Comparison of biochemical, microbial and mucosal mRNA expression in bile acid diarrhoea and irritable bowel syndrome with diarrhoea.

OBJECTIVE: There are altered mucosal functions in irritable bowel syndrome with diarrhoea (IBS-D); ~30% of patients with IBS-D have abnormal bile acid (BA) metabolism (ABAM) and diarrhoea (summarised as BAD). AIM: To compare biochemical parameters, gastrointestinal and colonic transit, rectal sensation and pathobiological mechanisms in IBS-D without ABAM and in BAD (serum 7C4>52 ng/mL). DESIGN: In patients with Rome III criteria of IBS-D, we compared biochemical features, colonic transit, rectal sensation, deep genotype of five BA-related genes, ileal and colonic mucosal mRNA (differential expression (DE) analysis) and stool dysbiosis (including functional analysis of microbiome). Results in BAD were compared with IBS-D without ABAM. RESULTS: Compared with 161 patients with IBS-D without ABAM, 44 patients with BAD had significantly faster colonic transit, lower microbial alpha diversity, different compositional profile (beta diversity) and higher Firmicutes to Bacteroidetes ratio with evidence of decreased expression of bile acid thiol ligase (involved in transformation of primary to secondary BAs) and decreased sulfatases. In BAD (compared with IBS-D without ABAM), terminal ileal biopsies showed downregulation of SLC44A5 (a BA transporter), and ascending colon biopsies showed upregulation in barrier-weakening genes (CLDN2), serine protease inhibitors, immune activation, cellular differentiation and a cellular transporter (FABP6; BA binding). No DE of genes was documented in descending colon biopsies. The two groups had similar rectal sensation. CONCLUSION: Though sharing clinical symptoms with IBS-D, BAD is associated with biological differences and mechanisms that have potential to enhance diagnosis and treatment targeting barrier dysfunction, inflammatory and microbial changes.

Impact of Bile Acid Diarrhea in Patients With Diarrhea-Predominant Irritable Bowel Syndrome on Symptoms and Quality of Life.

BACKGROUND & AIMS: Bile acid diarrhea (BAD) affects approximately a quarter of patients with irritable bowel syndrome with diarrhea (IBS-D). We aimed to compare the demographics, bowel and somatic symptoms, and quality of life of patients with IBS-D, with or without BAD. METHODS: On one occasion, patients with IBS-D (positive for Rome III criteria) completed the following questionnaires: bowel disease questionnaire, Hospital Anxiety and Depression inventory, general quality of life (Symptom Checklist-90), and IBS-specific quality of life. A fasting serum C4 level higher than 52.5 ng/mL was used as a biomarker for BAD. Statistical analysis included a multiple variable logistic model to identify strong predictors of BAD in IBS-D. RESULTS: Among 219 patients (79% female) with IBS-D, 44 had BAD; the BAD group was significantly older and had a higher body mass index than the patients without BAD. Patients with BAD had more severe bowel dysfunction and impact on IBS-specific quality of life (need of toilet proximity) compared with patients with IBS-D without BAD. Patients with BAD were more likely than other IBS-D groups to receive antidiarrheals, bile acid binders, and antacid secretory agents. The severity of diarrhea and need of toilet proximity were predictors of BAD in IBS-D (P < .01). Patients with BAD were more likely to have a depression score higher than 8 on the Hospital Anxiety and Depression inventory. CONCLUSIONS: There is a greater impact on bowel and somatic symptoms and quality of life in IBS-D with BAD compared with IBS-D without BAD. Screening for BAD in IBS-D is especially relevant, with more severe and frequent diarrhea along with urgency.

Safety and Efficacy of Eluxadoline in Patients with Irritable Bowel Syndrome-Diarrhea With or Without Bile Acid Diarrhea: Open-Label Study.

