Figure 3. Microbial production of secondary bile acids in CVD.

Initially, primary bile acids are synthesized in the host liver from cholesterol. De novo synthesized primary bile acids such as cholic acid, chenodeoxycholic acid (CDCA) and muricholic acid (MCA; only produced in rodents) are then conjugated with either glycine (humans) or taurine (humans and mice) at the C-24 carboxyl position. Following conjugation, resulting bile salts are secreted into bile along with cholesterol and phospholipids to form mixed micelles, which are transiently stored in the gall bladder. When a meal is ingested, the gall bladder contracts to release mixed micelles into the proximal intestine where they function as essential emulsifiers to enable proper absorption of hydrophobic molecules such as fatty acids and fat-soluble vitamins (such as vitamin A, vitamin D, vitamin E and vitamin K) (not shown). Importantly, bile salts are left behind in the intestinal lumen where they ultimately traverse to the colon. Once in the colonic microenvironment, they participate in a bi-directional interplay regulating microbial community structure, and they are subsequent microorganism-driven metabolism of primary bile salts into secondary bile acids (deoxycholic acid and lithocholic acid), which can have an impact on host physiology and disease susceptibility. Importantly, after aiding in intestinal lipid absorption both primary bile salts and secondary bacterial metabolites are almost quantitatively re-absorbed (>95% recovered) in the ileum via dedicated host transporters in ileal enterocytes (not shown). This reabsorptive process provides newly diversified bile acid species, which can then signal to the host through dedicated receptor systems, including farnesoid X receptor (FXR), protein-coupled bile acid receptor 1 (TGR5), pregnane X receptor (PXR), vitamin D receptor (VDR), muscarinic receptors 2 and 3 (M2/M3), and sphingosine-1-phosphate receptor 2 (S1PR2).