Gut Dysbiosis and Immune System in Atherosclerotic Cardiovascular Disease (ACVD)

Abstract

Atherosclerosis is a leading cause of cardiovascular disease and mortality worldwide. Alterations in the gut microbiota composition, known as gut dysbiosis, have been shown to contribute to atherosclerotic cardiovascular disease (ACVD) development through several pathways. Disruptions in gut homeostasis are associated with activation of immune processes and systemic inflammation. The gut microbiota produces several metabolic products, such as trimethylamine (TMA), which is used to produce the proatherogenic metabolite trimethylamine-N-oxide (TMAO). Short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, and certain bile acids (BAs) produced by the gut microbiota lead to inflammation resolution and decrease atherogenesis. Chronic low-grade inflammation is associated with common risk factors for atherosclerosis, including metabolic syndrome, type 2 diabetes mellitus (T2DM), and obesity. Novel strategies for reducing ACVD include the use of nutraceuticals such as resveratrol, modification of glucagon-like peptide 1 (GLP-1) levels, supplementation with probiotics, and administration of prebiotic SCFAs and BAs. Investigation into the relationship between the gut microbiota, and its metabolites, and the host immune system could reveal promising insights into ACVD development, prognostic factors, and treatments.

Keywords: SCFAs; TMAO; atherosclerosis; atherosclerotic cardiovascular disease (ACVD); gut dysbiosis; gut microbial metabolites; immune system.

Figure 1

Mechanisms by which microbiota participate in atherosclerosis. The dietary nutrients choline and carnitine are selectively converted into TMA by TMA-producing and metabolizing enzymes from anaerobic gut microbiota. TMA is transferred to the liver via portal circulation and oxidized by the hepatic flavin monooxygenase 3 (FMO3), resulting in the production of TMA–N-oxide (TMAO). Increasing TMAO has been demonstrated to decrease the bile acid pool size and inhibit bile acid synthesis, impacting cholesterol metabolism via altered intestinal cholesterol transport, specifically reverse cholesterol transport (RCT). TMAO has also been associated with enhanced macrophage cholesterol accumulation and atherosclerosis development. Supplementation with pro/prebiotics, such as resveratrol, can increase butyrate-producing bacteria. With the increase in butyrate-producing bacteria, TMA-producing bacteria become less prominent as they are outcompeted for resources. This results in increased levels of butyrate, which binds to G protein-coupled receptors (GPCRs), leading to decreased intestinal inflammation and an overall decreased risk of atherosclerosis, myocardial infarction, and cerebral infarction.

Figure 2

SCFAs bring about system-wide improvements in ACVD risk factors via GLP-1. Following food intake, dietary fibers are digested by gut microbiota into SCFAs including acetate, propionate, and butyrate. These SCFAs activate intestinal L cells, leading to the release of GLP-1 both independently of and in conjunction with FFAR2 and FFAR3 activation. GLP-1 modulates a variety of organ functions including the liver, pancreas, and brain. It also systemically improves insulin sensitivity and glucose tolerance. This ability to improve various cardiovascular and metabolic risk factors for ACVD implicates GLP-1 and its synthetic mimetics as a viable treatment option for atherosclerosis.