Abstract: Bile acid diarrhea (BAD) is characterized by increased frequency of bowel movements, looser stool consistency, urgency, and need for proximity to toilet facilities owing to the severity of the diarrhea, when compared with or relative to irritable bowel syndrome with diarrhea. Consequently, BAD leads to decreased quality of life. The condition is often misdiagnosed as irritable bowel syndrome with diarrhea or functional diarrhea. Patients with BAD have accelerated colonic transit, increased intestinal or colonic mucosal permeability, and altered stool microbiome composition associated with reduced dehydroxylation of primary to secondary bile acids. The established diagnostic test, selenium-75 homocholic acid taurine retention, is not available in the United States. Therefore, 48-hour fecal bile acid excretion has been the gold standard for diagnosis. With recent validation of combined measurement of primary bile acids in a single, random stool in addition to fasting serum 7α-hydroxy-4-cholesten-3-one, a practical point-of-care diagnostic test will soon be available. Randomized controlled trials have documented superiority of colesevelam to placebo and, in a separate study, superiority of the glucagon-like peptide 1 agonist liraglutide compared with colesevelam. Novel experimental approaches for BAD include farnesoid X receptor agonists and fibroblast growth factor 19 analogs. This article updates information on the pathophysiology, mechanisms, manifestations, diagnosis, and treatment of BAD.
Bile acids (BAs) are actively absorbed in the ileum1-3 by the apical sodium-dependent BA transporters in distal ileal mucosa,4,5 and they are passively absorbed through the small intestinal6 and colonic mucosa7,8 along a concentration gradient. Bile acid diarrhea (BAD) results from delivery of excessive BAs to the colon (and this may result from malabsorption), excessive hepatic synthesis, or delivery to the small intestine that is not synchronized with the entry of food into the small intestine as may occur postcholecystectomy. BAD has been defined as BA sequestrant-responsive diarrhea in the presence of BA malabsorption (BAM), as can be measured by direct or indirect tests.9 The mechanisms whereby BAs induce diarrhea include the effects on the surface epithelium (such as denudation of surface mucus and increased permeability resulting from detergent effects), as well as through binding to the G protein–coupled BA receptor-1, also called Takeda G protein–coupled receptor 5 (TGR5), and inducing 3’,5’-cyclic adenosine monophosphate (cAMP)-dependent changes of function. These mechanisms lead to increases in motility, visceral sensation, and fluid secretion. All BAs can bind to TGR5, and the most potent BA is lithocholic acid (LCA).10-12 On the other hand, the di-alpha hydroxy BAs, chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), have significant detergent effects, which are not shared by cholic acid (CA) and LCA.13
This article summarizes the latest research on BAD, provides further understanding of its pathophysiology and mechanisms, and reviews validated simple diagnostic tests and novel treatments that have enhanced opportunities to diagnose and treat BAD.
Bile Acid Synthesis and Enterohepatic Circulation
The primary BAs, CA and CDCA, are synthesized from cholesterol and undergo conjugation with taurine and glycine in the liver. In this synthesis, the rate-limiting enzyme is cytochrome P450 7A1 isozyme (CYP7A1), and an intermediate is 7α-hydroxy-4-cholesten-3-one (C4). Up to 95% of primary BAs are actively reabsorbed by apical sodium-dependent BA transporters in terminal ileal enterocytes, and actively and passively absorbed BAs are transported to the liver via portal circulation. In the ileal enterocytes, BAs bind to the nuclear farnesoid X receptor (FXR) and induce synthesis of the enteroendocrine hormone fibroblast growth factor 19 (FGF19). FGF19 reaches the liver via portal circulation, binds to the fibroblast growth factor receptor 4 and Klotho B, inhibits CYP7A1, and reduces BA synthesis, providing a feedback regulation loop.14 Thus, there is an inverse relationship between C4 and FGF19 (Spearman rank rs = −0.53; P=.01).15,16 Patients with BAD have increased serum C4, which reflects excessive BA synthesis, and the increased synthesis of BAs overcomes the absorptive capacity of the ileum, reaching the colon and causing BAD and increased fecal BA excretion. Patients with type I BAD (secondary to ileal disease or resection) or type II BAD (idiopathic) also have decreased serum FGF19, the negative feedback regulator of BA synthesis.15 The remaining 5% of BAs reach the colon, undergo deconjugation and dehydroxylation by bacterial enzymes to secondary BAs, DCA, and LCA, or epimerization to ursodeoxycholic acid, and are either passively absorbed in the colon or excreted in stool.7
