There is overwhelming evidence that chronic inflammation plays a critical role in both metabolic and cardiovascular diseases (CVD). Recent evidence points at a crucial role for the commensal gut microbiota. The composition of the gut microbiota is determined by dietary, environmental and host genetic factors. It produces a large amount of metabolites that control host inflammatory responses in the adipose tissue, liver and blood leukocytes. In turn, inflammatory mediators released from these organs, in combination with the gut metabolites, might determine the susceptibility to developing CVD. Besides metabolic processes, leakage through the intestinal barrier can also lead to bacterial components entering into the systemic circulation and activating the immune system. In this study, we hypothesize that the activation of chronic inflammation is initiated and driven by a disturbed interaction between gut microbiota, the intestinal barrier, blood leukocytes, liver and adipose tissue. The resulting chronic inflammation increases the risk for atherosclerosis and cardiovascular disease.

The aim of this project is to investigate the role of the gut microbiota and chronic inflammation as drivers of cardiovascular disease.

500 participants (BMI>27, 55-75 years old) are invited to participate, approximately half of these without and half with cardiovascular complications. Several parameters are investigated: diet, genetic variation, microbiome, immune function and vascular status.

DNA is collected from all participants, and genetic variation with be assessed using an exome-based SNP-chip with 2 million SNP’s. Microbiome composition and the function of the immune system will analyzed at several levels: immunophenotyping, measurement of circulating factors in plasma or serum, in-vitro stimulations of cells and analysis of mRNA and cytokine responses. In vitro studies are performed on adipocytes acquired by biopsy of subcutaneous abdominal and thigh adipose tissue.

The metabolic profile is investigated using anthropometric measurements, MRI  (focusing on the fat mass and distribution) and MR spectroscopy of the liver (hepatic steatosis). Subclinical atherosclerosis is investigated by ultrasonography of the  carotid arteries (including IMT and plaque measurements and elastography (focusing on the vulnerability of plaques)), assessment of arterial stiffness (distensibility, PWA and PWV) and measurement of ankle-brachial index (ABI). Furthermore, subjects are followed for 3-5 years to register incident cardiovascular disease. At the conclusion of our study we will have a well-characterized cohort of individuals with obesity with or without CVD traits, which we will use to establish the association between gut microbiota, chronic low grade inflammation and CVD, and eventually to develop gut microbiota-based predictive biomarkers and novel leads for treatment of CVD. This study is part of a national research consortium sponsored by the Dutch Heart Foundation, participating centers are: Radboudumc, Groningen University, Leiden UMC, Wageningen University, Amsterdam Medical Centre, Maastricht University.

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