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

绘制 3D 宿主-微生物-代谢物相互作用图，寻找饮食来源的免疫增强剂

• 批准号: 10450189
• 负责人: ROB KNIGHT
• 金额: $ 110.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450189
• 关键词: 3-Dimensional; American; Antimicrobial Resistance; Back; Biocompatible Materials; Biological Assay; Biological Markers; Chemicals; Communicable Diseases; Consumption; DNA sequencing; Data; Data Set; Diet; Dietary Component; Disease Resistance; Enhancers; Gene Expression; Human; Immune system; Immunity; Individual; Infrastructure; Laboratory Study; Liquid substance; Maps; Mass Spectrum Analysis; Metabolite Interaction; Microbe; Minerals; Miniaturization; National Health and Nutrition Examination Survey; Nutritional status; Pharmaceutical Preparations; Phytochemical; Population; Process; Research Personnel; Resistance; Robot; Sampling; Supplementation; System; Testing; United States; Visual; Vitamins; Work; base; burden of illness; cohort; cost; deep learning; dietary; human subject; immunological status; improved; insight; metabolome; microbiome; mouse model; nanolitre scale; prevent; public health relevance; side effect; transcriptome sequencing

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.

项目摘要 抗菌素耐药性是一个越来越多的问题，当前的药物管道并没有跟上加快的步伐 抗菌素抗性。另一种策略是提高宿主免疫力。经常被忽略的副作用 1940年代的维生素和矿物补充项目是，这些补充剂大大减少了 传染病负担。最近的工作表明，可能是可能的，尤其是在增加 植物化学物质可以追溯到美国通常在美国食用的高度加工饮食。但是，我们缺乏 对微生物组如何处理这些组件的基本了解以及饮食衍生的方式 分子，微生物组和宿主免疫系统共同起作用以抵抗传染病。 阻止我们发现这些发现的关键障碍是每个单独的测定法（微生物组，主机 基因表达代谢组，饮食化合物）是昂贵且高度多变量的。三个关键见解 启用当前项目是对晚期纳米列仪的DNA和RNA测序测定的微型化 - 比例液体处理机器人，大大降低了成本，不靶向质量的组合 高吞吐量中相同样品上的光谱法，以发现更大的化学空间， 以及在多个尺度上使用明确空间图以将数据集集成到整个身体和 基于空间数据启用视觉分析和深度学习方法。这些突破会 从根本上对饮食代谢产物如何促进疾病的抗药性提供了新的了解，并将 允许我们开发一个新的基础架构，以整合不同实验室中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 人类受试者的生物标志物提供有关内部营养和免疫状况的最大信息。 结果将针对NHANES和美国肠道队进行测试。 因此，该项目的结果将是：小鼠模型的3D地图显示微生物组，饮食和 宿主基因表达产生免疫力；创建和共享这些地图的基础架构；和 初步测试结果是否扩展到人类大量人群。