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

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.

Based on current literature and our previous preliminary findings, we have the following hypotheses for the causal pathways. Briefly, unhealthy, imbalanced dietary patterns lead to metabolic syndromes represented by obesity, dyslipidaemia and liver fat accumulation. Gut dysbiosis and gut microbiota-derived metabolites may play pivotal roles in mediating the effects from diet to metabolic syndromes. People with metabolic syndromes are vulnerable to chronic inflammations, which further incur a series immune responses, including excessive cytokine release, hyperactivation of complement system and coagulation cascade triggered by endothelial damage. All these over-reacted immune responses may explain the severity of infections, such as COVID-19.