There is overwhelming evidence that chronic inflammation plays a central role in both metabolic and cardiovascular diseases (CVD). The most prevalent cause of low-grade chronic inflammation is obesity,which can be associated with inflamed adipose tissue and an inflamed fatty liver, leading to chronic systemic inflammation, also termed metaflammation. We hypothesise, that metaflammation, which is causally linked to CVD development, is modulated by a complex interaction between host genetic factors,the intestinal microbiota, and metabolic processes. Recent mechanistic insights have emerged from mainly mouse studies suggesting a pivotal role for the inflammasome and autophagy in triggering and modulating the activation of a chronic inflammatory response. At present, however, there is an insufficient knowledge of the inflammatory mechanisms in humans, and a better understanding would aid in translating the targeting of metaflammation into clinical practice. The factors influencing the variability of inflammatory complications in patients with obesity remain poorly understood. Therefore, this project aims to delineate the host and environmental factors that influence inflammatory and metabolic complications in a cohort of 300 individuals with obesity, with or without CVD traits. We aim to: 1) understand whether the immune characteristics of the individual influence the extent of CVD complications; 2) correlate the transcriptional, genetic and epigenetic variations of immune cells responses in obese individuals with metabolic and cardiovascular complications; and 3) investigate the metabolic pathways related to microbiome composition that impact the inflammatory reaction in obesity. To achieve these aims, we will perform a system biology approach that integrates immune parameters with genomic, transcriptomic, metabolomic, and microbiome data derived from a deeply phenotyped cohort of 300 individuals with obesity, among whom approximately half have CVD complications and the other half are healthy obese without metabolic or cardiovascular complications. This work is part of a multinational effort to understand metaflammation development that may drive the increased risk for CVD in obesity in humans using a functional genomics approach with which we have previous experience. We will take advantage of the deep knowledge in microbiome analysis at the Broad Institute in Cambridge (USA), the clinical competence as well as a battery of functional immune phenotyping assays at Radboud University in Nijmegen (The Netherlands), the expertise in genomic analysis at Groningen University (The Netherlands), and the expertise in immunology, metaflammation and cellular reprogramming as well as bioinformatic analysis within this CRC in Bonn (Germany).