The MetaCardis scientific project is structured around four pillars and five work packages (WPs). Three work packages (WP6-8) are dedicated to transversal activities.

Pillar	WP1	WP2	WP3	WP4	WP5
Pillar 1 - Cohorts and biobanks	Existing Cohorts		MetaCardis Cohort
Pillar 2 - High throughput -omics	Metabolomics Lifestyle		Bioclinical phenotyping Lifestyle	Gut metagenomics Metabonomics RNA Sequencing
Pillar 3 - Systems biology modelling				Annotation metagenomic sequences MW²AS	Data hub, data integration and visualisation Patient stratification, prediction. iMiM and GEMS
Pillar 4 - Validation of targets		Cellular cross talk Animal models

 

WP	Title	WP Leader	WP Deputy
WP1	CMD risk biomarkers: gut microbiome and metabolome-derived target identification	Oluf Pedersen	Marc Dumas
WP2	Characterisation of gut microbiome-derived targets in experimental systems	Dominique Gauguier	Hervé Blottière
WP3	European biobanks and phenotype databases for studies of common cardiometabolic disorders (CMD)	Karine Clément	Michael Stumvoll
WP4	High-throughput genomic approaches	Dusko Ehrlich	Marc Dumas
WP5	Data integration and functional modelling	Peer Bork	Jens Nielsen
WP6	Dissemination, training and exploitation	Karine Clement	Catherine Clusel
WP7	Project management and coordination of the consortium	Catherine Clusel	Karine Clement
WP8	Regulatory and ethical issues	Jean-Michel Oppert	Karine Clement

WP1: CMD risk biomarkers: gut microbiome and metabolome-derived target identification

This WP capitalises on existing metagenomic sequencing data in samples generated by the MetaHIT consortium, the French Micro-Obes project and the Gothenburg study. The work package has the following aims:

• Based upon existing deep metagenomics sequencing data from 700 Europeans, we will identify gut microbiota species which associate with CMD risk factors including measures of insulin resistance, low-grade inflammation, dyslipidemia, impaired glucose regulation, and cerebrovascular events.
• Based upon novel metabolomics profiling of serum, urine and adipose tissue we will identify proteins, lipids, metabolites and organic acids which associate with specific gut microbiota compositions and associated dietary-induced metabolic risk changes.

This WP will focus on associations between CMD risk factors collected in these complementary groups with the goal of generating novel hypotheses to be tested in the WP3 CMD study samples collected from patients with gradual stages of CMD. As a first attempt to test the hypotheses generated in this work package, metagenomic information found associated with CMD risks will be validated in the Swedish part of the cohort with ischemic stroke and ischemic heart attack vs. controls. Lifestyle patterns will be included in the analyses to get a holistic overview of the interplay between lifestyle, microbiota and CMD risk variables.

WP2: Characterisation of gut microbiome-derived targets in experimental systems

We will establish novel mechanistic insights into the cross-talk between commensal gut bacteria and mammalian host genome expression, physiology and metabolism in the context of CMD susceptibility. This will be achieved through exploratory investigations in cellular systems and animal models, and validation studies of results from microbiome and metabolome analyses of CMD patients. Research will specifically focus on gut bacterial species, human metabolites and metabolic pathways associated with CMD uncovered in WP1 and WP3. This will provide causal and mechanistic insights and interpretation of their implications in CMD.

WP3: European biobanks and phenotype databases for studies of common cardiometabolic disorders (CMD)

In this work package, we will establish the MetaCardis cohort and a European biobank and phenotypic database to identify biomarkers and predictors of well-defined stages of CMD development and attempt to refine CMD phenotypes. The cohort will be used for replication purposes of WP1-generated hypotheses and also for the fine characterisation of subjects using systems medicine approaches that will be used in WP4 and WP5. The biobank and the phenotypic database will be constructed at three European centres of excellence in Paris (ICAN), Copenhagen (NNFCBMR) and Leipzig (IFB) and will all use harmonized procedures. Samples will include serum, plasma, faeces, urine and blood (in all subjects) as well as CD14+ monocytes and adipose tissue samples (for patients exhibiting the most typical phenotypes). A common phenotypic database will, besides assembling clinical, anthropometrical, and biochemical data, include information about lifestyle and health behaviours. Target recruited subjects will be: i) cross-sectionally sampled individuals at risk of CMD and patients with various stages and forms of overt CMD and; ii) prospectively sampled type-2 diabetic and non-diabetic obese patients, before and after gastric surgery, which is a situation associated with major improvement in CMD risks, and; iii) control groups selected from epidemiological on-going studies (such as in Nutrinet).T

The cohort constitution is done with the assistance of the subcontractor Quanta Medical (see below).

WP4: High-throughput genomic approaches

We will complete the patient phenotypes with signatures generated by high-throughput “omic” technologies. This will include metagenomic, metabolomics and host monocyte and adipose tissue transcriptomic studies. Metabolomic and metagenomic data will be generated in 2,000 individuals comprising CMD patients and controls. Because of the key contribution of CD14+ monocytes and adipose tissue biology in the pathophysiology of CMD, we will perform transcriptome profiling in a subset of 300 patients (600 transcriptome) from the MetaCardis cohort. This approach will guide stratification of MetaCardis subject cohorts through the use of linear and non-linear statistical tools to identify novel disease sub-phenotypes for subsequent profiling. Quality controlled data will be transferred to WP5 for integration and identification of biomarkers associated with CMD progression stages. In order to ensure MetaCardis and the community at-large will benefit from the vast amount of metagenomic sequencing data present in current and future databases, 100 samples will be compared across the two most popular sequencing technologies.

WP5: Data integration and functional modelling

We will ensure multilevel integration of information to identify signatures associated with CMD risk and stages. For this aim we will: i) develop software and design computing infrastructure capable of high throughput heterogeneous data integration (e.g., to combine microbiome data, omics-based host readouts, as well as phenotypic, clinical and environmental data), ii) identify and validate omics signatures predictive of CMD stages, iii) develop visualisation techniques that will allow clinical researchers to get overviews, to extract patterns, and to highlight important features in their data, iv) develop algorithms for prediction of disease stage and CMD risk and v) develop metabolic network models for human adipose tissue, monocyte and the gut microbiome.

WP6: Dissemination, training and exploitation

The aim of this WP is to ensure appropriate dissemination of the results, to set-up cross-thematic training and to ensure appropriate IP management and exploitation.

WP7: Project management and coordination of the consortium

The aim of this work package is to ensure legal and administrative coordination of the project.

WP8: Regulatory and ethical issues

The aim of this work package is to ensure that the clinical trial elements of MetaCardis are implemented in compliance with regulatory requirements and to apply for clinical trial authorisation to regulatory agencies. The work package will also address the highest ethical standards required of such an investigation. The clinical study will be made in agreement with the French, Danish, German and European legislation (Helsinki, French code of Public Health, Danish Act on Research Ethics Review of Health Research Projects, German Drug Law (Arzneimittelgesezt-AMG), Good Clinical Practice, Bioethics law, European Directive 95/46/CE).

 

Quanta Médical, a European company specialising in clinical trial design and implementation, has been present for the last 30 years in the fields of consultancy, organisation and management of interventional, non-interventional and health-risk studies. Since 2013, Quanta Médical has been working on the European METACARDIS project, in which, thanks to its Quanta View e-CRF, it has been involved in the management, collection and monitoring of project data, transportation and samples traceability, as well as auditing of the various study centres.