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

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

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 In the intestine, TGR5 is expressed by the obesity in mouse models and are in development into enterochromaffin cells and enteric neurons; DCA has therapeutic options for metabolic syndrome.35 TGR5 is been shown to act on these cells to release 5-hydroxy- expressed by monocytes and appears to have a role in tryptamine and glucagon-like peptide 1 (GLP-1).29,30 differentiation into dendritic cells.36 Its effect is anti- A recent study using TGR5 knockout mice found a 2.2- inflammatory and may be important in the down- fold decrease in colonic transit time and a 2.6-fold regulation of inflammation in response to gram-nega- increase in defecation frequency in mice that over- tive bacteria.37 These anti-inflammatory effects have expressed TGR5 compared to knockout. Water secre- been found to be protective in diseases such as tion was also increased in the TGR5 transgenic mice atherosclerosis, arthritis, and Crohn’s disease.35 (57%) and reduced in the knock-out mice (37%) compared to wild-type mice. This was associated with EFFECT OF BILE ACIDS ON THE decreased frequency of defecation in knock-out and an ESOPHAGUS AND STOMACH increased frequency in transgenic mice.31 Expression of TGR5 within the GI tract differs Gastro-esophageal reflux disease (GERD) affects 20% according to location; it is not expressed in the esoph- of adults at least once a week within the US.38 Most agus, but is readily found within the mucosa and (70%) patients will have a normal esophagogastroduo- muscularis externa of the small bowel and on inhibitory denoscopy. These can be characterized into those with myenteric neurons in the small and large bowel.32,33 In increased esophageal acid exposure (non-erosive reflux mice, stimulation of TGR5 with DCA within the small disease, NERD) and those with normal esophageal acid bowel inhibits gastric emptying and transit within the on ambulatory pH impedance testing. Patients with no small bowel and proximal colon, acting as an ‘Ileal evidence of increased acid reflux are classified as brake’ to enhance absorption of nutrients.32 In humans, hypersensitive esophagus if there is a positive associ- a TGR5 single nucleotide polymorphism (SNP) has ation of symptoms with reflux episodes or as func- been found to be associated with a faster small bowel tional heartburn if this is not present.39 As most bile transit time in a population of IBS-D.33 reflux occurs together with acid reflux, BAs do not The systemic effects of TGR5 are wide ranging. It seem to be responsible for most heartburn symp- mediates the itching sensation through afferent nerves toms.40 Around 30% of patients will fail to respond

to proton pump inhibitors (PPI) once daily and 75% of effect was probably through BA chelation in the these will not benefit from high dose PPI.41 It is worth duodenum, as removal of BAs from the duodenum noting that PPIs reduce BA reflux and addition of has been shown to stimulate Cholecystokinin release Baclofen increases efficacy.42 However, BA reflux alone previously.55 can still provoke heartburn and is implicated if symp- Although these mechanisms make a strong case BA toms do not respond to PPIs.43,44 involvement in functional dyspepsia, heartburn and Duodeno-gastric and duodeno-gastric-esophageal postprandial distress, the precise relationship with reflux of BAs induce mucosal production of IL-8 and clinical functional disease is poorly understood and stimulate COX-2.44 These are independent of peptic restricted by the poor availability of luminal bilirubin acid production and are implicated in metaplastic and or BA sensing. Further work is warranted. carcinogenic processes in the stomach and esophagus.45 They also increase mucosal permeability EFFECT OF BILE ACIDS ON THE COLON allowing further damage by peptic acid, pepsin and trypsin.46 Duodeno-gastro-esophageal reflux in the When BAs reach the colon in concentrations exceeding presence of Barrett’s esophagus promotes progression 3 mmol/L, changes to the physiology of the colon to adenocarcinoma.47 However, relationship of BAs to occur.56 Multiple mechanisms appear to mediate inflammation is complex as stimulation of TGR5 has secretion in the colon secondary to