METACARDIS applies a systems medicine multilevel approach to identify biological relationships between gut microbiota, assessed by metagenomics, and host genome expression regulation, which will improve understanding and innovative care of cardiometabolic diseases (CMD) and their comorbidities. CMD comprise metabolic (obesity, diabetes) and heart diseases characterized by a chronic evolution in ageing populations and costly treatments. Therapies require novel integrated approaches taking into account CMD natural evolution.METACARDIS associates European leaders in metagenomics, who have been successful in establishing the structure of the human microbiome as part of the EU FP7 MetaHIT consortium, clinical and fundamental researchers, SME, patients associations and food companies to improve the understanding of pathophysiological mechanisms, prognosis and diagnosis of CMD.We will use next-generation sequencing technologies and high throughput metabolomic platforms to identify gut microbiota- and metabolomic-derived biomarkers and targets associated with CMD risks. The pathophysiological role of these markers will be tested in both preclinical models and replication cohorts allowing the study of CMD progression in patients collected in three European clinical centres of excellence. Their impact on host gene transcription will be characterised in patients selected for typical features of CMD evolution. Application of computational models and visualisation tools to complex datasets combining clinical information, environmental patterns and gut microbiome, metabolome and transcriptome data is a central integrating component in the research, which will be driven by world leaders in metagenomic and functional genomic data analysis. These studies will identify novel molecular targets, biomarkers and predictors of CMD progression, paving the way for personalized medicine in CMD.