Microbial impact on cholesterol and bile acid metabolism: current status and future prospects

Abstract

Recently, the gut microbiota has emerged as a crucial factor that influences cholesterol metabolism. Ever since, significant interest has been shown in investigating these host-microbiome interactions to uncover microbiome-mediated functions on cholesterol and bile acid (BA) metabolism. Indeed, changes in gut microbiota composition and, hence, its derived metabolites have been previously reported to subsequently impact the metabolic processes and have been linked to several diseases. In this context, associations between a disrupted gut microbiome, impaired BA metabolism, and cholesterol dysregulation have been highlighted. Extensive advances in metagenomic and metabolomic studies in this field have allowed us to further our understanding of the role of intestinal bacteria in metabolic health and disease. However, only a few have provided mechanistic insights into their impact on cholesterol metabolism. Identifying the myriad functions and interactions of these bacteria to maintain cholesterol homeostasis remain an important challenge in such a field of research. In this review, we discuss the impact of gut microbiota on cholesterol metabolism, its association with disease settings, and the potential of modulating gut microbiota as a promising therapeutic target to lower hypercholesterolemia.

Keywords: cholesterol metabolism; gut microbiota; hypercholesterolemia; metabolic diseases.

Fig. 1.

Cholesterol origins and metabolism. Dietary cholesterol or “exogenous” cholesterol accounts for approximately one-third of pool body cholesterol, the remaining 70% is synthesized exclusively in the liver through a series of multiple biochemical steps. Cholesterol is first converted into BAs, which are absorbed by the apical sodium-dependent BA transporter (ASBT) into enterocytes and secreted into the portal circulation via the basolateral BA transporter, organic solute transporter subunit α (OSTα). In the liver, cholesterol is converted into lipoproteins. Hepatic cholesterol enters the circulation as VLDLs, which are further metabolized to LDLs. LDL supplies cholesterol to peripheral tissues for metabolic purposes. HDL, on the other hand, transports cholesterol back to the liver either directly by interacting with hepatic SR-B1 or indirectly by trans­ferring the cholesterol to VLDL or LDL.

Fig. 2.

A: Bacterial conversion of cholesterol into coprostanol. Two major pathways are proposed for the conversion of cholesterol to coprostanol. The first pathway involves direct reduction of the 5,6-double bond. The second pathway starts with the oxidation of the 3β-hydroxy group and isomerization of the double bond to yield 4-cholesten-3-one, which undergoes two reductions to form coprostanone and then coprostanol. The main bacterial taxa carrying such a reaction involve Eubacterium and Bacteroides. However, bacterial enzymes are still unknown. B: Bacterial BA modifications in the host GIT. In the intestine, microbial enzymes from gut bacteria metabolize primary BAs into secondary BAs. Glyco-conjugated and tauro-conjugated CA and CDCA are first deconjugated via BSHs, epimerized, and then 7α-dehydroxylated to form secondary BAs (DCA and LCA). The main bacterial genera involved in BA metabolism include Bacteroides, Clostridium, Bifidobacterium, Lactobacillus, and Listeria in BA deconjugation; Bacteroides, Clostridium, Eubacterium, and Peptostreptococcus in the oxidation and epimerization of hydroxyl groups at C3, C7 and C12; Clostridium and Eubacterium in 7-dehydroxylation; and Clostridium and Fusobacterium in desulfation. GCA, glycocholic acid; TCA, taurocholic acid; GCDCA, glycochenodeoxycholic acid; TCDCA, taurochenodeoxycholic acid.