The gut-cardiovascular connection: new era for cardiovascular therapy

Abstract

Our gut microbiome is constituted by trillions of microorganisms including bacteria, archaea and eukaryotic microbes. Nowadays, gut microbiome has been gradually recognized as a new organ system that systemically and biochemically interact with the host. Accumulating evidence suggests that the imbalanced gut microbiome contributes to the dysregulation of immune system and the disruption of cardiovascular homeostasis. Specific microbiome profiles and altered intestinal permeability are often observed in the pathophysiology of cardiovascular diseases. Gut-derived metabolites, toxins, peptides and immune cell-derived cytokines play pivotal roles in the induction of inflammation and the pathogenesis of dysfunction of heart and vasculature. Impaired crosstalk between gut microbiome and multiple organ systems, such as gut-vascular, heart-gut, gut-liver and brain-gut axes, are associated with higher cardiovascular risks. Medications and strategies that restore healthy gut microbiome might therefore represent novel therapeutic options to lower the incidence of cardiovascular and metabolic disorders.

Keywords: cardiovascular diseases; dysbiosis; endothelium; endotoxin; fecal microbiota transplantation; gut microbiome.

Figure 1:

Interplay between the host status and gut microbiome. Host statuses such as obesity, diabetes, and aging, may alter gut microbiome profile of the host. On the other hand, imbalance of gut microbiome alters metabolite pool and cytokine pool of the body, which consequently impair the host homeostasis (e.g. cardiovascular homeostasis).

Figure 2:

Intestinal permeability and cardiovascular risk. Improper lifestyles contribute to the increased intestinal permeability (leaky gut), which leads to the influx of endotoxin and microbiome-derived metabolites into the systemic circulation. Endotoxin influx induces the immune cells to secrete pro-inflammatory cytokines. The altered metabolite pool and cytokine pool cause damage on cellular components of the cardiovascular system to increase cardiovascular risks. IFN: interferon; IL: interleukin; TMAO: trimethylamine N-oxide; TNF: tumor necrosis factor.

Figure 3:

Gut-derived substances and endothelial homeostasis. Healthy gut microbiome and normal intestinal permeability protect endothelial function. On the other hand, dysbiosis and leaky gut trigger endothelial dysfunction via causing entry of endotoxin, cytokines, and metabolites into the bloodstream. GLP-1: Glucagon-like peptide 1; H₂S: hydrogen sulfide; MT: endothelial-to mesenchymal-transition; NO: nitric oxide; SCFAs: short-chain fatty acids; TMAO: trimethylamine N-oxide.

Figure 4:

Dysbiosis-associated VSMC dysfunction. Dysbiosis may cause VSMC dysfunction by directly impairing VSMC homeostasis, and by disrupting the communication between endothelial cells and VSMCs. Reduced NO bioavailability, increased oxidative stress, and pronounced inflammation in endothelial cells would drive the dysfunction of VSMCs. Dysfunctional VSMCs are associated with increased contractility, syntheticity, inflammation, ROS overproduction, calcification, proliferation, and migration. NO: nitric oxide; ROS: reactive oxygen species; VSMC: vascular smooth muscle cell.

Figure 5:

Gut-heart axis and cardiomyocyte homeostasis. Commensal and pathogenic microbes resident in the intestine can generate both beneficial and toxic substances and release them into the circulation. The beneficial substances sustain cardiomyocyte homeostasis, while the toxic agents promote cardiomyocyte dysfunction. H₂S: hydrogen sulfide; PCA: protocatechuic acid; SCFAs: short-chain fatty acids; TMAO: trimethylamine N-oxide.

Figure 6:

Gut-liver axis and cardiovascular risk. Dysbiosis leads to the influx of more gut-derived precursor metabolites, which are further metabolized by the liver to form cytotoxic chemicals to impair the cardiovascular function. In addition, leaky gut causes the leakage of endotoxin into the portal vein, damaging the liver function. The occurrence of hepatic disorders increase the cardiovascular risk. LPS: lipopolysaccharide; LTA: lipoteichoic acid; MA: trimethylamine; TMAO: trimethylamine N-oxide.

Figure 7:

Bidirectionality in brain-gut axis and cardiovascular risk. The vicious cycle between the inflammatory intestine and the inflammatory CNS. Chemical transmitters, neural pathways and the immune system may collectively participate in the pathogenesis of cardiovascular dysfunction. CNS: central nervous system.