BAs. CDCA and a mostly anti-inflammatory effect and has recently DCA have been shown to decrease net sodium absorp- shown to protect mice from non-steroidal induced tion and increase chloride secretion in human ileal and gastrointestinal mucosal injury.48 The pathophysiol- colonic tissue.56,57 However, this effect has not been ogyofBArefluxwasrecentlyreviewedbyFarrein seen with CA.58 In fact, the prosecretory effects of BAs this journal and we refer the reader to this for greater have been shown to be structure-specific and depen- detail.46 dent on bacterial actions, such as the bacterial conver- The reactive gastropathy/gastritis caused by gastro- sion of the non-secretory CA to the prosecretory duodenal reflux of BAs is well described and is DCA.59 Bacteria also have the ability to convert associated with pyloric relaxation during phase II of prosecretory BAs to non-secretory forms, such as the the migrating motor complex.49 This is particularly sulfation of CDCA.60 prevalent after cholecystectomy, in a prospective trial Rectal administration of CDCA has been shown to of 85 patients with no dyspeptic symptoms and induce colonic propagation waves and decrease the normal gastroscopy undergoing laparoscopic chole- pain threshold to rectal balloon insufflation in healthy cystectomy, seven developed symptomatic gastritis volunteers.30 Oral administration of CDCA accelerates with endoscopic evidence of BA reflux 6 months colonic transit and increases defecation frequency in afterward. Furthermore, 20 patients developed gastric healthy volunteers in a dose-dependent manner.61 metaplasia, which may indicate clinically silent Diarrhea was a frequent adverse effect of CDCA given duodeno-gastric BA reflux seen only on biopsy.50 An for gallstone dissolution and this eventually meant Italian study of 60 patients with symptomatic postc- that ursodeoxycholic acid, which has no prosecretory holecystectomy reactive gastritis found that Sucral- or motility effect on the colon, prevailed for this fate or Rabeprazole were equally effective in reducing indication.62 symptoms and reducing the endoscopic and histolog- A summary of the effect of BAs in the colon is ical inflammation scores (around 50% absolute reduc- shown in Table 1. The effects are wide ranging, from tion).51 homeostasis to mucosal permeability. The systemic Several large studies have found delayed gastric effects of BAs, FXR, TGR5, and FGF19 are outside the emptying to be associated with functional dyspepsia scope of this review but are of considerable interest in in around 40% of subjects, although these findings are metabolic diseases. disputed.52 As BA stimulation of TGR5 slows gastric emptying and small bowel transit (the ‘ileal brake’), it CHRONIC CONSTIPATION is possible that BAs are implicated in the pathogenesis of a subgroup of functional dyspepsia. Administration It has been postulated that BAs are endogenous of glycocholic acid into the stomach has been shown to laxatives.60 Thereforeareductionintheconcentra- increase the visceromotor response to distension in tion of BAs delivered to the colon may result in rats.53 Cholestyramine, a BA sequestrant, has been constipation. CDCA BA has the greatest prosecretory shown to slow gastric emptying and decrease appetite effects in the colon, but is vulnerable to bacterial in healthy subjects.54 The authors concluded that this metabolism in the colon and loses its prosecretory

Table 1 A summary of the effects of bile acids in the colon

Effect Method Mechanism

Laxative Water secretion Activation of CFTR via adenylate cyclase63,64 Inhibition of apical ClÀ/OHÀ exchange by tauro-CDCA65 Mucus secretion Increased mucus secretion, direct effect on goblet cells66,67 Accelerated colonic motility Likely via TGR5 stimulation of myenteric ganglionic neurons and nitric oxide synthase (NOS)68 Possible cholinergic agonism of tauro-LCA69 Metabolic GLP-1, GLP-2 and PYY release Via TGR5 from enteroendocrine L-cells70 Increased BA transport and decreased synthesis Increased transcription of FGF19, ASBT, IBABP, OSTa/OSTb through FXR stimulation12 Inﬂammatory Increased mucosal permeability to bacteria Via muscarinic and nicotinic afferent nerves71 Tight junction expression decreased in TGR5 null mice72 Enteroprotection in inﬂammation Multiple mechanisms through FXR activation24,73 Inhibition of leukocyte Formyl-peptide receptor antagonism by CDCA74 chemotaxis Cell turnover Epithelial proliferation Activation of epidermal growth factor receptors75 Activation of mitogen-activated protein kinase signaling pathways76 Apoptosis resistance Cause apoptosis in supraphysiological concentrations77 Induce apoptosis resistance in chronic exposure78 DNA/mitotic damage Oxidative DNA damage and spindle formation disruption79

