The Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis

Abstract

Hypercholesterolemia plays a causal role in the development of atherosclerosis and is one of the main risk factors for cardiovascular disease (CVD), the leading cause of death worldwide especially in developed countries. Current data show that the role of microbiota extends beyond digestion by being implicated in several metabolic and inflammatory processes linked to several diseases including CVD. Studies have reported associations between bacterial metabolites and hypercholesterolemia. However, such associations remain poorly investigated and characterized. In this review, the mechanisms of microbial derived metabolites such as primary and secondary bile acids (BAs), trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) will be explored in the context of cholesterol metabolism. These metabolites play critical roles in maintaining cardiovascular health and if dysregulated can potentially contribute to CVD. They can be modulated via nutritional and pharmacological interventions such as statins, prebiotics, and probiotics. However, the mechanisms behind these interactions also remain unclear, and mechanistic insights into their impact will be provided. Therefore, the objectives of this paper are to present current knowledge on potential mechanisms whereby microbial metabolites regulate cholesterol homeostasis and to discuss the feasibility of modulating intestinal microbes and metabolites as a novel therapeutic for hypercholesterolemia.

Keywords: atherosclerosis; bile acids; cholesterol; dietary fibers; gut microbiota; hypercholesterolemia; nutraceuticals; probiotics; short-chain fatty acids; trimethylamine N-oxide.

Figure 1

Metabolism, import, and export of cholesterol in polarized cell. The bulk of endogenous cholesterol is synthesized by the liver and starts from acetyl coenzyme A (acetyl-CoA) and concerted actions of more than 20 enzymes. Once cholesterol is formed, it is either esterified to cholesterol ester (CE) and stored in lipid droplets or secreted into the bloodstream as lipoproteins. Excess cholesterol can be excreted by ABC subfamily G member 5 and member 8 (ABCG5/8) transporters to the intestine or to the bile or packaged with lipoproteins for subsequent secretion into the blood.

Figure 2

The endogenous (white) and exogenous (gray) pathways of cholesterol transport. The exogenous pathway starts with the dietary cholesterol whereas the liver is the starting point of the endogenous pathway.

Figure 3

Reverse cholesterol transport pathways between intestine, liver and macrophage. RCT begins in the liver and the intestine with the synthesis of ApoA-1. ApoA-1 associates with phospholipids and free cholesterol through an interaction with ABCA1 located on various cell types (enterocytes, hepatocytes and macrophages). Gut microbiota modulates the RCT by increasing the level of ABCA1 and ABCG1 via the transformation of Cy-3-G into PCA. LDLR: LDL receptor; TG: Triglycerides; CETP: cholesteryl ester transfer protein; PLTP: phospholipid transfer protein; LCAT: lecithin-cholesterol acyltransferase; Cy-3-G: cyanidin-3-O-ß-glucoside; PCA: protocatechuic acid.

Figure 4

Enterohepatic recirculation of bile acids via reverse cholesterol transport. In the liver, cholesterol is metabolized to BAs by hepatic cytochromes, notably 90% of the time by the rate-limiting enzyme cholesterol 7 α-hydroxylase (CYP7A1). When BAs are conjugated, they are actively transported into bile via the bile salt export pump (BSEP) or via ABCG5/8. In the small intestine, certain gut microbes contain an enzyme known as bile salt hydrolase (BSH) capable of deconjugating (i.e., remove glycine or taurine conjugates) BAs preventing their reuptake by the ASBT transporter BAs: Bile acids; apical sodium-dependent bile acid transporter: ASBT; organic solute transporters: OST α/β; nuclear farnesoid X receptor: FXR; bile salt export pump: BSEP; Na+/taurochlorate cotransporting polypeptide: NTCP; fibroblast growth factor receptor 4 (FGFR4).

Figure 5

Mechanisms linking the pro-atherosclerotic activity of gut microbial metabolite TMAO and cholesterol transport and synthesis in the intestine, liver, and macrophage. The intestinal microbiota metabolizes choline, phosphatidylcholine, L-carnitine, and betaine to trimethylamine (TMA), which is oxidized into TMAO by hepatic flavin monooxygenases (FMO). Green arrows indicate an increase of expression or activation whereas red arrows indicate a reduction of the expression. Yellow arrows indicate that the results in the literature are controversial.

Figure 6

Mechanisms linking the anti-atherosclerotic activity of short-chain fatty acids (SCFAs) and cholesterol transport and synthesis in the intestine and liver. Dietary fibers could be fermented and transformed into short chain fatty acids (SCFA) by some species present in the gut. Green arrows indicate an increase of activity or expression whereas the red arrows indicate an inhibition or reduction of expression.

Figure 7

Hypocholesterolemic mechanisms of action of probiotics. It has been observed that some probiotics could reduce cholesterol and ultimately atherosclerosis. Some of the major strains used as probiotics are indicated. The mechanisms are still speculative and could be associated with an increase (green arrows) or a decrease (red arrows) of the expression or activities.