Mechanisms of Bile Acid Diarrhea
Loss-of-function mutations in BA transporters, such as apical sodium-dependent BA transporters, have been identified as rare potential causes for BAD that may pre-sent in infancy.17-19
There is evidence of decreased FGF19 messenger RNA (mRNA) expression in ileal mucosa in patients who have reduced selenium-75 homocholic acid taurine (75SeHCAT) retention (diagnostic of BAD) and lower serum FGF19 leading to reduced feedback inhibition of hepatic BA synthesis.20 There is also evidence that patients with BAD (serum C4 ≥65.87 ng/mL) have significantly lower ileal FGF19 protein expression compared with patients with chronic diarrhea without evidence of BAD.21
Ileal and colonic mRNA expressions of several genes were compared in 10 patients with BAD, 34 with diarrhea-predominant irritable bowel syndrome (IBS-D), and 30 healthy volunteers. In the ileal mucosa of patients with BAD, there was downregulation of SLC44A5 (a transporter of bile salts as well as glucose, other sugars, organic acids, metal ions, and amines).22 This finding requires replication, and its biological significance is yet unclear. Expressions in ileal biopsies of other candidate genes (FGF19, NR1H4 [gene for FXR], and SLC10A2 [gene for apical sodium-dependent BA transporters]) were not different in BAD compared with IBS-D.22 In contrast, ascending colon biopsies from patients with BAD showed upregulation in genes that reflect increased mucosal permeability to water (CLDN2), immune activation (controlling complement, chemokines, and interleukin-1 receptor antagonists), and cellular differentiation that are consistent with the detergent effects of BAs.23 No differential expression of genes was documented in descending colon biopsies from the 2 groups.22
Pathophysiology of Bile Acid Diarrhea
Several pathophysiologic mechanisms may result from the effects of BAs in the colon, although these mechanisms may not be present in all patients. For example, colonic secretion of water and electrolytes may concur with increased colonic mucosal permeability, but they may be independent of effects on colonic motility.
Colonic Motility
BAs stimulate colonic motility mainly through TGR5.24 Ileocolonic release of sodium chenodeoxycholate, 500 mg or 1000 mg, significantly accelerated overall and ascending colonic transit and was associated with increase in stool frequency and looser stool consistency.25 Rectal administration of sodium chenodeoxycholate was associated with stimulation of colonic high amplitude propagating contractions.26
Fluid and Electrolyte Secretion in the Colon
BAs stimulate fluid and electrolyte secretion in the colon7,27 through a variety of mechanisms: stimulation of colonocyte intracellular mediators, mainly cAMP28,29; upregulating expression of colonic aquaporin channels30; increased serotonin-induced secretion31; neurocrine secretion through activation of TGR5 and submucosal cholinergic neurons32; and increased mucosal permeability.23 There is also evidence that conjugated BAs can prevent water and sodium absorption and, at higher concentrations (≥5 mM), evoke secretion in human jejunum.33 However, this effect was abolished in the presence of a polar lipid molecule, suggesting that the secretory effect occurs only after fat absorption has occurred.
Intestinal Permeability
Patients with BAD have increased intestinal permeability and an altered gut microbiome. In a Mayo Clinic prospective study, 44 patients with BAD had a significantly higher 13C-mannitol excretion at 2 to 8 hours, 8 to 24 hours, and 2 to 24 hours than 161 patients with IBS-D without BAD.34 Moreover, patients with BAD had a significantly lower microbial alpha diversity and a significantly different stool bacterial compositional profile than patients without BAD.22 An important functional difference in the microbial functions is the reduced expression of thiol ligases that are associated with conversion of primary to secondary BAs, and this was associated with higher primary BA excretion in stool of patients with BAD.22 These results are consistent with a previous study, involving 55 patients with IBS-D and 28 matched healthy controls, which hypothesized that altered BA metabolism in patients with IBS-D was associated with dysbiosis.35
Clinical Features of Bile Acid Diarrhea
There are 3 types of BAD: type I in patients with ileal disease or resection; type II, also called idiopathic BAD, in patients with functional diarrhea or IBS-D; and type III in patients with gastrointestinal conditions other than ileal disease.36 Patients with hypertriglyceridemia20 and patients on metformin treatment37 may also develop BAD.