CFTR, cystic fibrosis transmembrane conductance regulator; CDCA, chenodeoxycholic acid; TGR5, transmembrane G-coupled receptor 5; LCA, lithocholic acid; GLP, glucagon-like peptide; PYY, peptide YY; BA, bile acid; FGF, fibroblast growth factor; ASBT, apical sodium bile acid transporter; IBABP, ileal bile acid binding protein; OSTa, organic solute transporter a; OSTb, organic solute transporter b; FXR, Farnesoid X receptor. effects. This hypothesis was tested in a pediatric OATT were found to have high baseline levels of population of 73 children with functional constipa- serum C4 indicating increased BA synthesis, whether tion. These children had higher fecal levels of mono- this translated into increased fecal BAs is not known, sulfatedCAandCDCAwhencomparedtonon- but it is possible that these patients had bowel flora constipated controls (5.5% vs 3.4%). This increase that were sulfating secretory BAs. was mostly attributable to six outliers whose major fecal BA was 3-sulfate-CDCA. Sulfation of CDCA TREATMENT OF CHRONIC abolishes its laxative effect, leading the authors to CONSTIPATION conclude, that in a subset of functional constipation, bacterial sulfation may be a causative factor.60 Oral administration of BAs has been shown to shorten Although this study has not been repeated in an colonic transit in females with IBS-C. This placebo- adult population, a recent study has shown that controlled study of 36 subjects compared colonic patients with IBS-C (constipation predominant IBS) release CDCA at doses of 500 and 1000 mg and found have a lower amount of total BAs in feces compared that CDCA improved stool form, frequency and ease of to healthy volunteers. A difference in the composi- passage in a dose-dependent manner.82 CDCA reduced tion of the fecal BAs was seen, with a reduction in the colonic transit time but retarded gastric emptying as prosecretory DCA and an increase in the non-secre- seen in other studies. They also found that patients tory LCA. This study also found a negative correla- with IBS-C had reduced fasting serum C4 compared to tion between the colonic transit time and the healthy volunteers, suggesting decreased BA synthesis. percentage of LCA of the fecal BA composition.80 The recognition of the role of BAs in constipation In addition to undergoing bacterial modification, has led to the development of a new class of drug. there is evidence that BA production is altered in Elobixibat is a first in class ileal BA transporter (IBAT, constipation. A Swedish study of 26 female subjects also known as ASBT) inhibitor and is currently with IBS-C or functional constipation by Rome II recruiting in phase 3 trials, due for completion in criteria found that 11 (42%) had markedly prolonged September 2014 (ClinicalTrials.gov: NCT01827592 oral-anal transit times (OATT) of over 4.3 days.81 This and NCT01833065). In a single-center double-blind, subgroup was found to lack the three- to four-fold placebo-controlled phase IIa study, elobixibat was increase in serum C4 (an intermediary step in BA shown to decrease colonic transit time, improve stool production and a marker of de novo hepatic BA form, frequency and ease of passage.83 A multicenter, synthesis) at lunchtime that has been shown to be Phase IIb, double-blind, placebo-controlled trial part of a normal diurnal variation in healthy showed a dose-dependent improvement in number of volunteers.81 Three patients with severely delayed spontaneous bowel movements (SBM), with an

