Ischemic disease is currently the most important cause of heart failure, which is considered a major public health problem. Consequently, the best prevention for this type of heart disease is to reduce recurrent episodes of coronary instability. Recently, numerous studies have shown the existence of a very important link between the intestinal microbiota and the onset of cardiovascular diseases including atherosclerosis. In particular, it has been shown that metabolites produced by the microbiota and derived from the diet such as TMAO can promote the onset of atherosclerosis and increase the risk of thrombosis. Therapeutic approaches can be represented by personalized nutritional interventions, use of probiotics and / or probiotics or specific inhibitors of TMAO precursors. Considering the latter approach, agents capable of inhibiting the cascade of reactions that lead to the formation of TMAO should also have other beneficial effects such as reducing the decline in renal function and the progression to heart failure. Further, the role of microbiome in plaque instability is still unknown.
The overall goal of the present research project is to verify whether atherosclerosis susceptibility is transmitted via gut microbial transplantation from patients with stable and unstable plaques to ApoE KO mice and suggest a potential therapeutic approach for the prevention of atherosclerosis.
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 (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.
This substance has been shown to have no effect on circulating levels of cholesterol and it has also been shown that, in addition to attenuating plasma levels of TMAO, it promotes the reduction of some bacterial species that are associated with plasma levels of TMA and TMAO and extension of the aortic plaque.
The success of the proposed therapeutic strategy, which sees the use of a non-lethal bacterial inhibitor, could have a strong socio-economic impact as it would lead to significant health benefits and a potential reduction in morbidity, mortality and national healthcare costs.
The rise in cardiovascular disease represents a serious and growing public health problem.
By demonstrating the involvement of intestinal bacteria in the pathogenesis of atherosclerosis and in the onset of atherosclerotic plaque that is not only stable but also unstable, new important pharmacological interventions could be suggested. The use of the structural analogue of choline (DMB) has proved to be an effective method not only to prevent and treat stable plaque but also to mitigate the progression of cardiorenal pathology and heart failure. This substance is able to attenuate the rise in plasma TMAO levels but also reduce some bacterial populations associated with high plasma levels of both TMA and TMAO and with the extension of the aortic plaque. Furthermore, it seems that it is able to selectively accumulate in the intestinal microbiota, thus avoiding exposure of the host at a systemic level.
Given these premises, what we would like to demonstrate is that this inhibitor could be used as a potential therapeutic approach not only for the prevention and treatment of stable plaques but also of unstable plaques that are more involved in the onset of acute coronary syndromes including unstable angina, acute myocardial infarction and sudden death.
Promising preliminary studies have helped to generate a series of expectations on the possibility of inhibiting the onset and progression of atherosclerosis by treatment with inhibitors of the formation of TMAO, a metabolite that is formed starting from nutrients taken in the diet following the action of intestinal bacteria.
Our hypothesis, namely that the same inhibitor may also be effective for the treatment of unstable plaques, can only be verified in an animal model since the formation of atherosclerotic plaques, in our model, involves the host's intestinal microbiota. Therefore, the same results cannot be obtained through the alternative use of primary cell cultures as this does not allow the in vitro reconstitution of the physiological interactions between the different types of cells that make up cardiac tissue and the metabolites produced by intestinal bacteria starting from nutrients.