Epidemiology and Associated Diseases
A systematic review of the literature showed that the prevalence of BAD among patients with chronic functional diarrhea or IBS-D is estimated to be about 25% to 50%.38 It is also estimated that the prevalence of BAD is about 1% of the general population. Diseases of the gastrointestinal tract, particularly Crohn’s disease, ulcerative colitis, microscopic colitis, and celiac disease,39 and intestinal neuroendocrine tumors40 may all be associated with evidence of BAD, as documented in clinical practice medical records.
Symptoms
Diarrhea is the predominant symptom of BAD. In an online survey of patients in BAM Support UK, 91 of 100 respondents reported a diagnosis of BAD, either following a 75SeHCAT scan (n=58) or clinically (n=33) based on symptoms alone or on response to a trial of BA binders. Among those patients, 38% had type II BAD and 37% had type III BAD. The most common symptoms were explosive, offensive smelling, or watery diarrhea (80%), urgency (85%), and abdominal bloating or swelling (54%). Moreover, 88% reported at least occasional stool incontinence or accidents, and 52% reported they felt the need to always be close to a toilet.41 In the Mayo Clinic prospective study of 44 patients with BAD and 161 control patients with IBS-D, those with BAD had higher body mass index and more severe bowel dysfunction (urgency and frequency of bowel movements and loose stools).42
Quality of Life
Patients with BAD have lower quality of life. Among BAM Support UK participants, diarrhea symptoms affected the respondents’ mental health, physical well-being, and ability to work. Greater than 80% reported sometimes or often having low self-esteem and/or feeling embarrassed, nervous to leave the home, isolated, depressed, or helpless. Furthermore, 44% reported inadequate support at work and changing jobs to reduce travel time.41
Patients with BAD surveyed in the Mayo Clinic study were more likely to worry about losing control of their bowels and to value proximity to a toilet than were patients with IBS-D. These symptoms were associated with depression based on the Hospital Anxiety and Depression Questionnaire.42 Treatment of BAD with BA sequestrants resulted in significantly improved mean scores on the 36-Item Short Form Survey (SF-36) in the “Role limitation due to physical health” dimension and in the overall mental component summary.43
On the other hand, in a placebo-controlled randomized trial of colesevelam, quality of life assessed by some of the SF-36 items was improved, but the authors commented that the improvement seemed to be driven by diarrhea severity and diarrhea impact on everyday life, whereas general quality of life was mostly unchanged.44 In the same study, physical and mental component scores and the general well-being item based on SF-36 (version 2) were largely unchanged from baseline to the end of 12 treatment days and at 6-month follow-up.44
Diagnosis of Bile Acid Diarrhea
The availability of diagnostic tests for BAD varies by country and health care centers.45 The Table describes advantages and pitfalls of the different diagnostic tests.14
Selenium-75 Homocholic Acid Taurine Test
The 75SeHCAT test measures the retention of selenium-75 in the abdomen 7 days after oral ingestion of the radioisotopic-labeled BA. This test is considered the gold standard for diagnosis of BAD. A retention of less than 5% suggests severe BAD, of 5% to 10% suggests moderate BAD, and of 10% to 15% suggests mild BAD.46 The 75SeHCAT test is not available in the United States.
The 48-Hour Fecal Total Bile Acid Test
The 48-hour fecal total BA test measures the total BAs excreted and the percentage of primary BAs (CA + CDCA) in stool that is collected during the last 2 days (48 hours) of a 4-day, high-fat diet (100 g/day). The cutoffs of total BAs greater than 2337 µmol/48 hours, primary BA greater than 10%, or fecal total BA of at least 1000 µmol/48 hours plus primary BA greater than 4% have shown good sensitivity and specificity to identify diarrhea defined as fecal weight greater than 400 g/48 hours.47,48
Fasting Serum C4
Serum C4, an intermediate in BA synthesis, is collected fasting before 9 am owing to diurnal variation. The cutoff of 52.5 ng/mL has been shown to have a sensitivity of 29% and a specificity of 83% when compared with the 48-hour fecal BA test (using the extremely stringent cutoff of >2619 µmol/48 hours rather than the usual cutoff of >2337 µmol/48 hours) in 101 patients with IBS-D or chronic functional diarrhea.49 It has a high negative predictive value (79%) when normal and, therefore, when assessed alone, it is most useful to exclude BAD.49 Levels between 17 and 52 ng/mL should be followed by total 48-hour fecal total BA excretion or a therapeutic trial with a BA sequestrant. There are also data acquired in patients with type I or type III BAD (but excluding idiopathic BAD) suggesting sensitivity, specificity, positive predictive value, and negative predictive value of 90%, 79%, 73%, and 92%, respectively, for C4 greater than or equal to 48 ng/mL.50 This suggests that the utility of the serum C4 may be greater with intestinal disease or resection.