increase to 5.4 (4.4–6.4) SBMs/week for the highest diarrhea.90 In a study of 141 patients, with all three 15 mg dose compared to 1.7 (0.7–2.8) for placebo. sub-types of IBS according to Rome II criteria, 40% had Elobixibat also improved bloating severity, but not a SeHCAT retention below 20% and within the IBS-D abdominal pain or discomfort.84 The drug seems well- group, a retention value below 10% correlated with a tolerated at the lower doses of 5–10 mg, with a faster colonic transit time.91 This study reported discontinuation rate during the phase IIb trial of 13%, similar characteristics (SeHCAT retention values, rising to 23% for the 15 mg group. Of the total colonic transit time, stool consistency and form) patients, 54% reported adverse events, with abdominal between the IBS-A and IBS-D groups, raising the cramps relieved by defecation and diarrhea the most possibility that these subtypes share colonic BA expo- common. There have been no serious adverse events to sure as a predisposing factor. This is further supported date. by the observation that 55% of the patients with a SeHCAT <20% had a good response to a BA sequestrant (Colestipol) as defined as >50% reduction in IBS CHRONIC DIARRHEA Symptom severity score after 8 weeks on treatment. The role of BAs in chronic diarrhea is the most well Despite being in use in Europe for over 20 years, described association with functional bowel disease. SeHCAT is not available in the US and many other Alan Hofmann first described the syndrome of Choler- countries, leading to under-recognition of BAD. The heic Enteropathy in 1967 in patients who had under- pragmatic approach of a therapeutic trial of BA gone ileocecal resection.85 This form of bile acid sequestrants has never been validated against fecal malabsorption (BAM), is now termed secondary (or BA measurement or SeHCAT testing. type 1) and commonly seen in patients with terminal In a systematic review of 18 studies including 1223 ileal Crohn’s disease, either active or resected. In 1976, subjects with IBS-D, 32% were found to have SeH- diarrhea due to colonic BAs was described in patients CAT retention values of <10% and hence would with a histologically normal terminal ileum.86 This benefit from BA sequestrants. This figure of around a was termed idiopathic, primary, or type 2 BAM. Type 3 third of patients with chronic diarrhea was reasonably BAM is associated with a heterogeneous range of consistent across all the studies and populations gastrointestinal conditions including celiac disease included. Based upon the relative prevalence of IBS- and postcholecystectomy. As there is usually no D in the UK, this review suggested that the prevalence malabsorptive defect in idiopathic BAM, we prefer to of primary BAD in the general population of the UK term this primary or type 2, bile acid diarrhea (BAD), may be as high as 1%.88 In a recently published and for types 1 and 3, use secondary BAD. prospective trial of 152 patients with diarrhea undergoing SeHCAT, 54 (36%) had primary BAD, 26 (17%) had secondary BAD (types 1 and 3), and 72 (47%) DIAGNOSIS OF BILE ACID DIARRHEA patients had diarrhea with normal SeHCAT values. Diagnosis of BAM/BAD previously required measure- Patients with primary BAD were as likely to report ment of fecal BAs, which is unpopular with patients, pain and bloating (59% and 73%, respectively) as the time consuming and generally not available outside diarrhea controls.92 research institutions. An advance on this is fecal 14C Despite the reliability of SeHCAT, there is still a taurocholate, in which radiolabeled BAs are measured need for a simplified test that can be made widely in stool, but this still requires a 72 h stool collection. available in the US. In 1993, raised Serum C4 was Other methods have recently been reviewed.87 shown to correlate with low SeHCAT results.93 In a The most useful diagnostic test is the 75Selenium– study comparing serum C4 to SeHCAT in 23 patients homocholic acid taurine (SeHCAT) retention scan. with diarrhea, a sensitivity and specificity of 90% and This test requires the oral administration of the 78%, respectively was observed for C4 predicting a gamma-emitting synthetic BA, 75SeHCAT, which positive SeHCAT.94 This study may have reported a enters the enterohepatic circulation, and is measured higher specificity had the C4 been taken in the morning using a gamma camera usually at 3 h and 7 days. in the fasting state since the diurnal variation of C4 has Whole body retention of less than 15% at day 7 is been described.95 A value of 60.7 ng/mL is above the abnormal, and predictive of a clinical response to BA 95th percentile and taken to be diagnostic for BAD.96 sequestrants.88 SeHCAT has been shown to have a The C4 assay requires high-performance liquid sensitivity of 100% and a specificity of 94% for BAD.89 chromatography-tandem mass spectrometry, which is It is not affected by increased colonic transit and is technically demanding.96 It is unstable in serum at therefore able discriminate BAD from other causes of room temperature, and requires either immediate

