Bile Acids, Their Receptors, and the Gut Microbiota

Abstract

Bile acids (BAs) are a family of hydroxylated steroids secreted by the liver that aid in the breakdown and absorption of dietary fats. BAs also function as nutrient and inflammatory signaling molecules, acting through cognate receptors, to coordinate host metabolism. Commensal bacteria in the gastrointestinal tract are functional modifiers of the BA pool, affecting composition and abundance. Deconjugation of host BAs creates a molecular network that inextricably links gut microtia with their host. In this review we highlight the roles of BAs in mediating this mutualistic relationship with a focus on those events that impact host physiology and metabolism.

Keywords: BA receptors; FXR; bile acids; farnesoid X receptor; gut microbiota.

FIGURE 1.

Bile acid (BA) hydrophobicity is determined by the number and position of hydroxyl and sulfate groups to the sterol ring as well whether the BA is conjugated to an amino acid, which in mice is predominantly taurine and in humans is mostly glycine. Hydroxylation at carbons 3, 6, 7, and 12 on the sterol core of primary (highlighted gray) and secondary (white) BAs increases the BA hydrophobicity index (blue shaded arrow). Adapted from Heuman et al. (7).

FIGURE 2.

Bile acid (BA) biosynthesis and metabolism in the liver and intestine. The primary BAs, chenodeoxycholic acid (CDCA) and cholic acid (CA) are synthesized from cholesterol and other precursors via Cyp7a1 in the liver yielding the precursors 7α-hydroxycholesterol (7α -HCO) and (7,12-dihydroxycholesterol (7α,12α-diHCO), respectively, the latter generated via the 12α-hydroxylase activity of Cyp8b1. In mice, Cyp2c70 6-hydroxylates CDCA yielding α-muricholic acid (αMCA), which is further epimerized into βMCA and ursodeoxycholic acid (UDCA) via the same enzyme. CA and CDCA are primary BAs in humans while CA, CDCA, MCAs, and UDCA, are primary BAs in mice. After conjugation with glycine (G) or taurine (T) via hepatic BA amino transferase (BAAT), these BAs are secreted into bile which is then released into the intestines. Bacterial 7α-hydroxysteroid dehydrogenase (7α-HSDH) generates deoxycholic acid (DCA), and lithocholic acid (LCA) and 7β-hydroxysteroid dehydrogenase (7β-HSDH) render UDCA. Hepatic Cyp2a12 rehydroxylates DCA and LCA into CA and CDCA, respectively. In humans, CA, CDCA, and DCA are conjugated derivatives are predominant. In mice, CA, αMCA, and βMCA and conjugated derivates are predominant. Cyp2c70^-/- mice have increased CDCA and are void of MCAs. Cyp2a12^-/- mice have increased DCA, CDCA, and LCA. Cyp2c70^-/- and Cyp2a12^-/- [double knockout (DKO)] mice have increased DCA, CDCA, and LCA.