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

项目摘要/摘要 我的首要目标是了解 人类微生物区系调节宿主衰老和与年龄相关的健康下降。人类的肠道是 居住着数以万亿计的微生物，统称为微生物区系，它有助于 胃肠健康和系统免疫。虽然元基因组测序揭示了年龄相关 肠道微生物区系的组成变化，人类微生物区系的单个细菌物种如何 在功能上促进宿主衰老的生理机制在很大程度上仍未被探索。最近的研究发现， 少量肠道微生物衍生分子，可与宿主细胞表面和核受体结合 细胞，并延长模式生物的寿命，解开依赖微生物区系的分子 影响人类健康。然而，人类微生物群产生的分子数量巨大， 化学多样性，对微生物组科学领域提出了巨大的挑战，以系统和 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库和一个 基于质谱学的代谢组学流水线，使快速和高通量鉴定 在不同的宿主样本中有超过1000+的代谢物。我的代谢组学分析100+个杰出的个人 人类肠道物种和定植于单个模式肠道微生物的灵知菌小鼠发现了一组 高丰度，保守的肠道微生物衍生分子。这些候选人正在诱人的候选人 调节寄主生理。亚精胺，多胺途径的一个候选者，已经被证明是 延长哺乳动物的健康寿命和寿命。然而，肠道微生物依赖的多胺的作用 调节寄主衰老的生物合成途径尚未被研究。此外，这种互动 剩下的候选基因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区系衍生的分子机制 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和影响宿主生理的各个方面 系统性衰老。我的实验将使用Bt等肠道微生物模型的遗传操作 灵知生菌小鼠实验系统研究微生物区系衍生分子对宿主衰老的影响 生物学。使用质谱学、代谢组学和微生物遗传学的组合，该项目将i) 研究肠道微生物区系依赖的多胺生物合成在调节年龄相关性衰老中的作用 宿主胃肠功能，以及ii)鉴定高丰度的肠道微生物区系衍生的小分子 影响宿主肠道健康和组织寿命。这项研究将为我们提供新的洞察力。 肠道微生物区系、生物活性小分子、胃肠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.