Intestinal transport and metabolism of bile acids

Abstract

In addition to their classical roles as detergents to aid in the process of digestion, bile acids have been identified as important signaling molecules that function through various nuclear and G protein-coupled receptors to regulate a myriad of cellular and molecular functions across both metabolic and nonmetabolic pathways. Signaling via these pathways will vary depending on the tissue and the concentration and chemical structure of the bile acid species. Important determinants of the size and composition of the bile acid pool are their efficient enterohepatic recirculation, their host and microbial metabolism, and the homeostatic feedback mechanisms connecting hepatocytes, enterocytes, and the luminal microbiota. This review focuses on the mammalian intestine, discussing the physiology of bile acid transport, the metabolism of bile acids in the gut, and new developments in our understanding of how intestinal metabolism, particularly by the gut microbiota, affects bile acid signaling.

Keywords: enterohepatic circulation; microbiome; nuclear receptors; transporters.

Fig. 1.

Schematic of intestinal transport and metabolism of bile acids. The taurine (T) and glycine (G) conjugated and sulfated (S) primary and secondary bile acids are secreted into bile, stored in the gallbladder, and empty into the small intestine in response to a meal. Bile acids encounter high concentrations of the gut microbiota in the distal ileum and colon and undergo a variety of bacterial transformations including deconjugation, dehydroxylation, and epimerization (black arrows). Passive uptake (dotted lines) occurs down the length of the small intestine for the protonated uncharged fraction of glycine conjugated bile acids and any unconjugated bile acids that are formed. OSTα-OSTβ may participate in the export of those bile acids across the enterocyte or colonocyte basolateral membrane. In the ileum, active uptake of conjugated bile acids across the apical brush border membrane is mediated by the ASBT. The bile acids interact in the cytosol with IBABP, and then are exported across the basolateral membrane by the OSTα-OSTβ. Unconjugated dihydroxy bile acids that are passively absorbed in the distal ileum and colon can be glucuronidated (U) by UGT and exported across the apical membrane by MRP2 or ABCG2 or across the basolateral membrane by MRP3. A fraction of the bile acids taken up in the distal small intestine may also be sulfated by the SULT2A1 and exported back across the apical brush border membrane by MRP2 or ABCG2 for elimination. The bile acids absorbed from the intestine are carried back in the portal circulation to the liver for uptake and may undergo repair by the hepatocyte. Repair includes essentially complete reconjugation with taurine or glycine, reepimerization of iso (β-hydroxy) bile acids to their α-hydroxy form, reduction of oxo groups to hydroxyl groups, and rehydroxylation at the C-7 position to generate the original primary bile acid (in mice but not humans). Adapted with permission from (238).

Fig. 2.

Scheme for intestinal phase 2 conjugation and bacterial metabolism of bile acids in humans and mice. A: Bacterial metabolism includes deconjugation, 7-dehydroxylation, oxidation, and epimerization of bile acids. B: The phase 2 conjugation reactions carried out by the gut epithelial cells include glucuronidation and sulfation (sulfonation). C: Structure and abbreviations for the bile acid species. Adapted from (53) using the nomenclature system of Hofmann et al. (239).