The Role of Bile Acids in Functional GI Disorders

Neurogastroenterology & Motility Neurogastroenterol Motil (2014) 26, 1057–1069 doi: 10.1111/nmo.12370 REVIEW ARTICLE The role of bile acids in functional GI disorders RICHARD N. APPLEBY & JULIAN R. F. WALTERS Section of Hepatology and Gastroenterology, Imperial College London, Imperial College Healthcare, Hammersmith Hospital, London, UK Key Messages • Bile acids are metabolically active substances that have a variety of effects. • New understanding of bile acid regulation has led to novel therapies that have potential in functional gastrointestinal disorders. • 30% of patients with diarrhea predominant or alternating IBS may have bile acid diarrhea. • Identification of these patients so that they may benefit from treatment will require new diagnostic tests and greater clinical awareness. Abstract particular emphasis on recent trial data for emerging Background Bile acids are increasingly implicated in therapies such as Elobixibat and Obeticholic acid and the pathogenesis of functional GI disorders. New novel diagnostic tests for bile acid diarrhea such as mechanisms have recently been described in the 7a-Hydroxy-4-cholesten-3-one (C4) and FGF19. Finally irritable bowel syndrome, chronic diarrhea and we will discuss future directions for research in this chronic idiopathic constipation. Identification of bile rapidly evolving field, such as bacterial bile acid acid signaling through farnesoid X receptor (FXR), modification and identification of genetic anomalies transmembrane G-coupled receptor 5 (TGR5) and associated with functional disorders. fibroblast growth factor 19 (FGF19) has led to the Keywords bile acid diarrhea, bile acid malabsorption, development of new, directly acting therapeutic bile salts, chronic functional constipation, elobixibat, agents. Despite these advances primary bile acid enterohepatic circulation, ileum, obeticholic acid. diarrhea remains under-recognized partly because of the lack of a widely available diagnostic test. Purpose In this review we will summarize the effects of bile acids on bowel function throughout the gastrointesti- INTRODUCTION nal tract and their roles in the pathogenesis of Functional gastrointestinal disorders (FGID) are com- functional diseases. We will review established diag- mon and constitute a significant proportion of consul- nostic tests and therapies for functional heartburn, tations in both primary and secondary care.1 The most dyspepsia and bile acid diarrhea. There will be a prevalent FGIDs are the irritable bowel syndrome (IBS) and functional dyspepsia, with a prevalence of around Address for Correspondence 20% each, regardless of the nationality of the popula- Prof. Julian Walters, Department of Gastroenterology, tion.2,3 A recent study using Rome III criteria found Imperial College London, Hammersmith Campus, Du Cane that 42% of attendees in the gastroenterology outpa- Road, London W12 0HS, UK. tient clinic met the criteria for a functional lower GI Tel: +44-203-313-2361; fax: +44-208-383-3976; 4 e-mail: [email protected] diagnosis. Of these patients, 24.5% met the criteria for Received: 10 March 2014 IBS-diarrhea (IBS-D), 6.1% functional diarrhea (FD), Accepted for publication: 28 April 2014 22.1% IBS-constipation, and 22.1% chronic idiopathic © 2014 John Wiley & Sons Ltd 1057 R. N. Appleby and J. R. F. Walters Neurogastroenterology and Motility constipation. Over the last decade, understanding of affinities for different BAs, with CDCA being the the pathogenesis of these conditions has advanced and strongest. Less abundant BAs such as LCA show much a clear relationship between bile acids (BAs) and these lower potency as FXR agonists.13,14 SHP transcription FGIDs have become apparent. This has led to the occurs as a result of FXR stimulation in hepatocytes development of novel therapeutic agents that are and inhibits CYP7A1 along with liver receptor homo- undergoing further study before entering clinical log in order to reduce BA synthesis, but a second practice. pathway of negative feedback was suspected after it was found that removing elements of the SHP pathway did abolish the ability of BAs to self-regulate.5 In 2005, BILE ACID SYNTHESIS AND METABOLISM it was shown that FGF15 (the mouse orthologue of Bile acids are formed from cholesterol within hepato- FGF19) was up-regulated by FXR stimulation in the cytes. These pathways involve 17 enzymes, of which small intestine and inhibited CYP7A1 through FGF the rate-limiting step is the 7a-hydroxylation of sterol receptor 4 (FGFR4) in the hepatocyte.15 This mecha- precursors by the enzyme cholesterol 7a-hydroxylase nism has now been well described in humans, showing (CYP7A1). The BAs are then conjugated with glycine or that BA production is regulated by a negative feedback taurine. This classical pathway