Cardiovascular disease remains the leading cause of death and disability in developed countries. Therefore, it is important to discover novel strategies for their prevention and treatment.
Gut microbiota is emerging as a new potential therapeutic target for preventing and treating cardiovascular diseases. Experimental studies demonstrated that alteration of gut permeability induces vascular damage and in turn atherosclerotic process.
In light of what has been said about the role of intestinal permeability in the onset of cardiovascular events, the aim of the project is to will be to assess the degree of alteration of intestinal permeability in patients at risk of cardiovascular disease and whether an alteration of intestinal permeability is observed, and it is a predictor of cardiovascular events or worsening disease. In particular, our research plan proposes a unique translational approach from bench to bedside to clarify whether:
1) there is a relation between gut permeability, measured by a newly developed method, and cardiovascular disease, correlating and comparing endothelial dysfunction, platelet activation, inflammation pathway and cardiovascular events;
2) LPS or other microbiota products are involved in the alteration of gut permeability, vascular damage and platelet activation by in in vitro experiments.
If successful, our work may provide new evidence supporting the potential role of gut microbiota in cardiovascular diseases and extending, on a large scale, the use of direct and non-invasive methods could be a valid instrument to stratify the risk of atherothrombosis could help prevent the onset of cardiovascular events in clinical practice.
In this project we will study for the first time on a population of CVD patients the alteration of gut permeability by a direct method and its association with endothelial dysfunction, platelet activation, inflammation pathway. We will demonstrate that CVD patients have an increased gut permeability compared to control subjects and this induces vascular damage that may be predisposing factor to a worsening of disease. Importantly, we will demonstrate that inflammation, and oxidative pathways have a deleterious vascular effect acting also on intestinal barrier. Moreover, we will elucidate the potential impact of gut microbiota on the development of CVDs in human subjects. We will study the association between a dysregulation of gut microbiota and a worsening of cardiovascular clinical outcomes in CVD patients.
Finally, we will investigate the mechanisms underlying the close relationship between increased gut permeability and CVD. We will elucidate the impact of LPS, microbial product, on platelet and vascular homeostasis and function, focusing on the role of redox signaling as prominent players. The results obtained in our study will be a major scientific breakthrough in the cardiovascular field.
Significant interest in recent years has focused on gut microbiota-host interaction because accumulating evidence has revealed that gut microbiota plays a significant role in human health and disease, including CVDs. Changes in the composition of gut microbiota associated with disease, referred to as dysbiosis, have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity and type 2 diabetes mellitus. In addition, the recognition of the gut permeability has paved the way to reveal potential pathophysiological mechanisms behind numerous associations between the gut microbiota and CVD.
A direct measure of gut permeability in patients with CVD is a very important step that will support the interplay between gut permeability and heart disease. Moreover, evaluation by direct and non-invasive methods could be a valid instrument to stratify the risk of atherothrombosis on a large scale.
The development and use of direct and non-invasive techniques for microbiological analysis will uncover the complexity of the bacterial microbiome at various anatomic sites. Modulation of gut microbiota function through diet, pre- and probiotics, and targeted non-lethal antimicrobial enzyme inhibitors may enable, in the long term, the capacity to alter host metabolic profile in a desired favorable direction. This proposal could reduce the high social and medical costs for the clinical management of CVDs with a considerable positive impact on the National Health Service.