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Periodic Report Summary 4 - METACARDIS (Metagenomics in Cardiometabolic Diseases)

Project Context and Objectives:
Today there are unmet needs in the phenotypic description, pathophysiological knowledge, diagnosis and treatment of metabolic syndrome (MS), obesity, type-2 diabetes (T2D) and their complications such as atherothrombotic diseases and heart failure. These pathologies are so intrinsically linked that they can be grouped under the unifying concept of cardiometabolic diseases (CMD). The characteristically heterogeneous phenotypes of these diseases continually develop and worsen over time. With current diagnostic techniques, it is virtually impossible to predict which patients will develop cardiovascular complications. Thus there is a clear need for early intervention in the natural cycle of these multifactorial diseases, before irreversible damage occurs. Thus a major challenge is to take advantage of systems medicine approach in order to examine CMD throughout its entire lifecycle: from identifying individual susceptibility, to prevention, early diagnosis and prediction of chronic comorbidities, whilst avoiding tissue damage. CMD represents an enormous burden on worldwide healthcare services, with the total annual EU cost of cardiovascular diseases estimated at more than €192 billion.
Advances in CMD molecular genetics have borne fruit by identifying specific pathophysiological pathways. Predictive tools, however, remain elusive as environmental factors (food, nutrition, physical activity, psychosocial factors) play roles in the development of these linked pathologies. The METACARDIS project is based on the hypothesis that lifestyle changes, personal biology, and CMDs are all interrelated due to shared pathogenic factors. An inadequate nutritional environment combined with poor lifestyle choices induces health deterioration resulting in CMD progression. Here, the characterization of the gut microbiome (i.e. collective bacterial genome) has opened new avenues enabling the generation of fundamental knowledge about putative shared CMD pathways, as well as biomarkers and predictors involved in CMD progression.
Until now, the gut microbiome was mostly studied in the context of metabolic diseases (i.e. obesity and diabetes), thus the role of gut microbiota and its interaction in human CMD progression towards chronic states is currently unknown. Investigating the metabolome is also of interest since resulting data can describe both qualitative and quantitative microbiome variations. Given its direct relationship with environmental factors, the gut microbiome is likely to have an even greater impact than genetic characteristics. In addition to being amenable to the development of original predictive and/or diagnostic tools, the gut microbiota is an attractive target for novel CMD therapeutic approaches since it can be manipulated by various methods (such as dietary changes).
Due to the complexity of the gut microbiome, and its interactions with human (host) metabolic and immune systems, it is only through integrative analyses, where metabolic network models act as analytic scaffolding, that it will be possible to identify markers and shared pathways, contributing to improved patient stratification.
METACARDIS takes advantage of recent developments in both metabolic network modeling and gut metagenomics which, combined with transcriptome and metabolome analyses (i.e. metabolomics), will significantly advance systems medicine in the CMD field. The METACARDIS consortium uses next-generation sequencing (NGS) and functional genomic tools to generate comprehensive information about the gut microbiome, metabolome and clinical data sets. These objectives will be accomplished by novel bioinformatics methodologies (i.e. integrative analysis) applied to resources (lifestyle and bioclinical information) from existing and new patient cohorts. Eight highly interactive work packages (WPs) have been created via the careful selection of outstanding EU clinicians and fundamental scientists, patient associations and medium- to large-sized companies.

Project Results:
Over the first 3 years of the project, researchers involved in WP1 used existing cohorts to analyze associations between dietary patterns and changes in various aspects of whole body metabolism and low grade inflammation. Association studies were performed between metabolic phenotypes, gut microbial signatures, and networks of specific bacterial groups, as well as metabolomic features. This work has led to several original publications. The integration of metabolomic profiling with gut metagenomic data has identified metabolomic-metagenomic networks associating with cardiometabolic risks. These new findings have generated hypotheses that will be tested in the new Metacardis cohort (WP3). Continuing analyses on data from legacy cohorts will be the subject of systems biology work in WP5.

WP2 provides consortium partners with a portfolio of experimental systems to generate material and information relevant to gut microbiota functions and molecular mediators. Until now, results from WP2 have demonstrated the pathophysiological consequences of human gut microbiota and gut microbial metabolites, which were identified from research activities in WP1. This work has mainly focused on in vivo rodent models (rat and mouse) using an experimental pipeline designed to assess a broad range of cardiometabolic phenotypes. Additionally, successful purification of active fractions of metagenomic clones are being tested in cellular systems, the relevance of which will be examined using translational in vivo rodent models. Finally, molecular mechanisms mediating the biological roles of gut microbial metabolites have been identified and provide information of gene and gene pathways linking gut microbiota with cardiometabolic phenotypes.

Since the beginning of the project, we have officially finished recruitment of the main cohort, with ongoing recruitment of a sub-group (obese patients undergoing bariatric surgery). As such, the main cohort consists of 8 groups: 1) Metabolic Syndrome, 2a) Obese, 2b) Obese with bariatric surgery, 3) T2DM, 4) Acute Coronary Artery Disease (CAD) (no Congestive Heart Failure (CHF)), 5) Chronic CAD (no CHF), 6) Chronic CAD with CHF, 7) Chronic CHF no CAD, 8) Healthy (control) patients. Currently, the collective cohort is over 2000 patients for which we have detailed clinical data. We have also obtained social (lifestyle, dietary habits, etc) and biological data (circulating hormones and inflammatory markers) along with clinical measurements, which will allow us to characterize our patient cohort. Through stringent database cleaning and management, we have identified potential confounders, regrouped patients into the proper groups based on clinical status, and excluded certain patients from cohort analysis. Collectively, this WP has been fundamental in ensuring high quality database delivery into upstream analysis of the cohort in WP5, which will answer the key questions of MetaCardis. There curation of the data were performed in order to obtain a “core cohort” which combines metagenomics ad metabolomic and clinical full data as a data set to address these prioritized questions.