creates 95% of BAs.5 mechanism involving FGF19.16 Action of FGF15/19 on The conjugated BAs are secreted by the hepatocytes FGFR4 is further modulated by Klothob (KLB).17 into the biliary tract by the bile salt export protein and can be stored in the gall bladder.6 When food enters the BILE ACID SIGNALING duodenum, cholecystokinin is released, stimulating gall bladder contraction and secretion of bile into the Bile acids all share a sterol-ring structure, so it is small bowel. When conjugated BAs reach the terminal perhaps not surprising that they act via nuclear ileum, over 90% are absorbed and returned to the liver hormonal receptors to exert metabolic effects (Fig. 1). via the portal circulation.7 Uptake of BAs at the apical FXR was described in 1995 but was not recognized to surface of the ileal mucosa is by active transport. This be a BA receptor until 1999.18,19 FXR expression is is performed by the apical sodium linked BA highest in the intestine and liver of human adults and transporter (ASBT, also known as the ileal bile acid has a wide range of metabolic effects in the liver transporter, IBAT). BAs are then bound to the ileal bile including decreasing lipogenesis and gluconeogene- acid binding protein (IBABP) within the cytoplasm and sis.20 FXR stimulation reduces liver inflammation transported out of the cell by the heterodimer organic and fibrosis and has regenerative effects.21 FXR null solute transporter a and b (OSTa and OSTb).8 Approx- mice have increased bacterial translocation across the imately 600 mg of BA is produced daily, with the small bowel epithelium, an effect that is also seen with entire BA pool cycling six to seven times per day.9 The a bile duct ligation.15 FXR has complex interactions liver in humans synthesizes two primary BAs: cheno- with other nuclear BA receptors. Pregnane X receptor deoxycholic acid (CDCA) and cholic acid (CA), but (PXR) and constitutive androstane receptor have sim- these can be dehydroxylated by intestinal bacteria to ilar effects within the liver to FXR but PXR also has the secondary BAs, lithocholic acid (LCA) or deoxy- anti-inflammatory effects on the bowel and can be cholic acid (DCA). All four of these BAs can be stimulated by vitamin A to induce FGF15.22 Vitamin D absorbed as conjugated salts in the ileum; unconjugat- receptor is another nuclear receptor which can induce ed BA salts are absorbed more widely, usually by FGF15.23 passive diffusion throughout the small bowel. They are Farnesoid X receptor agonists have direct antisecre- then conjugated and re-excreted by the liver.10 In the tory effects in the colon. A recent study in T84, colon, the BAs undergo further bacterial modification a human colonic cell line, showed that ClÀ conduc- changing the BA structure through oxidization or tance across the cell membrane was reduced by modification of their side-chains.11 GW4064, a synthetic, non-BA based FXR agonist.24 The BA pool is maintained within limits by control This was attributed to a 33% decrease in cystic fibrosis of BA synthesis by positive and negative feedback transmembrane conductance regulator (CFTR) expres- mechanisms. Central to the control of BA synthesis is sion. In the same study, an antidiarrheal effect was the Farnesoid X receptor (FXR), which binds BAs and noted in two mouse models of experimental colitis. activates expression of genes involved in BA metabo- GW4064 has a similar potency for FXR as CDCA.25 Its lism.12 These include the genes encoding IBABP, development into a therapeutic agent has been ham- OSTa, and OSTb, fibroblast growth factor 19 (FGF19) pered by poor bioavailability and partial agonist activ- and short heterodimer partner (SHP). FXR has different ity with other receptors.26,27 1058 © 2014 John Wiley & Sons Ltd Volume 26, Number 8, August 2014 Bile acids and functional GI disorders Figure 1 Schematic of the enterohepatic circulation. Green arrows indicate up-regulation and red arrows down-regulation. Curved arrows indicate transport across the cell membrane. (BSEP bile salt export protein; CYP7A1 Cholesterol 7 hydroxylase; LRH-1 Liver Receptor Homolog-1; SHP Small Heterodimer Partner; FXR Farnesoid X Receptor; RXR Retinoid X Receptor; FGFR4 Fibroblast Growth Factor Receptor 4; FGF19 Fibroblast Growth Protein 19; BA Bile Acid; OST Organic Solute Transporter; IBABP Ileal Bile Acid Binding Protein; ASBT Apical Sodium Bile Acid Transporter, NTCP Sodium-taurocholate Cotransporting Polypeptide). The G protein-coupled BA receptor (GPBAR1, also in skin and has an analgesic effect through macrophage known as TGR5) is ubiquitous in human tissue and is expression in a mouse model of cholestatic disease.34 preferentially stimulated by the secondary BAs, DCA TGR5 agonists improve insulin sensitivity and reduce and LCA.28

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