Project overview

Scientific Abstract

Cardiometabolic diseases (CMDs) and their comorbidities currently represent a considerable burden for health care systems in the EU.

The cost of cardiovascular disease alone to the European economy is currently estimated to have reached €192 billion per year.This is despite the fact that such diseases are regarded as largely preventable and amenable to modification through dietary changes.

CMD and particularly CVD, obesity and diabetes often remain resistant to treatment and changes to diet/lifestyle and are characterised by a chronic evolution in terms of symptoms. This is particularly so in old age. Research suggests that alterations in gut microbiota composition may contribute to altered host genome expression and that this subsequently contributes to cascades of cellular events that result in the various symptoms of CMD.

The difficulty with unravelling this relationship is that the respective cellular systems (i.e. microbial and human) are extremely complex at both the cellular and genomic levels.

To understand these systems, MetaCardis is applying a systems medicine multilevel approach that combines metagenomics to understand the gut microbiome and advanced phenotyping approaches in humans (metabolomics and transcriptomics) and applying these in cohorts of patients with various manifestations of CMD. These include patients with early stage CMD right through to chronic (non-)ischemic heart failure. Healthy volunteers represent a control group. This approach will generate a considerable amount of information and understanding about this complex relationship. It will also contribute to the development of tools to predict evolution of CMD and ultimately will inform patient care with the aim of preventing progression to the more chronic stages of the various CMD. In that way, MetaCardis will contribute to better patient care and ultimately reduce the worrying economic burden that is CMD.

The MetaCardis consortium groups together European leaders who are experts in clinical aspects of CMD, metagenomics (certain members include researchers that were successful in establishing the structure of the human microbiome as part of the EU FP7 MetaHIT consortium), metabolomics and transcriptomics, systems biology and bioinformatics (including an SME specialising in this area), patients associations and food companies. It will only be possible to improve the understanding of pathophysiological mechanisms, prognosis and diagnosis of CMD if such a diverse range of skillsets are brought together in one consortium.

In more specific terms, MetaCardis uses 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. The impact of the gut microbiota 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 that combine clinical information, environmental patterns and gut microbiome, metabolome and transcriptome data is a central integrating component in the research. These studies will identify novel molecular targets, biomarkers and predictors of CMD progression. This will contribute to a general ambition to deliver effective more personalized medicine in CMD.

Detailed Objectives

• To identify novel targets and shared pathways involved in the natural progression of CMD (from cardiometabolic risks towards more chronic stages such as atherothrombosis with or without heart failure) through a multidisciplinary strategy applying systems biology approaches combining (gut) metagenomics and host /transcriptomic/metabolic phenotyping approaches in patients and healthy subjects characterised for lifestyle and CMD advanced phenotypes.  
• To validate the contribution of novel gut microbiome-derived targets and prognostic markers identified in original experimental systems including human cellular systems and rodent models as well as in newly recruited CMD patients at successive stages of disease progression.
• To deliver new insights into shared pathophysiological targets of CMD and associated comorbidities that can be used as targets for the development of novel therapeutics and diagnostic tools. In this respect, we envision that the project could lead to a “redefinition” of CMD progression stages. We will also deliver new software as well as new means of integration of data collected from different sources (i.e. environment and biology).
• To transfer and disseminate new knowledge to the scientific community, to health professionals and scientists via training programmes, and to the public and stakeholders thanks to the contribution of patient associations and MetaCardis dissemination actions. Indeed the development of large-scale tools (metagenomic, transcriptomic and metabolomic) and of new devices for phenotyping CMD patients is a strategic issue for the EU economy and industry. New skills for further EU health professional and scientists are needed to improve patient care.