Gut microbiota and microbiota-derived metabolites in cardiovascular diseases

Abstract

Cardiovascular diseases, including heart failure, coronary artery disease, atherosclerosis, aneurysm, thrombosis, and hypertension, are a great economic burden and threat to human health and are the major cause of death worldwide. Recently, researchers have begun to appreciate the role of microbial ecosystems within the human body in contributing to metabolic and cardiovascular disorders. Accumulating evidence has demonstrated that the gut microbiota is closely associated with the occurrence and development of cardiovascular diseases. The gut microbiota functions as an endocrine organ that secretes bioactive metabolites that participate in the maintenance of cardiovascular homeostasis, and their dysfunction can directly influence the progression of cardiovascular disease. This review summarizes the current literature demonstrating the role of the gut microbiota in the development of cardiovascular diseases. We also highlight the mechanism by which well-documented gut microbiota-derived metabolites, especially trimethylamine N-oxide, short-chain fatty acids, and phenylacetylglutamine, promote or inhibit the pathogenesis of cardiovascular diseases. We also discuss the therapeutic potential of altering the gut microbiota and microbiota-derived metabolites to improve or prevent cardiovascular diseases.

Figure 1

Gut microbiota-derived metabolites regulate vascular diseases. TMA is produced from dietary phosphatidylcholine, choline, and carnitine by microbial TMA lyases, such as CutC/D and Cnt A/B, in the gut. TMA then enters the liver via portal vein circulation and is oxidized by FMOs to produce TMAO. Dietary fiber can be fermented by gut microbiota to generate SCFAs, mainly acetate, propionate, and butyrate. Dietary phenylalanine can be converted into phenylacetic acid by the microbial porA gene, with further production of PAGln and phenylacetylglycine in the liver. LPS: lipopolysaccharide; TMA: trimethylamine; FMOs: Flavin monooxygenases; PAGln: Phenylacetylglutamine; SCFAs: Short-chain fatty acids; TMAO: Trimethylamine N-oxide.

Figure 2

Roles of gut microbiota-generated metabolites, TMAO, and SCFA, in HF and CHDs. Gut microbiota-derived metabolites, TMAO, are produced from dietary sources of phosphatidylcholine, choline, and carnitine, and SCFAs such as acetate, propionate, and butyrate are produced from dietary fiber. Increased levels of TMAO and decreased levels of SCFA in the host serum are associated with HF and CHDs through regulation of cholesterol accumulation, circulatory and liver levels of lipids, lipid transportation, and activation or inhibition of inflammatory pathways. CHD: Coronary heart disease; HF: Heart failure; SCFAs: Short-chain fatty acids; TMAO: Trimethylamine N-oxide.

Figure 3

TMAO participates in vascular diseases. High levels of TMAO can decrease reverse cholesterol transport and BA metabolism and increase vascular inflammation and cell pyroptosis, contributing to atherosclerosis. TMAO activates platelets and increases the release of TFs to promote thrombosis. TMAO increases blood pressure by increasing inflammation, oxidative stress, and water reabsorption. BA: Bile acid; TF: Tissue factor; TMAO; Trimethylamine N-oxide; CDK: chronic kidney disease; TMA: trimethylamine; FMOs: Flavin monooxygenases.