Intestinal barrier dysfunction as a therapeutic target for cardiovascular disease

Abstract

The gut microbiome and intestinal dysfunction have emerged as potential contributors to the development of cardiovascular disease (CVD). Alterations in gut microbiome are well documented in hypertension, atherosclerosis, and heart failure and have been investigated as a therapeutic target. However, a perhaps underappreciated but related role for intestinal barrier function has become evident. Increased intestinal permeability is observed in patients and mouse models of CVD. This increased intestinal permeability can enhance systemic inflammation, alter gut immune function, and has been demonstrated as predictive of adverse cardiovascular outcomes. The goal of this review is to examine the evidence supporting a role for intestinal barrier function in cardiovascular disease and its prospect as a novel therapeutic target. We outline key studies that have investigated intestinal permeability in hypertension, coronary artery disease, atherosclerosis, heart failure, and myocardial infarction. We highlight the central mechanisms involved in the breakdown of barrier function and look at emerging evidence for restored barrier function as a contributor to promising treatment strategies such as short chain fatty acid, probiotic, and renin angiotensin system-targeted therapeutics. Recent studies of more selective targeting of the intestinal barrier to improve disease outcomes are also examined. We suggest that although current data supporting a contribution of intestinal permeability to CVD pathogenesis are largely associative, it appears to be a promising avenue for further investigation. Additional studies of the mechanisms of barrier restoration in CVD and testing of intestinal barrier-targeted compounds will be required to confirm their potential as a new class of CVD therapeutic.

Keywords: atherosclerosis; cardiovascular disease; gut microbiome; hypertension; intestinal permeability.

Fig. 1.

Mechanisms of intestinal barrier function. A: normal intestinal barrier function in a healthy subject. LHS, a thick layer of mucus creates a barrier between the intestinal epithelium and the luminal contents. Each villus has its own vasculature, further regulating entry of intestinal contents into circulation (gut-vascular barrier). Some immune cells are present and contribute to homeostasis. RHS, enlarged view of epithelial cells demonstrating the structure of the apical junctional complex made up of the tight junction, adherens junction and desmosome. These protein complexes work together to regulate epithelial permeability. Below the epithelium, the vascular endothelium also contains tight and adherens junctions that regulate vascular permeability. B: intestinal barrier dysfunction occurs through multiple mechanisms including reduced mucus thickness, increased inflammation, and reduced epithelial and endothelial tight junction protein expression and function. This leads to the translocation of intestinal bacteria and antigens into circulation, leading to systemic inflammation. These processes have been shown to occur during the development of cardiovascular diseases such as atherosclerosis, hypertension and myocardial infarction. Figure was created with BioRender.com and published under license.