Title: Pleiotropic Roles of Bile Acids in Metabolism
Abstract: Enzymatic oxidation of cholesterol generates numerous distinct bile acids that function both as detergents that facilitate digestion and absorption of dietary lipids, and as hormones that activate four distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility and bacterial growth, inflammation, liver regeneration, and hepatocarcinogenesis. This review covers the roles of specific bile acids, synthetic agonists, and their cognate receptors in controlling these diverse functions, as well as their current use in treating human diseases. Enzymatic oxidation of cholesterol generates numerous distinct bile acids that function both as detergents that facilitate digestion and absorption of dietary lipids, and as hormones that activate four distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility and bacterial growth, inflammation, liver regeneration, and hepatocarcinogenesis. This review covers the roles of specific bile acids, synthetic agonists, and their cognate receptors in controlling these diverse functions, as well as their current use in treating human diseases. The first description of a bile acid was made in 1848 when cholic acid (CA) was discovered in ox gall. Subsequent studies in the early 1900s identified additional bile acids that included lithocholic acid (LCA), chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA), and muricholic acid (MCA) from ox, goose, bear, and rodents, respectively, as described by Wieland in his 1928 Nobel lecture (Wieland, 1966Wieland H.O. Nobel Prize Lecture (1928): the chemistry of the bile acids.in: Nobel Lectures, Chemistry 1922–1941. Elsevier Publishing Company, Amsterdam1966Google Scholar). More sophisticated methodologies subsequently led to the identification of multiple additional species of bile acids, including deoxycholic acid (DCA), that contribute to the “bile acid pool” (2–4 g in humans) (Figures 1A and 1B ). The relative concentrations of individual bile acids within the bile acid pool of different mammals can vary significantly (Figure 1B) and may affect bile acid-dependent signaling. Bile acids are known to play a number of roles in lipid metabolism. First, bile acids are essential for the formation of mixed micelles in the small intestine that facilitate solubilization, digestion, and absorption of dietary lipids and fat-soluble vitamins. Second, the micelles present in the gall bladder serve to solubilize cholesterol in bile, thus impairing cholesterol crystallization and gallstone formation. Third, bile salts induce bile flow from hepatocytes into the bile canaliculi and then gall bladder. Fourth, the hepatic conversion of cholesterol to bile acids and the subsequent excretion of bile acids in the feces represent the major route for cholesterol excretion that is important in whole-body sterol homeostasis. Bile is also thought to have a bacteriostatic function that maintains sterility in the biliary tree. Consistent with these roles, disruption of normal bile acid synthesis and metabolism is associated with cholestasis, gallstones, inflammation, malabsorption of lipids and fat-soluble vitamins, bacterial overgrowth in the small intestine, atherosclerosis, neurological diseases, and various inborn errors such as progressive familial intrahepatic cholestasis types I–III (PFIC I-III). The discovery that specific bile acids differentially activate three nuclear receptors, namely farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR) and one G protein-coupled receptor (TGR5), identified bile acids as hormones that alter multiple metabolic pathways in many tissues. The synthesis and use of specific agonists for FXR or TGR5 in rodents, together with preliminary clinical findings with FXR agonists, suggest that such agonists may prove useful in the treatment of a number of diseases. In this review, we emphasize the mechanisms that maintain bile acid homeostasis through the regulation of bile acid synthesis and transport, and the diverse roles that these bile acids have on the four bile acid-responsive receptors. We also briefly discuss the current clinical uses of bile acids and FXR agonists to treat human diseases. We cite only a small fraction of the appropriate references, as the literature on these topics is extraordinarily extensive. We refer those interested to many excellent related reviews on bile acids, FXR, or TGR5 (Angelin et al., 2012Angelin B. Larsson T.E. Rudling M. Circulating fibroblast growth factors as metabolic regulators—a critical appraisal.Cell Metab. 