Impact of gut microbiota-derived molecules on mammalian host health and longevity

项目概要/摘要 我的首要目标是了解的机制，突出的成员， 人类微生物群调节宿主衰老和与年龄相关健康衰退。人体的肠道 居住着数万亿的微生物，统称为微生物群，这有助于 胃肠道健康和全身免疫力。虽然宏基因组测序揭示了与年龄相关的 肠道微生物群的组成变化，人类微生物群中的单个细菌物种 在功能上有助于宿主衰老生理学的作用仍然在很大程度上未被探索。最近的研究发现， 少量肠道微生物群衍生分子，可与宿主细胞表面和核受体结合 细胞和延长模型生物的寿命，揭示了微生物依赖性分子的潜力， 影响人类健康。然而，人类微生物群产生大量的分子， 化学上的多样性，对微生物组科学领域提出了巨大的挑战， 准确识别它们。为了克服这一挑战，我建立了一个全面的化学参考图书馆和一个 基于质谱的代谢组学管道，能够快速和高通量地鉴定 在不同的宿主样品中有超过1000+种代谢物。我对100多个个体的代谢组学分析 人类肠道物种和用单个模型肠道微生物定殖的gnotobiotic小鼠发现了一组 高丰度、保守的肠道微生物衍生分子。这些候选人是诱人的候选人， 调节宿主生理亚精胺是多胺途径的一种候选物， 延长哺乳动物的健康和寿命。然而，肠道微生物依赖性多胺的作用 生物合成途径在调节宿主衰老中的作用尚未研究。此外，互动 其余候选者和宿主中保守的长寿途径之间的关系在很大程度上是未知的。 我的建议的目标是研究微生物来源的分子机制， 分子调节哺乳动物宿主的健康和寿命。具体地说，我假设其中的一个子集 候选分子通过调节胃肠道健康影响宿主生理学方面， 系统老化我的实验将使用基因操作的模式肠道微生物，如Bt在 gnotobiotic小鼠实验系统，以研究微生物衍生分子对宿主衰老的影响 生物学使用质谱分析、代谢组学和微生物遗传学的组合，该项目将i） 研究肠道微生物群依赖性多胺生物合成在调节年龄相关性衰老中的作用。 宿主胃肠道功能，和ii）鉴定高丰度、肠道微生物群衍生的小分子，其 影响宿主肠道健康和生物体寿命。这项研究将提供新的见解， 肠道微生物群，小生物活性分子，胃肠道健康和衰老之间的关系。

Project Summary/Abstract My overarching goal is to understand the mechanism by which prominent members of the human microbiota modulate host aging and age-associated health decline. The human intestinal tract is inhabited by trillions of microorganisms, collectively referred to as the microbiota, which contributes to gastrointestinal health and systemic immunity. While metagenomic sequencing has revealed age-associated compositional changes in the gut microbiota, how individual bacterial species of the human microbiota functionally contribute to host aging physiology remain largely unexplored. Recent studies have uncovered a small number of gut microbiota-derived molecules that can bind to cell-surface and nuclear receptors in host cells and extend lifespan in model organisms, unraveling the potential of microbiota-dependent molecules to impact human health. However, the human microbiota produces molecules that are vast in numbers and chemically diverse, posing a tremendous challenge for the field of microbiome science to systematically and accurately identify them. To overcome this challenge, I built a comprehensive chemical reference library and a mass spectrometry-based metabolomics pipeline, which enables rapid and high-throughput identification of over 1000+ metabolites in diverse host samples. My metabolomics profiling of 100+ individual prominent human gut species and of gnotobiotic mice colonized with individual model gut microbes uncovered a panel of high abundance, conserved gut microbe-derived molecules. These candidates are tantalizing candidates for modulating host physiology. Spermidine, one candidate from the polyamine pathway, has been shown to extend healthspan and lifespan in mammals. However, the role of gut microbe-dependent polyamine biosynthetic pathway in modulating host aging has not been investigated. Furthermore, the interactions between the remaining candidates and conserved longevity pathways in the host are largely unknown. The goal of my proposal is to investigate the molecular mechanisms by which microbiota-derived molecules regulate mammalian host health and longevity. Specifically, I hypothesize that a subset of these candidate molecules impact aspects of host physiology via regulating gastrointestinal health and systemic aging. My experiment will use genetic manipulations of model gut microbes such as Bt in the gnotobiotic mouse experimental system to study the impact of microbiota-derived molecules on host aging biology. Using a combination of mass spectrometry, metabolomics, and microbial genetics, this project will i) investigate the role of gut microbiota-dependent polyamine biosynthesis in regulating age-associated decline in host gastrointestinal function, and ii) Identify high-abundance, gut microbiota-derived small molecules that impact host intestinal health and organismal longevity. This study will provide new insights into the mechanistic relationships between gut microbiota, small bioactive molecules, gastrointestinal health, and aging.