processing or freezing at À80 °C. Despite these limi- FGF19 <145 pg/mL was found to have a 74% sensitiv- tations, the ability to perform a single, serological test ity and 72% specificity to detect a C4 >60 ng/mL.105 means that serum C4 measurement remains an attrac- A prospective study of patients with chronic diarrhea tive diagnostic test for BAD. comparing FGF19 and C4 with SeHCAT found the Experimental tests are in development and include same inverse relationship with FGF19 and C4 and that detecting differences in volatile organic compounds in a FGF19 <145 pg/mL was predictive of a positive urine using an ‘electronic nose’. A recent study of 110 SeHCAT. A modified score adjusted for C4, age and subjects including 45 healthy controls, 42 with ulcer- body mass index (BMI; all factors that change FGF19 ative colitis and 23 with BAD diagnosed by SeHCAT levels) showed a negative predictive value of 86% and found a distinct chemical signature in the urine of positive predictive value of 61% for a SeHCAT <10%. patients with BAD that could be developed into an Furthermore, a FGF19 of <145 pg/mL was highly instant, portable test for BAD.97 The fact that this predictive of having a full response to BA sequestrants hardware will differentiate between and diagnose in 94% of patients.92 FGF19 is relatively stable in multiple conditions increases its appeal. stored serum and is measured by a commercially available ELISA kit; it may be the simple diagnostic test primary BAD requires. PATHOGENESIS OF PRIMARY BILE ACID The identification of the FGF19 pathway in BA DIARRHEA homeostasis has led to renewed interest in finding The pathogenesis of primary BAD is not completely SNPs associated with low FGF19 and diarrhea. In 2010, understood. A malabsorptive defect of the ASBT Wong et al. analyzed 15 SNPs associated BA transport seemed a likely explanation but in 1991 normal BA and regulation in 435 subjects with IBS.106 They found transport was shown in brush-border vesicles,98 and in that a SNP for KLB (rs17618244) was associated with 1996 it was shown that ileal biopsies had the same faster colonic transit and was prevalent in patients activity of sodium/BA co-transport as healthy con- with the IBS-D subtype, but not within other IBS trols.99 In 1997, two functional mutations (L243P and subtypes or healthy volunteers. This SNP coded for an T626M) in the ASBT gene were described in a family unstable variant of KLB that has significantly shorter with diarrhea.100 These mutations were found to be no half-life. KLB binds to FGFR4 in the endoplasmic more common in the adult population with primary reticulum of hepatocytes to permit FGF19 mediated BAD than in controls.101 Similarly, polymorphisms in inhibition of BA production by CYP7A1 making this a the ileal BA-binding protein (IBABP) and expression of biological plausible cause of primary BAD.17 A study IBABP and the basolateral membrane transporters by the same group used a smaller population of 26 OSTa and OSTb were not significantly different in patients with IBS-D and compared total fecal BAs, C4, patients with diarrhea and controls.102 FGF19 and polymorphisms in KLB and FGFR4 to healthy controls and IBS-C.107 They found increased fasting C4 and fecal BAs in the IBS-D group, but this FIBROBLAST GROWTH FACTOR 19 was not associated with the same polymorphism in In 2009, a completely new mechanism for primary KLB or fasting FGF19. There was a small association BAD was suggested.103 Significantly lower median with three polymorphisms in FGFR4 (rs1966265, fasting serum FGF19 were found in patients with rs351855, and rs1768244) with stool BA excretion, primary BAD compared to healthy controls. C4 was perhaps indicating that primary BAD is a heteroge- increased with a negative correlation between C4 and neous group of different polymorphisms and associa- FGF19. It was suggested this supported evidence for an tions. Both the KLB rs497501 and the FGFR4 rs351855 increased BA pool in primary BAD with a defective SNPs are predictors of a good response to the BA negative