2012; 16: 693-705Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar; Chiang, 2009Chiang J.Y. Bile acids: regulation of synthesis.J. Lipid Res. 2009; 50: 1955-1966Crossref PubMed Scopus (153) Google Scholar; Keitel and Häussinger, 2012Keitel V. Häussinger D. Perspective: TGR5 (Gpbar-1) in liver physiology and disease.Clin. Res. Hepatol. Gastroenterol. 2012; 36: 412-419Crossref PubMed Scopus (13) Google Scholar; Lefebvre et al., 2009Lefebvre P. Cariou B. Lien F. Kuipers F. Staels B. Role of bile acids and bile acid receptors in metabolic regulation.Physiol. Rev. 2009; 89: 147-191Crossref PubMed Scopus (261) Google Scholar; Matsubara et al., 2013Matsubara T. Li F. Gonzalez F.J. FXR signaling in the enterohepatic system.Mol. Cell. Endocrinol. 2013; 368: 17-29Crossref PubMed Scopus (4) Google Scholar; Pols et al., 2011bPols T.W. Noriega L.G. Nomura M. Auwerx J. Schoonjans K. The bile acid membrane receptor TGR5: a valuable metabolic target.Dig. Dis. 2011; 29: 37-44Crossref PubMed Scopus (8) Google Scholar; Porez et al., 2012Porez G. Prawitt J. Gross B. Staels B. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease.J. Lipid Res. 2012; 53: 1723-1737Crossref PubMed Scopus (19) Google Scholar; Russell, 2003Russell D.W. The enzymes, regulation, and genetics of bile acid synthesis.Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (459) Google Scholar, Russell, 2009Russell D.W. Fifty years of advances in bile acid synthesis and metabolism.J. Lipid Res. 2009; 50: S120-S125PubMed Google Scholar; Thomas et al., 2008Thomas C. Pellicciari R. Pruzanski M. Auwerx J. Schoonjans K. Targeting bile-acid signalling for metabolic diseases.Nat. Rev. Drug Discov. 2008; 7: 678-693Crossref PubMed Scopus (215) Google Scholar). Bile acids are soluble products derived from the catabolism of highly insoluble cholesterol (Figure 1A and Figure 2A). In general, bile acids are composed of four steroid rings forming a hydrocarbon lattice with a convex hydrophobic face and a concave hydrophilic face containing hydroxyl groups, and a short five carbon acidic side chain that is subsequently amidated with taurine or glycine (Figure 1A). This amphipathic structure gives bile acids the detergent properties that allow for micelle formation and facilitates the digestion and absorption of dietary lipids and fat-soluble vitamins A, D, E, and K from the small intestine. The presence or absence of hydroxyl groups in the α or β orientation at positions 3, 6, 7, and 12 on the steroid backbone (Figure 1A) affects both their solubility and their hydrophobicity (rank order from hydrophobic to hydrophilic: LCA > DCA > CDCA > CA > UDCA > MCA). These small structural differences also have significant effects in the specificity of activation of the four bile acid-responsive receptors (Table 1). Surprisingly, a recent study demonstrated that β-muricholic acid, a major bile acid in rodents, functions as an antagonist of FXR (Sayin et al., 2013Sayin S.I. Wahlström A. Felin J. Jäntti S. Marschall H.U. Bamberg K. Angelin B. Hyötyläinen T. Orešič M. Bäckhed F. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.Cell Metab. 