DS0406 - Microbiomes et relations microbiomes-hôte

Microbiome functionalities and cardiomatabolic disease: a proteomic approach – ProteoCardis

Submission summary

The generic call for proposals from the ANR 2015 clearly encourages and supports integration of reliable, multi-sourced data that, when efficiently analyzed, interpreted, disseminated and used, can become an almost inexhaustible source of knowledge to fuel a learning healthcare system.

This is exactly the purpose of ProteoCardis which proposes an unprecedented intestinal metaproteome-wide association study of coronary artery disease (CAD), where newly acquired huge metaproteomics data (several thousands of bacterial proteins and several tens of thousands of peptides) will be put into perspective with patient records, metabolic features, complete cardio-vascular exams and outcomes that are acquired in the FP7 MetaCardis framework and will be refined with the ANR’s support.

In the MetaCardis FP7 framework (2013-2017), the gut metagenomes of more than 2000 patients at different stages of their cardio-metabolic disease is characterized by high throughput sequencing of the total fecal DNA. This will provide an enormous reservoir for the discovery of unsuspected metagenomic signatures that can represent predictive biomarkers and unsuspected new therapeutic targets for different disease phenotypes or stages.

The accompanying challenge proposed here is a holistic metaproteomics approach to move beyond the genetic potential addressed by metagenomics and get closer to the real functionality of the gut microbiome by exploring the expression of metabolic and cellular pathways. Understanding how they are altered in disease can have a profound impact on patient treatment and disease prevention. This may open new avenues for reducing risk, including the discovery of new biomarkers, new targets and new therapeutic molecules.

ProteoCardis will follow a step-by-step approach that we have already successfully experienced on a modest scale.

First, in a well-controlled shotgun metaproteomics approach, and without any a priori assumption of the metabolic and/or cellular pathways that can accompany the disease, we will search for metaproteomic variables that are associated with CAD in 50 patients with acute event and 100 patients with chronic coronaropathy with or without congestive heart failure (CHF), compared to 50 healthy controls (CTRL) matched with BMI and sex. The change of protein signals before and one year after bariatric surgery (BS), an intervention known to reduce the cardiovascular risk, will also be examined (two observation times in the same 20 BS subjects). Finally, we will provide a set of relevant variables from those obtained in both contexts of aggravation (CAD vs. CTRL) and improvement (BS2 vs. BS1) of the clinical status.

Then, to confirm the candidates and test their predictive value in high-risk patients, a multiplexed SRM (selected reaction monitoring) assay will be developed, targeting and precisely quantifying those proteins/peptides of interest. The validation process will be done by a recognized team in an independent manner, first on a subset of 20 CAD patients and 20 matched controls. ProteoCardis will subsequently examine the presence of these signals in 150 additional individuals at high risk of CAD (50 subjects with metabolic syndrome, 50 obese and 50 type 2 diabetic subjects) and association of these signals with any risk factors as well as complications or adverse cardiovascular outcomes of the patients over a four year period.

The expected results have two levels of impact: immediate, since the whole experiment as a Standard Operational Procedure (SOP) will define new standards and share best practice among the scientific community for quantitative metaproteomics; longer-term, by pioneering a new map of knowledge linking together metaproteomic, metagenomic and clinical data related to CAD pathology, that will contribute to the opening of new avenues for maintaining or restoring health.

Project coordination

Catherine Juste (UMR1319/MICALIS)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INRA UMR1319/MICALIS
LSMBO-IPHC IPHC UdS/CNRS UMR7178
INRA INRA - MGP
INST CARDIOMETABOLISME NUTRITION
INRA MaIAGE

Help of the ANR 638,000 euros
Beginning and duration of the scientific project: September 2015 - 42 Months

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