Fasting Serum FGF19
Serum FGF19 is also collected before 9 am after fasting.51 The test performance was consistent with good specificity and negative predictive value, suggesting utility as a screening test to exclude BAD.49
Serum Lipidome
A single lipidome study of serum showed decanoylcarnitine, cholesterol ester (22:5), eicosatrienoic acid, L-alpha-lysophosphatidylinositol (18:0), and phosphatidylethanolamine (O-16:0/18:1) distinguished BAD (diagnosed with 75SeHCAT retention) from controls with 78% sensitivity and 93% specificity.52 Further experience with this test is awaited.
Single Stool Bile Acid Measurements
Measuring the concentration of fecal BAs in a single, random stool sample was tested in 113 patients with chronic diarrhea who had undergone 75SeHCAT testing. Patients who had severe BAD (75SeHCAT retention <5%) had a significantly higher fecal BA concentration compared with patients who had moderate or mild BAD.53 Different laboratories use different measurements for total BAs, including high-performance liquid chromatography–tandem mass spectrometry47,48 or an enzymatic assay for 3 alpha-hydroxy BAs.53
Combined Fecal Primary BAs and Fasting Serum C4
The combination of fecal primary BAs and fasting serum C4 in a single stool sample was examined in 25 healthy volunteers, 59 patients with IBS-D, and 4 patients with terminal ileal resection. The combination was predictive of increased stool frequency (sensitivity 79%, specificity 94%) and BAD diagnosed by the 48-hour fecal total BA test (Figure).54
Treatment of Bile Acid Diarrhea
It is important to note that there are advantages of firm diagnosis over an empiric trial. In clinical practice cohorts, it has been demonstrated that when patients are formally diagnosed with BAD and treated with BA sequestrants, there is an approximately 70% likelihood of achieving clinical benefit in the gastrointestinal manifestations. In contrast, when patients with a negative diagnostic test are empirically treated with the same BA sequestrants, the response rate was approximately 35%.55 A study conducted in the United Kingdom showed cost implications for missing the diagnosis of BAD. While 75SeHCAT was found to be underused, late diagnosis was associated with treatment delay, whereas early diagnosis reduced cost and improved outcomes.56
Diet
A diet low with 20% energy from fat led to a significant reduction in abdominal pain, stool urgency, and nocturnal diarrhea in 116 patients with BAD based on 75SeHCAT retention less than 20%.57
Bile Acid Sequestrants
BA sequestrants are used off-label for the treatment of BAD and include colesevelam, colestipol, and cholestyramine, which are available in either tablet or powder form. The latter is reported by many patients to lack palatability. Cholestyramine was associated with a 28.1% response rate in a treatment trial in 139 unselected patients.58 Colesevelam tablets may have improved tolerability over the other BA sequestrants in powder formulation.59
Although previously validated in open-label trials (efficacy documented in a systematic review59) for effects on bowel function and improved quality of life,43 there is also evidence of efficacy from a placebo-controlled trial.44 In this placebo-controlled trial of colesevelam, the adjusted odds ratio for achieving remission was 9.1 (95% CI, 1.9-62.8) in the C4-defined BAD group and 11.1 (95% CI, 3.4-45.6) for the 75SeHCAT-defined group.44
Colesevelam did not alter bacterial α/β-diversity, but patients who clinically responded to treatment had a significantly greater abundance of Fusobacteria and Ruminococcus, both of which aid in the conversion of primary to secondary BAs.60
BA sequestrants may interfere with the absorption of other medications and thus it is usually advisable to take other medications 2 hours before or 4 to 6 hours after the ingestion of the BA sequestrant. It is also important to note that the dosing schedule of a BA sequestrant for BAD has not been studied as well as that for the approved indication to reduce cholesterol, for which intake of the sequestrant with meals is recommended. In contrast, the antidiarrheal effect of the BA sequestrant relies on the binding of BAs in the colon rather than in the small intestine where binding of the BAs might interfere with absorption and therefore impair fat absorption. Thus, it is our practice to administer the BA sequestrant away from mealtimes, such as 2 hours after the intake of any meals or important medications, to avoid interference with absorption, and then give the second dose at bedtime to sequester BAs that may continue to undergo enteral hepatic circulation at nighttime in the absence of food. It is hypothesized that this approach may also reduce the total BA pool, reducing the potential for excessive BAs to reach the colon during other times of the day.