2013; 17: 225-235Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar).Table 1Functions and Sites of Action of Bile AcidsFunctionSite of ActionMicelles prevent cholesterol crystallizationGall bladder and bile ductMicelles facilitate lipid digestion by pancreatic enzymesIntestinal lumenMicelles facilitate vitamin A, D, E, and K absorptionIntestinal lumenImpair bacterial overgrowthIntestinal lumenMaintain intestinal barrier to infectionIntestineFXR activation: CDCA > DCA > LCA ≫ CALiver, ileum, kidney, adrenal glandTGR5 activation: LCA > DCA > CDCA > CA (taurine conjugation reduces EC50)Gall bladder, intestinal neuroendocrine cells, enteric neurons, brown adipose tissue, macrophages, brainPXR activation: LCA∼3-keto-LCAIntestine, liverVDR activation: LCA∼3-keto-LCAIleal enterocytesSummary of known functions and sites of action of bile acids present in the rodent and human bile acid pool. Open table in a new tab Summary of known functions and sites of action of bile acids present in the rodent and human bile acid pool. At least 17 enzymes are involved in the modification of the cholesterol steroid ring, cleavage of the side chain, and subsequent conjugation with glycine or taurine to form primary bile salts (Figure 2A) (Russell, 2003Russell D.W. The enzymes, regulation, and genetics of bile acid synthesis.Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (459) Google Scholar, Russell, 2009Russell D.W. Fifty years of advances in bile acid synthesis and metabolism.J. Lipid Res. 2009; 50: S120-S125PubMed Google Scholar). The finding that patients with inborn errors of nine of these genes exhibit various diseases, including neonatal cholestasis, neurological defects, and malabsorption of fat and fat-soluble vitamins, emphasizes the critical requirement for cholesterol catabolism to bile acids (Heubi et al., 2007Heubi J.E. Setchell K.D. Bove K.E. Inborn errors of bile acid metabolism.Semin. Liver Dis. 2007; 27: 282-294Crossref PubMed Scopus (36) Google Scholar). The classic or neutral bile acid pathway is regulated by cholesterol 7α-hydroxylase (CYP7A1), a cytochrome P450 enzyme that converts cholesterol to 7α-hydroxycholesterol (Figure 2A, inset). The latter intermediate is either converted to CDCA or is converted to CA by a pathway that depends on 12-hydroxylation of the steroid ring by CYP8B1 (Figure 2A). Deletion of Cyp7a1 in mice suggested that this pathway contributes ∼75% of total bile acid synthesis (Schwarz et al., 1996Schwarz M. Lund E.G. Setchell K.D. Kayden H.J. Zerwekh J.E. Björkhem I. Herz J. Russell D.W. Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase.J. Biol. Chem. 1996; 271: 18024-18031Crossref PubMed Scopus (166) Google Scholar). The alternative, or acidic, pathway generates CDCA and accounts for ∼9% and 25% of the total bile acid synthesis in humans and mice, respectively (Duane and Javitt, 1999Duane W.C. Javitt N.B. 27-hydroxycholesterol: production rates in normal human subjects.J. Lipid Res. 1999; 40: 1194-1199Abstract Full Text Full Text PDF PubMed Google Scholar; Schwarz et al., 2001Schwarz M. Russell D.W. Dietschy J.M. Turley S.D. Alternate pathways of bile acid synthesis in the cholesterol 7alpha-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding.J. Lipid Res. 2001; 42: 1594-1603Abstract Full Text Full Text PDF PubMed Google Scholar) (Figure 2A, inset). Although initially identified in humans (Anderson et al., 1972Anderson K.E. Kok E. Javitt N.B. Bile acid synthesis in man: metabolism of 7 -hydroxycholesterol- 14 C and 26-hydroxycholesterol- 3 H.J. Clin. Invest. 1972; 51: 112-117Crossref PubMed Google Scholar), Russell and colleagues characterized the alternative pathway when they discovered that Cyp7a1–/– mice had high postnatal lethality, but the few surviving mice actually synthesized bile acids (Ishibashi et al., 1996Ishibashi S. Schwarz M. Frykman P.K. Herz J. Russell D.W. Disruption of cholesterol 7alpha-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation.J. Biol. Chem. 1996; 271: 18017-18023Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar; Russell, 2009Russell D.W. Fifty years of advances in bile acid synthesis and metabolism.J. Lipid Res. 2009; 50: S120-S125PubMed Google Scholar). Subsequent studies demonstrated that this latter pathway was dependent upon oxidation of the cholesterol side chain at C27 by CYP27A1, prior to hydroxylation of the steroid ring by oxysterol 7α-hydroxylase (CYP7B1) (Figure 2A, inset). C25- and C24-(S)-hydroxycholesterols can also enter the alternative pathway to generate bile acids (Schwarz et al., 1996Schwarz M. Lund E.G. Setchell K.D. Kayden H.J. Zerwekh J.E. Björkhem I. Herz J. Russell D.W. Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase.J. Biol. Chem. 1996; 271: 18024-18031Crossref PubMed Scopus (166) Google Scholar). Most of the oxysterols that feed into the alternative bile acid synthetic pathway are derived from the liver or macrophages (Russell, 2003Russell D.W. The enzymes, regulation, and genetics of bile acid synthesis.Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (459) Google Scholar). However, the brain and lung also contribute oxysterols to the alternative pathway as they synthesize 24-, 25-, or 27-hydroxycholesterols that are subsequently transported to the liver for metabolism by the alternative bile acid pathway (Björkhem et al., 2010Björkhem I. Leoni V. Meaney S. Genetic connections between neurological disorders and cholesterol metabolism.J. Lipid Res. 2010; 51: 2489-2503Crossref PubMed Scopus (21) Google Scholar). Prior to secretion, bile acids are conjugated with taurine or glycine (Figure 2A), a process that lowers their pKa and increases their solubility, thereby facilitating micelle formation in the acidic environment of the duodenum. However, unlike nonconjugated bile acids that can diffuse across membranes, bile salts require a transmembrane transporter to move them across membranes. The secretion of bile salts from hepatocytes into the canaliculi requires the bile salt export protein (BSEP; ABCB11), while transport of phospholipids requires ABCB4 (also known as MDR3 in humans or MDR2 in mice) (Figure 2A). Although cholesterol efflux into bile requires ABCG5/ABCG8, there is an additional requirement for ABCB4, consistent with phospholipids in the bile canaliculi functioning as a sink to accept cholesterol that has been flipped across the apical membrane by ABCG5/ABCG8 (Figure 2A) (Graf et al., 2003Graf G.A. Yu L. Li W.P. Gerard R.D. Tuma P.L. Cohen J.C. Hobbs H.H. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion.J. Biol. Chem. 2003; 278: 48275-48282Crossref PubMed Scopus (195) Google Scholar; Nicolaou et al., 2012Nicolaou M. Andress E.J. Zolnerciks J.K. Dixon P.H. Williamson C. Linton K.J. Canalicular ABC transporters and liver disease.J. Pathol. 2012; 226: 300-315Crossref PubMed Scopus (12) Google Scholar; Wang et al., 2009aWang D.Q. Cohen D.E. Carey M.C. Biliary lipids and cholesterol gallstone disease.J. Lipid Res. 2009; 50: S406-S411PubMed Google Scholar). The importance of these transporters can be seen in patients or mice that have inactivating mutations or gene deletions leading to loss of function. For example, loss of BSEP results in progressive familial intrahepatic cholestasis, a disease wherein bile salts accumulate in the liver to toxic levels (Nicolaou et al., 2012Nicolaou M. Andress E.J. Zolnerciks J.K. Dixon P.H. Williamson C. Linton K.J. Canalicular ABC transporters and liver disease.J. Pathol. 2012; 226: 300-315Crossref PubMed Scopus (12) Google Scholar). The bile salts together with phospholipids and cholesterol are passed into the gall bladder, where they are concentrated to form bile, which is composed of 85% water. The remaining solute is a complex mixture of bile salts (67%), phospholipids (22%), and cholesterol (4%), together with electrolytes, minerals, and minor levels of proteins, plus bilirubin and biliverdin pigments, which give it a yellow-green or even orange hue (Dawson, 2010Dawson P.A. Bile secretion and the enterohepatic circulation.in: Feldman M. Friedman L.S. Brandt L.J. Sleisenger M.H. Gastrointestinal and Liver Disease. Vol. 1. Saunders Elsevier, Philadelphia2010: 1075-1088Google Scholar). Small amounts of mucus and secretory IgA (sIgA) may contribute to the bacteriostatic functions of bile (Sung et al., 1992Sung J.Y. Costerton J.W. Shaffer E.A. Defense system in the biliary tract against bacterial infection.Dig. Dis. Sci. 1992; 37: 689-696Crossref PubMed Google Scholar). Bile salts and phospholipid micelles play a key role in solubilizing cholesterol in bile, thus preventing cholesterol crystallization and the formation of cholesterol gallstones (Wang et al., 2009aWang D.Q. Cohen