Gut Microbiota in Hypertension and Atherosclerosis: A Review

Abstract

Gut microbiota and its metabolites such as short chain fatty acids (SCFA), lipopolysaccharides (LPS), and trimethylamine-N-oxide (TMAO) impact cardiovascular health. In this review, we discuss how gut microbiota and gut metabolites can affect hypertension and atherosclerosis. Hypertensive patients were shown to have lower alpha diversity, lower abundance of SCFA-producing microbiota, and higher abundance of gram-negative bacteria, which are a source of LPS. Animal studies point towards a direct role for SCFAs in blood pressure regulation and show that LPS has pro-inflammatory effects. Translocation of LPS into the systemic circulation is a consequence of increased gut permeability. Atherosclerosis, a multifactorial disease, is influenced by the gut microbiota through multiple pathways. Many studies have focused on the pro-atherogenic role of TMAO, however, it is not clear if this is a causal factor. In addition, gut microbiota play a key role in bile acid metabolism and some interventions targeting bile acid receptors tend to decrease atherosclerosis. Concluding, gut microbiota affect hypertension and atherosclerosis through many pathways, providing a wide range of potential therapeutic targets. Challenges ahead include translation of findings and mechanisms to humans and development of therapeutic interventions that target cardiovascular risk by modulation of gut microbes and metabolites.

Keywords: atherosclerosis; cardiovascular disease; gut microbiota; hypertension.

Figure 1

Gut microbiota, gut permeability and lipopolysaccharides (LPS) absorption. Paracellular permeability of the intestinal epithelium is affected by zonulin production of the basal lamina, dietary factors and gut microbiota that produce zone occludens toxin. Increased permeability leads to more LPS translocation to the systemic circulation, which has a pro-inflammatory effect and further increases gut permeability.

Figure 2

Production of trimethylamine-N-oxide (TMAO). Gut microbiota enzymes, including trimethylamine (TMA) lyase, convert dietary L-carnitine, choline, and lecithin into TMA. The hepatic enzyme flavin mono-oxygenase 3 (FMO3) converts TMA into TMAO, and TMAO is primarily excreted by the kidneys.

Figure 3

Enterohepatic cycle of bile acids. Hepatic conversion of cholesterol results in primary bile acids, that are excreted postprandially by the gallbladder. Active reuptake takes place in the terminal ileum. In the colon, primary bile acids are converted to secondary bile acids by gut microbiota, and passively reabsorbed. Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) have a preference for secondary bile acids.

Figure 4

Summary of hypothesized pathways for the effects of gut microbiota on hypertension and atherosclerosis. Gut microbiota could affect hypertension through inflammatory factors, influenced by short chain fatty acids (SCFAs) and lipopolysaccharides (LPS), and through sympathetic activation by gut–brain interactions. The effects on inflammation and dyslipidemia in atherosclerosis could be mediated by bile acid receptors Takeda G-protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR), trimethylamine-N-oxide (TMAO) and trimethylamine (TMA), and direct vessel infiltration of microbiota. The grey arrows indicate interactions between pathways: FXR regulates the TMAO-converting enzyme flavin mono-oxygenase 3 (FMO3), sympathetic activation increases gut permeability, and short chain fatty acids can attenuate the inflammatory effects of LPS.