菌和感染性损伤的反应性的影响。 根据我们的初步数据，我们认为SCFA和cAMP是由肠道微生物区系和 进入肺部，影响居民免疫和非免疫的免疫代谢程序 肺泡巨噬细胞(AM)和肺泡2型(AT2)细胞。在目标一中，我们将表演 粪便和肺组织以及中间组织和血管床的代谢组学分析。这一目标将 也评估产生单链脂肪酸的微生物区系在建立肺的基线代谢物分布和 追踪特定营地从肠道到肺部的迁移。在第二个目标中，我们将重点识别肺部 能够感知cAMP和代谢物的细胞，以及它们如何通过 准备好的“准备好”状态或未准备好的“未准备好”状态相对于感染和伤害。此外，这一影响， 这些cAMP和代谢物对一般的肺和特定的肺细胞的代谢程序 接受检查。在第三个目标中，我们将探索通过使用抗生素、饮食、 集中的代谢物输送，并通过微生物组转移或修复。这些研究将试图 建立以微生物组为基础的疗法有助于恢复健康的肺部免疫的条件 响应性。总而言之，这个项目试图了解肠道微生物群和饮食的作用 维持健康肺部免疫的代谢物。总体而言，我们预计这些研究将有所帮助 从根本上增加我们对肠道微生物群对肺免疫的直接作用的认识 在这样做的过程中，为设计未来的新的治疗方案提供了有价值的见解 充分利用肠道-肺免疫轴。

Project Summary/Abstract The gut-lung axis is one of many communication axes between the gut microbiome and extra-intestinal systems, organs, and tissues. This axis has been shown to strongly influence lung immune and inflammatory responses, primarily in allergic asthma inflammation and lung infections. The mechanisms for this communication are speculated to be immune cell reprogramming and/or direct translocation of factors, including microbial ligands. This project focuses on the latter mechanism, namely the direct effects of gut microbiome products that make their way into circulation, on lung tissue. The goals of this proposal are to rigorously investigate 1) the gut-lung axis with a focus on metabolites, such as short-chain fatty acids (SCFAs), and commensal-associated molecular patterns (CAMPs), 2) the lung cells that integrate these gut-derived signals, and 3) the effects of these signals of the responsiveness of the lungs to sterile and infectious injury. Based on our preliminary data, we propose that SCFAs and CAMPs are released by the gut microbiota and travel to the lung where they affect the immunometabolic programming of resident immune and non-immune cells, such as alveolar macrophages (AM) and alveolar type 2 (AT2) cells. In Aim One, we will perform metabolomics analysis of stool and lung tissue as well as intervening tissue and vascular beds. This aim will also assess the role of SCFA-producing microbiota in establishing the lung’s baseline metabolite profile and track the migration of specific CAMPs from the gut to the lung. In Aim Two, we will focus on identifying the lung cells that are capable of sensing both CAMPs and metabolites and how they contribute to the lung adopting a primed “ready” state or an unprimed “unready” state vis-à-vis infection and injury. Furthermore, the effect of these CAMPs and metabolites on the metabolic program of the lung in general and the specific lung cells will be examined. In Aim Three, we will explore ways to manipulate the gut-lung axis through antibiotic use, diet, focused metabolite delivery, and through microbiome transfer or restoration. These studies will attempt to establish conditions whereby microbiome-based therapies may help restore healthy lung immune responsiveness. In summary, this project seeks to understand the role of the gut microbiome and dietary metabolites in maintaining healthy lung immunity. Overall, we anticipate that these studies will help fundamentally increase our knowledge of the direct acting effects of the gut microbiome on lung immune responses and in doing so provide valuable insights towards designing future novel therapeutic options that take advantage of the gut-lung immune axis.