D.E. Carey M.C. Biliary lipids and cholesterol gallstone disease.J. Lipid Res. 2009; 50: S406-S411PubMed Google Scholar). The presence of dietary fat in the duodenum causes the secretion of cholecystokinin (CCK) from the intestinal mucosa into the circulation, which in turn promotes contraction of smooth muscle cells of the gall bladder and relaxation of the sphincter of Oddi, thus allowing bile to enter the duodenum (Chandra and Liddle, 2007Chandra R. Liddle R.A. Cholecystokinin.Curr. Opin. Endocrinol. Diabetes Obes. 2007; 14: 63-67Crossref PubMed Scopus (50) Google Scholar). In the lumen the bile salt-containing mixed micelles facilitate absorption of the fat-soluble vitamins A, D, and E and the metabolism of dietary lipids by pancreatic enzymes, prior to their absorption. The gall bladder itself is not essential, since rats, which lack a gall bladder, and patients who have undergone cholecystectomy (removal of the gall bladder) are still able to absorb lipids from the diet as a result of direct secretion of bile into the duodenum. Following secretion of bile salts into the duodenum, most (∼95%) are reabsorbed in the distal ileum via the apical sodium-dependent transporter (ASBT) present on the enterocyte brush border (Figure 2B). Intestinal bile acid-binding protein (IBABP/fatty acid-binding protein subclass 6/FABP6) may facilitate transport of bile salts across the enterocyte to the basolateral membrane where they are effluxed into the blood by the heterodimeric transporter OSTα/OSTβ (Figure 2B) (Chiang, 2009Chiang J.Y. Bile acids: regulation of synthesis.J. Lipid Res. 2009; 50: 1955-1966Crossref PubMed Scopus (153) Google Scholar; Dawson et al., 2010Dawson P.A. Hubbert M.L. Rao A. Getting the mOST from OST: role of organic solute transporter, OSTalpha-OSTbeta, in bile acid and steroid metabolism.Biochim. Biophys. Acta. 2010; 1801: 994-1004Crossref PubMed Scopus (12) Google Scholar). However, a small percentage of the bile salts escape resorption and are deconjugated by bacterial flora before either being absorbed or converted into secondary bile acids (Figure 1A). Secondary bile acids may be absorbed by passive processes or excreted in the feces. The absorbed primary and secondary bile acids and salts are transported back to the liver where most, but not all, are actively transported into hepatocytes by sodium (Na+)-taurocholate cotransporting polypeptide (NTCP/SLC10A1) and organic anion transporters (OATPs; e.g., OAT1B2) that mediate the uptake of bile salts and bile acids, respectively (Figure 2A) (Chiang, 2009Chiang J.Y. Bile acids: regulation of synthesis.J. Lipid Res. 2009; 50: 1955-1966Crossref PubMed Scopus (153) Google Scholar; Thomas et al., 2008Thomas C. Pellicciari R. Pruzanski M. Auwerx J. Schoonjans K. Targeting bile-acid signalling for metabolic diseases.Nat. Rev. Drug Discov. 2008; 7: 678-693Crossref PubMed Scopus (215) Google Scholar). In the liver, bile acids are reconjugated and then resecreted together with newly synthesized bile salts to complete one cycle of the enterohepatic circulation. One exception is the secondary bile acid LCA that is present at low levels and is hepatotoxic at elevated concentrations. The small amount of LCA that is returned to the liver is sulfated prior to secretion into bile and excreted in the feces (Wang et al., 2009aWang D.Q. Cohen D.E. Carey M.C. Biliary lipids and cholesterol gallstone disease.J. Lipid Res. 2009; 50: S406-S411PubMed Google Scholar). In humans, the bile acid pool contains ∼2–4 g of bile acids. Recycling of bile acids/salts between the liver and intestine occurs six to ten times each day and transports 20–40 g bile acids. However, ∼0.2–0.6 g of bile acids are excreted in the feces each day, an amount that must be replenished by de novo synthesis from cholesterol (Dawson, 2010Dawson P.A. Bile secretion and the enterohepatic circulation.in: Feldman M. Friedman L.S. Brandt L.J. Sleisenger M.H. Gastrointestinal and Liver Disease. Vol. 1. Saunders Elsevier, Philadelphia2010: 1075-1088Google Scholar). It is notable that the hepatic recovery of bile acids from the portal vein (bile acid concentration 10–80 μM) is incomplete (Angelin et al., 1982Angelin B. Björkhem I. Einarsson K. Ewerth S. Hepatic uptake of bile acids in man. Fasting and postprandial concentrations of individual bile acids in portal venous and systemic blood serum.J. Clin. Invest. 