Microbiota-metabolic effects on the vascular thrombogenicity and inflammation

• Applicant: Dr. Marco Witkowski
• Subject Area: Cardiology, Angiology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 414722701

Thromboembolic complications are a leading cause for the morbidity and mortality of patients with cardiovascular diseases (CVD) representing a growing unmet clinical need. Accumulating evidence shows that the collection of microbes residing within the human intestinal tract (gut microbiome) influence host metabolism and vascular homeostasis by specific metabolites. The workgroup of Stanley Hazen at the Cleveland Clinic was among the first to identify novel microbiome-derived metabolites. For trimethylamine N-oxid (TMAO) and other metabolites the group found a strong association between plasma levels and thromboembolic complications, such as myocardial infarction or stroke, in large case control studies. Mechanistically, accelerated atherosclerosis and increased platelet reactivity have been identified as pathogenic features for TMAO. However, the impact of thrombosis-associated metabolites on the coagulation system remains unknown.Being the receptor of coagulation factor VIIa, Tissue Factor (TF) is the initiator of the extrinsic clotting cascade and highly thrombogenic. When present in the vasculature and blood, TF promotes vascular inflammatory singaling and thromboembolic complications.In this project, the impact of novel microbiota-derived metabolites on the blood thrombogenicity and vascular inflammation, particularly mediated by the TF pathway, will be assessed. The data will provide new insights in the pathogenesis of the bacterial metabolome that will allow for novel therapeutic strategies to improve the understanding and treatment of cardiometabolic diseases.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Stan Hazen