Mapping host-microbe-metabolite interactions in 3D to find diet-derived enhancers of immunity

项目摘要 抗菌素耐药性是一个日益严重的问题，目前的药物管道没有跟上上升的步伐 抗菌素耐药性。另一种策略是提高宿主免疫力。一个经常被忽视的副作用 20世纪40年代的维生素和矿物质补充计划是，这些补充剂大大减少了 传染病负担。最近的研究表明，可能会有进一步的收益，特别是在添加 植物化学物质回归到美国通常消费的经过深度加工的饮食中。然而，我们缺乏一个 基本了解这些成分是如何被微生物组处理的，以及饮食是如何衍生的 分子、微生物群和宿主免疫系统共同抵抗传染病。 阻止我们做出这些发现的一个关键障碍是每一个单独的测试(微生物组，宿主 基因表达代谢体，饮食化合物)是昂贵的和高度多元化的。三个关键的见解 目前的项目是在先进的纳升上实现DNA和RNA测序分析的微型化- 规模化液体搬运机器人，大大降低了成本，无针对性和针对性相结合的质量 高通量地对相同样品进行光谱分析，从而能够发现更大的化学空间， 以及在多个比例尺上显式使用空间地图以在全身集成数据集的能力，以及 启用基于空间数据的视觉分析和深度学习方法。这些突破将 为饮食代谢物如何提高抗病能力提供了一个全新的理解， 允许我们开发新的基础设施，以整合来自不同实验室的许多研究人员的结果 研究这些系统的各个方面。此外，结果将使我们能够选择生物材料和 人类受试者中的生物标志物，提供有关体内营养和免疫状态的最大信息。 结果将与NHANES和American Gut队列进行测试。 因此，该项目的结果将是：小鼠模型的3D地图，展示微生物群、饮食和 宿主基因表达产生免疫力；创建和共享这些图谱的基础设施；以及 初步测试这一结果是否适用于大量人口。

Project Summary Antimicrobial resistance is an increasing problem, and current drug pipelines are not keeping pace with the rise of antimicrobial resistance. An alternative strategy is to boost host immunity. An often overlooked side-effect of the vitamin and mineral supplementation projects of the 1940s is that these supplements greatly reduced infectious disease burden. Recent work has shown that further gains may be possible, especially in adding phytochemicals back to highly processed diets typically consumed in the United States. However, we lack a fundamental understanding of how these components are processed by the microbiome, and how diet-derived molecules, microbiome and host immune system work together to resist infectious disease. A key barrier preventing us from making these discoveries is that each individual assay (microbiome, host gene expression metabolome, dietary compounds) is expensive and highly multivariate. Three key insights that enable the current project are the miniaturization of DNA and RNA sequencing assays on advanced nanoliter- scale liquid handling robots, greatly reducing the cost, the combination of untargeted and targeted mass spectrometry on the same samples in high throughput to enable discovery of a much greater chemical space, and the ability to use explicitly spatial maps on multiple scales to integrate the dataset throughout the body and enable both visual analytics and deep learning approaches based on spatial data. These breakthroughs will provide a fundamentally new understanding of how dietary metabolites promote disease resistance, and will allow us to develop a new infrastructure to integrate results from many investigators in different laboratories studying various aspects of these systems. Additionally, the results will allow us to choose biomaterials and biomarkers in human subjects that provide maximum information about internal nutritional and immune status. Results will be tested against the NHANES and American Gut cohorts. The results of this project will therefore be: 3D maps of mouse models showing how the microbiome, diet, and host gene expression produce immunity; an infrastructure for creating and sharing these maps; and a preliminary test of whether the results extend to large human populations.