1982; 70: 724-731Crossref PubMed Google Scholar), thus accounting for the presence of low levels of bile acids (∼2–10 μM) in the peripheral circulation of humans and mice (Angelin et al., 1982Angelin B. Björkhem I. Einarsson K. Ewerth S. Hepatic uptake of bile acids in man. Fasting and postprandial concentrations of individual bile acids in portal venous and systemic blood serum.J. Clin. Invest. 1982; 70: 724-731Crossref PubMed Google Scholar; Zhang et al., 2011bZhang Y.K. Guo G.L. Klaassen C.D. Diurnal variations of mouse plasma and hepatic bile acid concentrations as well as expression of biosynthetic enzymes and transporters.PLoS ONE. 2011; 6: e16683https://doi.org/10.1371/journal.pone.0016683Crossref PubMed Scopus (11) Google Scholar). As might be expected, the concentrations of individual bile acids in the portal vein and systemic blood vary with food consumption, as resorption of bile acids is greatest in the postprandial period (Angelin et al., 1982Angelin B. Björkhem I. Einarsson K. Ewerth S. Hepatic uptake of bile acids in man. Fasting and postprandial concentrations of individual bile acids in portal venous and systemic blood serum.J. Clin. Invest. 1982; 70: 724-731Crossref PubMed Google Scholar). The relatively high concentrations of bile acids in the tissues involved in the enterohepatic circulation (liver, bile ducts, gall bladder, and intestine) is sufficient to activate receptors present in these tissues (Table 1; see below). However, since the total concentration of bile acids in the peripheral circulation is low under normal physiological conditions, additional studies are necessary to determine the importance of specific bile acids in activating TGR5 and FXR in peripheral tissues. Intestinal microbial organisms play an important role in bile acid metabolism, as they readily deconjugate and 7α-dehydroxylate primary bile salts that escape reabsorption in the distal ileum and convert them to secondary bile acids (LCA, DCA, UDCA, and, in rodents, ω-MCA) (Figure 1A) (Ridlon et al., 2006Ridlon J.M. Kang D.J. Hylemon P.B. Bile salt biotransformations by human intestinal bacteria.J. Lipid Res. 2006; 47: 241-259Crossref PubMed Scopus (214) Google Scholar). However, these secondary bile acids synthesized by the microbiome comprise only a small percent of the normal bile acid pool (Figure 1B). Recent studies have shown that the microbiome affects not only the composition of the bile acid pool but also the expression of genes controlled by the bile acid-activated receptor FXR (Swann et al., 2011Swann J.R. Want E.J. Geier F.M. Spagou K. Wilson I.D. Sidaway J.E. Nicholson J.K. Holmes E. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments.Proc. Natl. Acad. Sci. USA. 2011; 108: 4523-4530Crossref PubMed Scopus (52) Google Scholar). As compared to rats with normal flora, germ-free rats were shown to have reduced levels of bile acids in various tissues, an almost total loss of unconjugated and glycine- conjugated bile acids, a significant increase in taurine-conjugated bile salts, and changes in the hepatic expression of genes regulated by the bile acid-responsive nuclear receptor FXR (Swann et al., 2011Swann J.R. Want E.J. Geier F.M. Spagou K. Wilson I.D. Sidaway J.E. Nicholson J.K. Holmes E. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments.Proc. Natl. Acad. Sci. USA. 2011; 108: 4523-4530Crossref PubMed Scopus (52) Google Scholar). More modest changes were observed following treatment of rats with antibiotics that partially reduce the microbiome (Swann et al., 2011Swann J.R. Want E.J. Geier F.M. Spagou K. Wilson I.D. Sidaway J.E. Nicholson J.K. Holmes E. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments.Proc. Natl. Acad. Sci. USA. 2011; 108: 4523-4530Crossref PubMed Scopus (52) Google Scholar). In contrast, bile acid levels were significantly increased in the livers of germ-free C57BL/6 mice (Selwyn and Klaassen, 2012Selwyn F. Klaassen C.D. Characterization of bile acid homeostasis in germ-free mice.FASEB J. 2012; 26 (1155.1)Google Scholar). Although the reasons for these differences between germ-free rats and mice remain to be elucidated, both studies suggest that the microbiome is an important modulator of bile acid metabolism and function. Dietary components can also affect the microbiome, the bile acid pool, and intestinal inflammation. For example, administration of saturated milk-derived fatty acids to mice specifically increased taurocholate levels that provided a selective advantage in growth of Bilophilia wadsworthia, a sulphite-reducing pathobiont (Devkota et al., 2012Devkota S. Wang Y. Musch M.W. Leone V. Fehlner-Peach H. Nadimpalli A. Antonopoulos D.A. Jabri B. Chang E.B. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice.Nature. 2012; 487: 104-108PubMed Google Scholar). Consistent with this proposal, oral administration of taurocholate, but not glycocholate, increased the growth of B wadsworthia and increased inflammation and colitis in genetically susceptible mice (Devkota et al., 2012Devkota S. Wang Y. Musch M.W. Leone V. Fehlner-Peach H. Nadimpalli A. Antonopoulos D.A. Jabri B. Chang E.B. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice.Nature. 2012; 487: 104-108PubMed Google Scholar). Additional studies will be required to determine whether these latter findings in rodents are applicable to humans. The identification of the nuclear receptor farnesoid X receptor (FXRα, NR1H4, hereafter called FXR) (Forman et al., 1995Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. et al.Identification of a nuclear receptor that is activated by farnesol metabolites.Cell. 1995; 81: 687-693Abstract Full Text PDF PubMed Google Scholar; Seol et al., 1995Seol W. Choi H.S. Moore D.D. Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors.Mol. Endocrinol. 1995; 9: 72-85Crossref PubMed Google Scholar) and the subsequent demonstration that bile acids were the endogenous ligands for FXR (Makishima et al., 1999Makishima M. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. Hull M.V. Lustig K.D. Mangelsdorf D.J. Shan B. Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Crossref PubMed Scopus (1080) Google Scholar; Parks et al., 1999Parks D.J. Blanchard S.G. Bledsoe R.K. Chandra G. Consler T.G. Kliewer S.A. Stimmel J.B. Willson T.M. Zavacki A.M. Moore D.D. Lehmann J.M. Bile acids: natural ligands for an orphan nuclear receptor.Science. 1999; 284: 1365-1368Crossref PubMed Scopus (948) Google Scholar; Wang et al., 1999Wang H. Chen J. Hollister K. Sowers L.C. Forman B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.Mol. Cell. 1999; 3: 543-553Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar) were critical to our understanding of the molecular mechanisms that control bile acid metabolism. The rank order of potency of bile acids as FXR agonists is shown in Table 1. However, the synthesis of numerous FXR-specific agonists, including GW4064, 6α-ethyl-chenodeoxycholic acid (6-ECDCA; INT-747; obeticholic acid), fexaramine, and GSK2324 (Porez et al., 2012Porez G. Prawitt J. Gross B. Staels B. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease.J. Lipid Res. 2012; 53: 1723-1737Crossref PubMed Scopus (19) Google Scholar), has proven particularly important in overcoming the broader effects of bile acids on metabolism. FXR is one of 48 members of the human nuclear receptor superfamily of transcription factors. Rodents express one additional member, FXRβ (NR1H5), which is activated by lanosterol but insensitive to bile acids (Sonoda et al., 2008Sonoda J. Pei L. Evans R.M. Nuclear receptors: decoding metabolic disease.FEBS Lett. 2008; 582: 2-9Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). In contrast, human FXRβ is a pseudogene. FXR, like many of the nuclear receptors, contains a DNA binding domain (DBD), a ligand binding domain (LBD), and additional activation domains (Calkin and Tontonoz, 2012Calkin A.C. Tontonoz P. Transcrip