Newer Interventions
The FXR-FGF19 axis, which is pivotal in the pathophysiology of BAD, has been identified as a potential therapeutic target for BAD.
Obeticholic Acid
Obeticholic acid (6-ethyl chenodeoxycholic acid) is a first-in-class FXR agonist; it was demonstrated that this medication stimulates FGF19, reduces BA synthesis, and produces clinical benefits in BAD relative to a baseline run-in period.61 This medication has been associated with significant pruritus when used in the treatment of metabolic dysfunction-associated steatotic liver disease.
Tropifexor
Tropifexor is an FXR agonist. A double-blind, randomized, crossover study of tropifexor 60 µg in 20 patients with BAD showed a significant increase in FGF19, decrease in serum C4, and increase in ascending colon half-emptying time. No changes in stool frequency or consistency were observed with a single daily administration.62
Aldafermin
Aldafermin, a 190 amino acid engineered peptide analog of human FGF19 with 95.4% homology, was compared with placebo in a 28-day, randomized, double-blinded, placebo-controlled (1:1 ratio) trial in idiopathic BAD based on serum C4 of at least 52 ng/mL or standard 48-hour fecal BA criteria. Aldafermin significantly decreased serum C4, fecal total BA, and percentage of secretory BA at days 14 and 28. There was numerically improved stool consistency in patients on aldafermin during days 15 to 28 (P=.082), particularly in week 4 of treatment (P=.047). Moreover, aldafermin caused greater increase in low-density lipoprotein cholesterol from baseline compared with the placebo group (P=.052).63 Further studies in BAD are warranted.
Eluxadoline
Eluxadoline, a mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist, reduced abdominal pain and improved stool consistency, urgency, and quality of life in 525 patients with IBS-D.64 The efficacy of eluxadoline in patients with BAD was studied in a single-center, open-label study of 24 patients with IBS-D, 12 of whom had BAD. In this study, it was shown that eluxadoline improved stool consistency and decreased abdominal pain in patients with IBS-D regardless of BAD status.65
Liraglutide
Liraglutide, a glucagon-like peptide 1 agonist, was superior to colesevelam in reducing daily stool frequency by 25% after 6 weeks of treatment (77% of participants on liraglutide compared with 50% of participants on colesevelam), although no significant difference in the improvement in stool consistency was noted.66,67
Conclusion
BAD is a common gastrointestinal disorder that results from effects of increased BAs in the colon affecting permeability, transit, and microbiome changes. Stool and serum BA noninvasive tests are now widely available to facilitate diagnosis. They are affordable and have shown good sensitivity and specificity in diagnosis or screening to exclude BAD. While BA sequestrants are currently the mainstay of treatment for BAD, newer medications targeting the FXR-FGF19 axis have shown promising results.
Disclosures
Dr Camilleri’s work on BAD was supported by grant R01-DK115950 from the National Institutes of Health. Dr Camilleri has also received research support for single-center or multicenter clinical trials in BAD on the effect of tropifexor (Aliment Pharmacol Ther. 2020;52(5):808-820), the effect of eluxadoline (Dig Dis Sci. 2022;67(8):3911-3921), and the effect of the FGF19 analog aldafermin (Gastroenterology. 2023;165(2):499-501.e4). Dr BouSaba has no relevant conflicts of interest to disclose.
Acknowledgement
The authors thank Mrs Cindy Stanislav for excellent secretarial assistance.
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