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杰出成员的机制 人类微生物群调节宿主衰老和与年龄相关的健康衰退。人体的肠道是 栖息着数万亿微生物，统称为微生物群，它有助于 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发生变化，人类微生物群的各个细菌种类如何变化 在功能上对宿主衰老生理学的贡献在很大程度上仍未被探索。最近的研究发现了一个 少量肠道微生物衍生的分子可以与宿主细胞表面和核受体结合 细胞并延长模型生物体的寿命，揭示微生物群依赖性分子的潜力 影响人类健康。然而，人类微生物群产生的分子数量巨大，并且 化学多样性，对微生物组科学领域系统地和 准确地识别他们。为了克服这一挑战，我建立了一个全面的化学参考库和一个 基于质谱的代谢组学流程，能够快速、高通量地识别 不同宿主样本中超过 1000 种代谢物。我对 100 名杰出人士的代谢组学分析 人类肠道物种和定植有个体模型肠道微生物的限生小鼠发现了一组 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 调节宿主生理机能。亚精胺是多胺途径的候选者之一，已被证明可以 延长哺乳动物的健康寿命和寿命。然而，肠道微生物依赖性多胺的作用 调节宿主衰老的生物合成途径尚未被研究。此外，相互作用 其余候选者之间的差异以及宿主体内保守的长寿途径在很大程度上是未知的。 我的提案的目标是研究微生物群衍生的分子机制 分子调节哺乳动物宿主的健康和寿命。具体来说，我假设其中的一个子集 候选分子通过调节胃肠道健康和影响宿主生理学的各个方面 系统性老化。我的实验将使用模型肠道微生物（例如 Bt）的基因操作 限生小鼠实验系统研究微生物群衍生分子对宿主衰老的影响 生物学。该项目结合质谱、代谢组学和微生物遗传学，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退中的作用 宿主胃肠道功能，以及 ii) 识别高丰度、肠道微生物群衍生的小分子， 影响宿主肠道健康和机体寿命。这项研究将为机制提供新的见解 肠道微生物群、生物活性小分子、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.