feedback mechanism involving FGF19. This sequestrant Colesevelam.108 A recently published ex- was corroborated by previous work that described a ome sequencing of 16 patients with IBS-D (further 90% increase in the BA pool in patients with primary subgrouped by FGF19, and C4 and increased colonic BAD, despite their excessive fecal losses.104 These transit) revealed two further SNPs of FGFR4 and one of findings have changed the etiology from malabsorption KLB that appeared predictive of BAD.109 Two FGFR4 to overproduction of BAs, due to defective negative variants were also predictive of IBS phenotype and feedback by the hormone FGF19. increased colonic transit time in a cohort of 405 IBS A low FGF19 could be used in the diagnosis of patients and 228 healthy controls. primary BAD. In a retrospective trial of patients A summary of SNPs associated with BAD is pro- undergoing C4 measurement for diarrhea, serum vided in Table 2. Apart from one SNP within the TGR5

Table 2 Single nucleotide polymorphisms (SNP) associated with bile interest. A recent study in mice found that a murine BA acid related functional bowel disease acts as an FXR antagonist when conjugated, but 114 Protein affected SNP Associations becomes a FXR agonist after bacterial deconjugation. This BA is not found in primates so this study’s b Klotho Rs17618244 Accelerated colonic transit within significance to humans is unclear. IBS-D106 Accelerated colonic transit in response to lower dose CDCA in IBS-C82 TREATMENT OF BILE ACID DIARRHEA Klothob Rs1015450 Increased fecal bile acids109 Klothob Rs4975017 Reduced colonic transit in response Bile acid sequestrants remain the mainstay of treat- to Colesevelam108 ment for BA diarrhea. Cholestyramine is a BA binding 106 FGFR4 Rs1966265 Modulates rs17618244 effect resin that has been used since the 1960s for hyperlip- IBS-D with low FGF19 and 115 raised C4109 idemia and patients with ileal resection. A trial of 13 FGFR4 Rs351855 Modulates rs17618244 effect106 patients with primary BAM with a SeHCAT <10% 109 Accelerated colonic transit showed that cholestyramine reduced both small bowel IBS-D with low FGF19 and 116 raised C4109 and colonic transit times and stool frequency. In a Reduced colonic transit in larger study of 68 patients with diarrhea, a SeHCAT 82 response to Colesevelam scan <15% and no other cause (primary BAD), 75% had FGFR4 Rs434434 Accelerated colonic transit109 IBS-D with low FGF19 and a positive effect on bowel habit with cholestyramine, raised C4109 although this positive effect was not quantified.117 109 IBS-D phenotype However, adverse effects such as abdominal pain, FGFR4 Rs376618 Accelerated colonic transit in response to CDCA82 bloating and constipation are reported. Cholestyramine TGR5 Rs11554825 Accelerated small bowel transit33 reduces the intestinal absorption of other medications and its formation as a non-soluble powder is unpalat- IBS-D, IBS-diarrhea; IBS-C, IBS-constipation; CDCA, chenodeoxycholic acid; FGFR, fibroblast growth factor receptor; TGR, transmembrane able to some patients. These factors led to a 40–70% G-coupled receptor. discontinuation in asymptomatic patients taking it for hyperlipidaemia118 although we suspect compliance in gene, all the described associations are for FGFR4 and symptomatic responders may be higher. its modulator KLB. Both of these could increase BA Binding BAs only in the colon could reduce production and increase FGF19 release. No FXR poly- these side effects. Colonic release Cholestyramine has morphisms associated with primary BAD have been been shown to be effective with a reduction in colonic identified.110 An interesting observation has been transit time, stool mass, frequency and BA in a placebo made by many BAD studies and all FGF19 studies. cross-over study of 14 patients with ileal resection.119 Patients with IBS-D have a higher BMI than controls This preparation also had the advantage of being taken with IBS-C or healthy volunteers.92,107 FGF15 transgenic in tablet form and although the study did not report on mice have lower body masses despite increased food side effects, all patients were able to complete the uptake, these mice were also protected from diet week course. Currently there are no commercially induced obesity and had lower serum, glucose and lipid available colonic release preparations of