NUTRITION-RESPONSIVENESS OF THE IMMUNE SYSTEM: INTERPLAY BETWEEN INFECTIOUS DISEASES AND DIET-RELATED METABOLIC DISEASES AND THE POTENTIAL...

健康、均衡的饮食对保持新陈代谢健康和支持免疫系统很重要。肥胖与一系列代谢综合征有关，包括血脂异常、高血糖和脂肪肝。高血糖和脂质堆积可能引起脂质氧化，进一步导致细胞因子过度产生，补体系统过度激活和凝血系统激活，这些都是免疫学上触发严重感染新冠肺炎和其他传染病的因素，在本项目中将被视为免疫反应相关的结果。DIYUFOOD项目旨在利用从以色列、荷兰、英国和中国分别建立的四个基于人群的队列研究中收集的广泛的多组学和临床数据，这些队列研究具有不同的种族背景、饮食模式和社会经济地位，以观察性研究中的中介分析和孟德尔随机化(MR)分析为工具变量来理清因果关系。首先，我们将探索饮食模式和免疫反应之间的所有潜在关联，以及潜在的代谢相关调节因子，以通过在四个观察性研究中的中介分析来解释观察到的饮食和免疫反应之间的关联。其次，我们将深入探讨肠道微生物组成在饮食模式和免疫反应之间的联系中的中介作用。第三，一旦在第二步中确定了几种微生物，我们将进一步研究循环代谢物在调节肠道微生物组成和免疫反应之间的关系中的作用，因为肠道微生物区系产生的代谢物非常不同。最后，对于从第一步到第三步观察到的代谢综合征、肠道微生物区系衍生的代谢物和免疫反应之间的所有关联，我们将利用磁共振研究来进一步证实因果关联。此外，我们将利用多变量MR分析，通过特定的免疫反应，扩展到代谢综合征以及肠道微生物区系衍生的代谢物与新冠肺炎严重程度之间的关联。从饮食摄入到免疫反应和随后的疾病后果的生物学“食物路径”是复杂的，我们的项目将提供对潜在因果路径的更深层次的理解，这对于开发有效的食物解决方案来对抗疾病风险至关重要。

A healthy, balanced diet is important for keeping metabolic health and supporting immune system. Obesity is associated with a wide range of metabolic syndromes, including dyslipidemia, hyperglycemia and fatty liver. Hyperglycemia and lipid accumulation may provoke lipid oxidation and further lead to an overproduction of cytokines, hyperactivation of complement system and activation of coagulation system, which all serve as immunological triggers to severe infection of COVID-19 as well as other infectious diseases and will be considered as immune response related outcomes in the current project. The DIYUFOOD project aims to leverage extensive multi-omics and clinical data collected from four population-based cohort studies set up in Israel, the Netherlands, the UK and China respectively, with diverse ethnicity backgrounds, dietary patterns and socioeconomic status, to disentangle casual pathways using both mediation analysis in observational studies and Mendelian randomization (MR) analysis using genetic variants as instrumental variables for causal inference. First, we will explore all the potential associations between dietary patterns and immune response, as well as potential metabolic- related mediators to explain the observed associations between diet and immune response through mediation analysis in the four observational studies. Second, we will dive into the mediating roles of gut microbial composition in the associations between dietary patterns and immune response. Third, once several species of microorganisms are identified in the second step, we will further examine the roles of circulating metabolites in mediating the associations between gut microbial composition and immune response, due to extremely diverse metabolites are produced by gut microbiota. Last, for all the associations observed from step 1 to step 3 between metabolic syndromes, gut-microbiota derived metabolites and immune response, we will utilize MR studies to further corroborate the casual associations. In addition, we will extend to the associations between metabolic syndromes as well as gut- microbiota derived metabolites and severity of COVID-19, mediated through certain immune response, using Multivariable MR analysis. The biological "food path" from dietary intake to immune response and subsequent disease outcomes are complex, and our project will provide deeper understanding of underlying causal pathways, which is imperative to develop effective food solutions to combat disease risks.