In WP4, stool samples from the patients were received and stored at INRA. Total DNA was extracted from all samples and sequenced using an emerging technology, Ion Proton, which was benchmarked and found to be quicker, more robust, and reliable than Solid Wildfire. Profiles of genes, metagenomic species, units, and mOTUs were generated for all samples and transferred to the data hub at EMBL. For metabolome analysis, 2162 urine and 2251 serum samples were profiled by 1H NMR spectroscopy. All data were pre-processed followed by principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) analysis based on available clinical data (Age, Country, Gender, Pathology group). This data was collectively transferred to WP5 for systems biology analysis.

WP5 addresses the effort to go from massive parallel, high-dimensional -omics data to clinically applicable tools and findings, as well as to enable personalized medicine with regards to cardiovascular and metabolic conditions. Work so far has centered on preparing reception and processing WP1, 3, and 4 data. This includes storing and harmonizing data files so that the consortium can leverage partners’ expertise.. Likewise, the previous work in metabolic modelling, gut-specific annotations, dietary and other metadata representations, and machine learning techniques will allow MetaCardis to provide a unified understanding of microbiota’s implication in health and cardiometabolic disease progression. These data infrastructure and representation efforts have now been linked together with a repertoire of analysis techniques and algorithms for data integration, exploration, evaluation and visualization. These techniques have been evaluated, benchmarked and documented, and are accessible to consortium partners. Collectively, the synthesis of work across partners in the project will allow the proceeding to computational analysis on the novel datasets generated within the project.

Within WP6, we organized several fellowships for young investigators (doctoral and post-doctoral researchers) as an exchange between partners’ laboratories and to strengthen consortium collaboration and to increase knowledge sharing. In this light, we also organized several workshops on MetaCardis-related data and analysis. An internal exploitation panel is also established to monitor and gauge results of the project. The project website is regularly updated as well and displays the publications and press articles on the project.

In WP7,

In WP8, the consortium organized the first exchange with an ethical expert on questions relating to data exploitation. Specifically, these questions were addressed in context of the researcher and clinician and how this can be disseminated to patients as well as patients’ expectations for the project. Additionally, as the consortium has generated large datasets, we have discussed the ethical obligations and implications in handling these datasets.

Potential Impact:
MetaCardis aims to understand and alleviate highly complex health conditions: cardiovascular diseases, obesity, diabetes and metabolic syndrome. These cardiometabolic diseases are the leading cause of death and the source of enormous discomfort and reduced quality of life in ageing European populations. Direct and indirect economic costs are enormous, and there are additional elements of social inequality where access to information and protective lifestyle factors may differ between social strata. Exploring the gut microbiota in such conditions will contribute to the understanding of complex mechanisms, and the definition of new effective pathways to prevent or treat these conditions. New predictive models are necessary to understand the natural progression of these diseases. Metacardis’ ambition is to provide a boon of truly great value to both individuals and societies within EU and non-EU countries.
After three years, original results have already been obtained, and research articles based on previous available cohorts were published. The first uncovered generated new insights into nutrient deficiency in bariatric surgery patients, which could impact and modify the gut-microbiome. New nutritional recommendations will be produced and the search for predictive factors for bariatric surgery outcome is ongoing. Another work describes the relationship between Akkermansia muciniphila fecal abundance and markers of cardiometabolic health. Moreover an important step has been made toward the possibility of personalized nutrition with the description of the CASINO toolbox, enabling targeted dietary advice to ameliorate patient metabolism via modifying their gut microbiota. The newly recruited MetaCardis cohort (WP3) will allow further validation and development of this innovative toolbox.
WP2 has implemented tools to test hypotheses arising from other WP results and elaborates novel concepts in metagenomic research that can be tested in vitro and in vivo in experimental systems. Using original experimental pipelines, WP2 provides a platform to characterize the biological and pathophysiological roles of changes in the human gut microbiome associated with increased CMD risk. It is expected that identification of both active metabolites processed by the gut microbiome and signaling molecular pathways mediating their biological effects will improve knowledge in the function of the gut microbiome and may lead to important developments in diagnosing CMD patients.
In WP4, signatures predicting bariatric surgery outcome would be of a tremendous potential value in understanding metabolic improvements. These markers would also aid in selecting the most patient-appropriate treatments in the future. In addition, these signatures would be obtained in a non-invasive manner, and could be easily converted into a commercial kit via translation to routine platforms, such as qPCR, that can be directly implemented at points of care. WP5's quantitative understanding of these disorders, and the generation of predictive models for the multifactorial causes, complex mechanisms, and conditionally effective paths to prevent or treat these highly complex health conditions (cardiovascular disease, obesity and metabolic syndrome) may, in one stroke, provide enormous benefit to both the EU and the world at large, at both individual and societal levels. In WP8, one major improvement has been introduced as we are now planning to appoint an independent ethics advisory board to discuss the ethical use of “Big Data” which is central to the European MetaCardis project. This will bring an interesting point of view not only to our project, but also to future European and International projects.

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