Thesis title: microbiota in atherosclerosis
The early outcome of acute coronary syndrome (ACS) has considerably improved in the last decade; yet, cardiovascular diseases still represent the main cause of morbidity and mortality worldwide, because the recurrence of ACS eventually leads to the pandemics of heart failure. This calls for a reappraisal of the mechanisms responsible for coronary instability and for innovative preventive and therapeutic strategies. Recent studies suggest that gut microbiota might contribute to cardiovascular diseases mainly by converting dietary and endogenous molecules into active metabolites that can affect distal organs and tissue by entering the systemic circulation. Among them, trimethylamine N- oxide (TMAO) might be a good example of a new gut microbiota metabolite that is involved in development of cardiovascular diseases (CVD) but that needs further investigation to dissect the therapeutic value in the prevention of CVD. The causal link between TMAO and atherosclerosis has been demonstrated in a recent in vivo study through the finding that choline or TMAO supplementation in ApoE −/− mice resulted in enhanced aortic root atherosclerotic plaque and the involvement of gut microbes in atherosclerosis susceptibility, was suggested by demonstrating that dietary TMAO precursor-induced enhancement in atherosclerosis in these mice was prevented by suppression of gut microbes with poorly absorbed broad spectrum oral antibiotics. Interestingly, atherosclerosis susceptibility can be transmitted to a recipient host by microbial transplantation from an atherosclerosis-prone and high TMAO-producing donor strain. Even though the exact mechanism by which TMAO promotes this disease is currently under investigation, present studies suggest that reducing plasma TMA concentration could be a potential therapeutic approach for the treatment of atherosclerosis. However, some studies have already demonstrated the pro-atherogenic contribution of TMAO through the use of ApoE KO mice subjected to a diet rich in choline or carnitine and the possibility of transmitting the susceptibility to plaque through fecal transplants from mice prone to atherosclerosis to mice that instead do not tend to develop plaques after depletion of the intestinal bacterial flora. Demonstrating the possibility not only to develop plaques but also to cause the formation of unstable plaques in ApoE KO mice following transplantation with bacteria from patients with stable and unstable plaques could be very important since it could also be verified the possibility of reducing the formation of unstable plaques by using a substance (3,3-dimethyl-1- butanol or DMB, structural analogue of choline) that has been shown to inhibit the formation of TMA mediated by intestinal bacteria starting from nutrients rich in choline or carnitine and consequently also of TMAO.