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

项目总结/摘要 肠-肺轴是肠道微生物组和肠外微生物组之间的许多通信轴之一。 系统、器官和组织。该轴已被证明强烈影响肺免疫和炎症 反应，主要是在过敏性哮喘炎症和肺部感染。这种机制 通讯被推测为免疫细胞重编程和/或因子的直接易位， 包括微生物配体。本项目侧重于后一种机制，即肠道的直接影响， 微生物群产物进入循环，在肺组织上。本提案的目标是 严格研究1）肠-肺轴，重点是代谢物，如短链脂肪酸（SCFA）， 和肺相关分子模式（CAMPs），2）整合这些肠源性 信号，以及3）这些信号对肺对无菌和感染性损伤的反应性的影响。 基于我们的初步数据，我们提出SCFAs和CAMPs由肠道微生物群释放， 在那里它们影响常驻免疫和非免疫的免疫代谢编程 细胞，如肺泡巨噬细胞（AM）和肺泡2型（AT 2）细胞。在目标一，我们将执行 粪便和肺组织以及介入组织和血管床的代谢组学分析。这一目标将 还评估SCFA产生菌群在建立肺部基线代谢物谱中的作用， 追踪特定cAMP从肠道到肺部的迁移。在目标二中，我们将专注于识别肺 细胞能够感知CAMPs和代谢物，以及它们如何有助于肺采用 维斯感染和损伤的预处理“就绪”状态或未预处理“未就绪”状态。此外， 这些cAMP和代谢物对肺的代谢程序的一般和特定的肺细胞将 接受检查。在目标三中，我们将探索通过抗生素使用、饮食、 集中的代谢物递送，以及通过微生物组转移或恢复。这些研究将试图 建立条件，使基于微生物组的治疗可以帮助恢复健康的肺部免疫 响应能力。总之，该项目旨在了解肠道微生物组和饮食的作用， 代谢产物维持健康的肺免疫力。总的来说，我们预计这些研究将有助于 从根本上增加我们对肠道微生物组对肺部免疫的直接作用的认识， 反应，并在这样做提供了宝贵的见解，设计未来的新的治疗方案， 利用肠-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.