Cardiovascular Disease May Be Triggered by Gut Microbiota, Microbial Metabolites, Gut Wall Reactions, and Inflammation

Abstract

Cardiovascular disease (CVD) may be inherited, as recently shown with the identification of single nucleotide polymorphisms (SNPs or "snips") on a 250 kb DNA fragment that encodes 92 proteins associated with CVD. CVD is also triggered by microbial dysbiosis, microbial metabolites, metabolic disorders, and inflammatory intestinal epithelial cells (IECs). The epithelial cellular adhesion molecule (Ep-CAM) and trefoil factor 3 (TFF3) peptide keeps the gut wall intact and healthy. Variations in Ep-CAM levels are directly linked to changes in the gut microbiome. Leptin, plasminogen activator inhibitor 1 (PAI1), and alpha-1 acid glycoprotein 1 (AGP1) are associated with obesity and may be used as biomarkers. Although contactin 1 (CNTN1) is also associated with obesity and adiposity, it regulates the bacterial metabolism of tryptophan (Trp) and thus appetite. A decrease in CNTN1 may serve as an early warning of CVD. Short-chain fatty acids (SCFAs) produced by gut microbiota inhibit pro-inflammatory cytokines and damage vascular integrity. Trimethylamine N-oxide (TMAO), produced by gut microbiota, activates inflammatory Nod-like receptors (NLRs) such as Nod-like receptor protein 3 (NLRP3), which increase platelet formation. Mutations in the elastin gene (ELN) cause supra valvular aortic stenosis (SVAS), defined as the thickening of the arterial wall. Many of the genes expressed by human cells are regulated by gut microbiota. The identification of new molecular markers is crucial for the prevention of CVD and the development of new therapeutic strategies. This review summarizes the causes of CVD and identifies possible CVD markers.

Keywords: cardiovascular disease; gut microbiota; gut wall reactions; inflammation.

Figure 1

A basic explanation for the role of plasma kallikrein in inflammation and blot clotting. Prekallikrein is encoded by the trans-pQTL gene KLKB1 in the liver. Factor XII converts prekallikrein to plasma kallikrein and leads to the production of more factor XI. The early stages of blood clotting and the formation of bradykinin are initiated by a combined reaction of plasma kallikrein and factor XII. Bradykinin increases the permeability of blood vessel walls, leading to leakage and inflammation. Trans-pQTL = trans-protein quantitative trait loci. Created using Biorender.com (accessed on 22 August 2024).

Figure 2

A schematic representation explaining the role paraoxonases (PON1, PON2, and PON3) play in cardiovascular disease (CVD). PON1 and PON3 are attached to high-density lipoprotein (HDL) and oxidize lipid peroxides to prevent their accumulation on low-density lipoprotein (LDL). Oxidized LDL (OX-LDL) triggers macrophages to an anti-inflammatory state and forms foam cells. Foam cells and the release of pro-inflammatory cytokines from adipose tissue lead to plaque formation. Plague formation may also be triggered by hyperglycemia. The HDL-PON complex prevents the aggregation of platelets. PON2 represses the formation of reactive oxygen species (ROS) and has an antiatherogenic effect. ATP-binding cassette transporter A1 (ABCA1) mediates the cellular efflux of phospholipids and cholesterol to lipid-poor apolipoprotein A1 (apoA1)-HDL and plays a significant role in the metabolism of HDL. Blue dots in adipose tissue represent cytokines, lighter circles in the foam cell represent the accumulation of triglycerides, the yellow area in the artery represents hyperglycemia and atherosclerosis, LRP1 = low-density lipoprotein receptor-related protein 1, PAI1 = plasminogen activator inhibitor 1, ABCA1 = ATP-binding cassette transporter A1, SR = scavenger receptor. Created using Biorender.com (accessed on 20 August 2024).

Figure 3

The link between gut microbiota and atherosclerosis. Gut microbiota produces trimethylamine (TMA) from choline, derived from dietary phosphatidylcholine. Choline is microbially converted to TMA and then oxidized to the pro-atherogenic metabolite trimethylamine N-oxide (TMAO). TMAO may contribute to atherosclerosis by interference with cholesterol transportation, foam cell formation, and platelet aggregation. Platelet aggregation leads to atherosclerosis. Disruption of intestinal permeability by damaged intestinal epithelial cells (IECs) results in the leakage of bacterial toxins such as lipopolysaccharides (LPS) formed by microbiota, and cell wall peptidoglycan into the bloodstream. These toxins react with Toll-like receptors (TLRs), leading to systemic inflammation and the aggravation of atherosclerosis. A diet with less dietary fiber decreases the microbial production of short-chain fatty acids (SCFAs) such as butyrate. Butyrate is the main energy source for colonocytes and has an immunomodulatory effect on gut mucosa. Dotted lines denote the effect of diets on IECs and inflammation, lighter circles in the foam cell represent the accumulation of triglycerides, BAs = bile acids, ROS = reactive oxygen species, C/NF-κB = canonical nuclear factor kappa-B, FXRs = Farnesoid receptors, NLRP3 = Nod-like receptor protein 3, FMO3 = Flavin-containing monooxygenase 3. Created using Biorender.com (accessed on 20 August 2024).