Figure 4.

Meta-organismal bile acid metabolism as a contributor to T2DM progression. 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). 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. Importantly, bile salts are left behind in the intestinal lumen where they ultimately traverse to the colon, where they are subsequent to 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. This re-absorptive process provides newly diversified bile acid species, which can 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). By both regulating intestinal lipid absorption and host receptor activation both primary and secondary bile acids can have profound effects on T2DM progression.