cholestyr- levels.111 The reverse is also true, FGFR4 and FGF15 amine, but phase 2 trials of a preparation are in knockout mice show characteristics of the metabolic progress (ClinicalTrials.gov: NCT02078856). syndrome.112 Development of FGF19 pathway modula- Colesevelam is a newer BA sequestrant that is taken tors in diabetes and metabolic syndrome is underway. in tablet form.120 In a retrospective study of cancer patients with a SeHCAT value <10%, colesevelam improved diarrhea in 88% patients and was tolerated CHANGES OF THE MICROBIOTA IN BILE for up to 4 years in 67%. Of the cohort of 45 patients, ACID DIARRHEA only 18% discontinued because of adverse effects or Bacterial enzymes such as bile salt hydroxylases pro- tablet burden, the remainder were non-responders, or duce secondary BAs. The proportion of fecal primary symptoms ceased.121 Colesevelam seems to have effi- BAs are increased in BAD and this may be due to a cacy in IBS-D. A placebo-controlled trial of 24 patients decrease in Bifidobacteria and Leptum species and an with IBS-D and increased colonic transit measured by increase in Escherichia coli.113 Whether this is cause or scintigraphy showed significantly reduced ascending effect is uncertain, but the potential for the microbiome colon emptying times for 7 of 12 patients in the to change the affinity of BAs to FXR or TGFR5 and colesevelam arm.61 Only 4 of the 12 of the patients had hence influence the FGF19 feedback mechanism is of evidence of BAD as defined by a high C4, although

1064 © 2014 John Wiley & Sons Ltd Volume 26, Number 8, August 2014 Bile acids and functional GI disorders baseline C4 was a strong predictor of response. 17% of CONCLUSIONS patients noticed abdominal cramps during treatment, Recent advances in our understanding of BA metabo- and 24% reported increased flatulence. lism have firmly implicated them in the pathogenesis Obeticholic acid (OCA) is a synthetic BA and a of FGID. This greater understanding has already begun, potent FXR agonist that is currently in phase 3 trials and will continue, to drive new drug development. As for Primary Biliary Cirrhosis. In studies from our unit, these new BA modulators become available, the diag- ileal biopsies incubated with 1 lM of OCA for 6 h nostic criteria for functional bowel disease may have to resulted in a 70-fold increase in FGF19 mRNA expres- be revised to aid recognition of subgroups that will sion. CDCA at the same concentration did not induce benefit from treatment. In some countries, the lack of a response.13 Preliminary reports of a proof of concept widely available diagnostic tests for BAD and BA reflux study in 10 patients with primary BAD showed that will impede this. Serum C4 and FGF19 show promise 25 mg of OCA increased fasting FGF19 from 133 to as diagnostic tests for use in countries where SeHCAT 237 pg/mL and reduced stool frequency and form. is not available and it is hoped that their use will There was also a tendency toward improvement in expand. The precise role of BA in functional upper GI abdominal pain, urgency and bloating.122 The meta- disorders is not well defined and requires further work. bolic and anti-inflammatory effects of FXR agonists are However, exciting research continues on lower GI BA currently being evaluated in phase II trials in patients disorders, particularly regarding the effects of the with type 2 diabetes and non-alcoholic fatty liver microbiome on BAs, the genetic basis for primary disease. It is worth noting that the most common BAD and the effects and modulation of TGR5. adverse effect of OCA was constipation (5 out of 21 subjects on the higher dose of 50 mg).123 Glucocorticoids increase expression of ASBT and FUNDING increase BA uptake in the terminal ileum. An 8 week We acknowledge support from the Bardhan Research and Educa- trial of budesonide in patients with collagenous colitis tion Trust and Albireo AB. improved the median SeHCAT retention from 18% to 33% with a corresponding decrease in serum C4.124 The contribution of BAD to diarrhea in inflammatory DISCLOSURE diseases is difficult to quantify, but must be considered JW has received fees for lecturing or consulting from Albireo, in patients with diarrhea and otherwise quiescent GE Healthcare, Intercept, NGM, Novartis, Pendopharm and disease. Sanofi.

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