Gut Microbiota and Coronary Artery Disease: Current Therapeutic Perspectives

Abstract

The human gut microbiota is the community of microorganisms living in the human gut. This microbial ecosystem contains bacteria beneficial to their host and plays important roles in human physiology, participating in energy harvest from indigestible fiber, vitamin synthesis, and regulation of the immune system, among others. Accumulating evidence suggests a possible link between compositional and metabolic aberrations of the gut microbiota and coronary artery disease in humans. Manipulating the gut microbiota through targeted interventions is an emerging field of science, aiming at reducing the risk of disease. Among the interventions with the most promising results are probiotics, prebiotics, synbiotics, and trimethylamine N-oxide (TMAO) inhibitors. Contemporary studies of probiotics have shown an improvement of inflammation and endothelial cell function, paired with attenuated extracellular matrix remodeling and TMAO production. Lactobacilli, Bifidobacteria, and Bacteroides are some of the most well studied probiotics in experimental and clinical settings. Prebiotics may also decrease inflammation and lead to reductions in blood pressure, body weight, and hyperlipidemia. Synbiotics have been associated with an improvement in glucose homeostasis and lipid abnormalities. On the contrary, no evidence yet exists on the possible benefits of postbiotic use, while the use of antibiotics is not warranted, due to potentially deleterious effects. TMAO inhibitors such as 3,3-dimethyl-1-butanol, iodomethylcholine, and fluoromethylcholine, despite still being investigated experimentally, appear to possess anti-inflammatory, antioxidant, and anti-fibrotic properties. Finally, fecal transplantation carries conflicting evidence, mandating the need for further research. In the present review we summarize the links between the gut microbiota and coronary artery disease and elaborate on the varied therapeutic measures that are being explored in this context.

Keywords: TMAO; TMAO inhibitors; coronary artery disease; gut microbiota; prebiotics; probiotics; synbiotics.

Figure 1

The pathophysiology of gut microbial associations with coronary artery disease. Diet critically shapes the gut microbiota, providing substrates for fermentation. Undigested fiber consumed by bacteria leads to the production of SCFA. Low levels of SCFA have been linked to host inflammation, which may influence atherosclerosis. Many bacterial species also produce TMA using choline as a source. TMA is metabolized to TMAO in the liver by flavin monooxygenases, and is associated with atherosclerosis. Bacterial LPS leaking into the circulation from the gut initiates TLR-mediated systemic inflammation, also linked to atherosclerosis. LPS: Lipopolysaccharide, SCFA: short-chain fatty acids, TLR: toll-like receptor, TMAO: trimethylamine N-oxide.

Figure 2

Beneficial effects of gut microbiota modulators in coronary artery disease. ECM: extracellular matrix, EC: endothelial cell, TMAO: trimethylamine N-oxide, BP: blood pressure, ROS: reactive oxygen species. ↓: decreased, ↑ increased.

Figure 3

Examples of cellular and molecular mechanisms underlying the potential effects of pre- and probiotic administration in metabolic and coronary artery disease. GLP1: glucagon-like peptide-1, GPR: G-protein coupled receptor, NPC1L1: Niemann-Pick C1-like 1 protein, SCFA: short-chain fatty acids.

Figure 4

The effect of TMAO inhibition in atherosclerosis. Consumption of a high-choline diet leads to its conversion to trimethylamine (TMA) in the gut, with the aid of CutC/CutD and TMA-lyase. Inhibition of these enzymes by iodomethylcholine (IMC)/fluoromethylcholine (FMC) and 3,3-dimethyl-1-butanol (DMB) leads to lower trimethylamine N-Oxide (TMAO) production in the liver. As a result, atherosclerosis may be attenuated through multiple mechanisms. FMO: flavin-containing monooxygenase, ER: endoplasmic reticulum, ROS: reactive oxygen species.