Gut microbiota, carotid atherosclerosis and ischemic stroke
Prosjektstart er utsatt til 07.04.17 fordi lege ph.d Karolina Skagen som skal lede prosjektet er i foreldrepermisjon frem til den dato. Dette er godkjent av HSØ RHF (brev 11.10.16). Prosjektstart 07.04.17. Vi viser foreløpig til protokoll (dette etter avtale med Randi Vad, HSØ 08.02.17). The influence of diet on development of atherosclerosis and cardiovascular risk is well-established, and dietary advice has been given to at risk patients based on the belief that dietary risk factors are directly absorbed from the gut, to exert their adverse vascular effects. On this basis, past and present health promotion campaigns and dietary advice has focused on the reduction of low cholesterol foods. Diet however is not an independent risk factor for atherosclerosis and effect on stroke risk in patients who make dietary change is variable. What has been neglected until recently is the role of commensal intestinal microorganisms in the metabolism of food stuffs, and their potential consequences for host metabolism and disease pathogenesis. Gut flora can significantly influence the bioavailability of dietary consitutents and their metabolism in the mammalian host. The gut microbiota has not only been found to be associated with the inflammatory status of patients, but it has also been shown that patients with symptomatic atherosclerosis harbor characteristic changes in the gut metagenome14, 16. This has added a new dimension to atherosclerosis research, which is rapidly expanding. Recent studies have shown a mechanistic link between intestinal microbiota metabolism if dietary carnitin and cholin and coronary artery disease through the production of the proatherosclerotic metabolite trimethylamine-N-oxide (TMAO)17, 18. The gut microbiota, i.e. the microbial inhabitants of the gastrointestinal tract dominated by bacteria, is a metabolically highly active human organ, which has been linked to traditional, modifiable risk factors for cardiovascular disease, like diabetes19, hyperlipidemia 20and obesity21. Each person has a distinct and highly variable microbiota, but a core gut microbiota are shared among individuals. TMAO promotes atherosclerosis in part by enhancing the accumulation of cholesterol in foam cells, and elevated TMAO levels predict myocardial infarction, stroke and all cause mortality17, 22. TMAO has been proposed to be produced through dietary intake of carnitine (red meat) or phosphatidylcholine (egg yolk, soyabean) second by conversion to trimetylamine (TMA) by the intestinal microbiota, and third by oxidation from flavin-containing monooxygenases (FMOs) in the liver. Nutrient precursors and gut microbiota may in the future serve as new targets for the prevention and treatment of ischemic stroke. Hypothesis of this Project is: Raised serum levels of gut microbiota dependant metabolites (ƒÁBB and TMAO) are associated with development of atherosclerotic carotid plaque, and can be used to predict ischemic stroke/cardiovascular disease and mortality. The plasma levels are correlated to carnitin] and cholin]rich diets and gut microbiota (analysed in stool). This project aims to use translational research approach deomstrating an association between gut microbiota metabolites in blood and stool to carotid atherosclerosis and risk of ischemic stroke. The project is a prospective, case-control study using a multi-disciplinary, translational research approach. All patients >18 years with an atherosclerotic carotid stenosis = 50% admitting our department (Dep of Neurology, Rikshospitalet, OUS) as in-patient or out-patient will consecutively be considered for inclusion. This project is a part of an ongoing prospective study with a planned follow-up of 10 years with estimated inclusion rate of 100 patients annually. The methods included in this protocol are well established in international research and demands multi-disciplinary, translational research approach. Unique for this project is the combination of these methods including the new dimension in atherosclerosis research- the gut microbiota.