BACKGROUND: Eluxadoline, a peripherally acting, mixed µ- and κ-opioid receptor (OR) agonist and δ-OR antagonist, is approved for treatment of adults with irritable bowel syndrome-diarrhea (IBS-D). About a third of IBS-D patients has bile acid diarrhea (BAD); opioids may stimulate TGR5 (bile acid) receptors. AIM: To evaluate eluxadoline's efficacy on altered bowel functions and safety in IBS-D patients with or without BAD. METHODS: In a single-center, phase 4, parallel-group, open-label study, patients with IBS-D (cohort 1) and patients with BAD were treated with eluxadoline, 100 mg tablets BID, with food for 4 weeks. Patients recorded bowel functions by electronic daily diary. BAD was based on fasting serum 7αC4 (> 52.5 ng/mL) or concurrent criteria of increased total or primary fecal BAs excreted in 48 h. We assessed efficacy on treatment compared to baseline in the two cohorts. Primary outcome measures were changes from baseline in average stool consistency Bristol Stool Form Scale (BSFS) score (range 1-7) and safety. RESULTS: Mean changes from baseline in cohorts 1 and 2 (data presented in this order) were similar for: BSFS score averaged over 4 weeks' treatment (- 1.25 and - 1.09); daily bowel movement frequency (- 1.48 and - 0.79); daily urgent bowel movements (- 0.52 and - 0.80); IBS-QoL (5.9 and 13.6); serum 7αC4 (- 5.59 and - 8.78 ng/mL). There were no deaths, serious treatment-emergent adverse events, or discontinuations due to adverse events during the study. CONCLUSION: Eluxadoline is similarly efficacious in the treatment of IBS-D and BAD, and it appears to be safe and efficacious as documented in large clinical trials.

Increased Fecal Bile Acid Excretion in a Significant Subset of Patients with Other Inflammatory Diarrheal Diseases.

BACKGROUND: Increased fecal bile acid excretion (IBAX) occurs in a third of patients with functional diarrhea. AIMS: To assess the prevalence of IBAX in benign inflammatory intestinal and colonic diseases presenting with chronic diarrhea. METHODS: All patients with known inflammatory diseases or resections who underwent 48 h fecal fat and BA testing for chronic diarrhea at a single center were included. Quiescent disease was based on clinical evaluation and serum, endoscopic and imaging studies. IBAX was defined by: > 2337 µmol total BA/48 h; or primary fecal BAs > 10%; or > 4% primary BA plus > 1000 µmol total BA /48 h. Demographics, fecal weight, fecal fat, stool frequency and consistency were collected. Nonparametric statistical analyses were used for group comparisons. RESULTS: Sixty patients had celiac disease (51 quiescent, 9 active), 66 microscopic colitis (MC: 34 collagenous, 32 lymphocytic), 18 ulcerative colitis (UC), and 47 Crohn's disease (CD). Overall, fecal fat, 48 h stool weight, frequency and consistency were not different among subgroups except for inflammatory bowel disease (IBD) based on disease location. Almost 50% patients with celiac disease and MC had IBAX, with a greater proportion with increased primary fecal BA. Among UC patients, rates of IBAX were higher with pancolonic disease. A high proportion of patients with ileal resection or CD affecting ileum or colon had IBAX. IBAX was present even with quiescent inflammation in UC or CD. CONCLUSIONS: A significant subset of patients with MC, quiescent celiac disease and IBD had increased fecal BA excretion, a potential additional therapeutic target for persistent diarrhea.

Associations of gastric volumes, ingestive behavior, calorie and volume intake, and fullness in obesity.

Whereas gastric emptying significantly predicts calorie intake, the association between gastric capacity and satiation and satiety is unclear. To study the associations between gastric volumes and ingestive behaviors with satiation and satiety in obesity, 62 healthy adult obese patients (57 female) with no eating disorders underwent measurements of satiety, as determined by kilocalories of ingestion at a buffet meal, and satiation by volume to comfortable fullness (VTF) and maximum tolerated volume (MTV), while drinking Ensure (30 mL/min). Fasting and postprandial gastric volumes were measured by validated single-photon emission computed tomography. We also measured eating [Weight Efficacy Life-Style Questionnaire score (WEL)] and exercise behaviors associated with obesity. Spearman correlation-assessed relationships of measured traits and linear regression analysis to identify predictors of satiation or satiety. The participants were aged 38 ± 10.1 yr and the body mass index (BMI) 36.8 ± 4.8 kg/m2. Fasting gastric volume was significantly correlated with VTF (rs = 0.3, P = 0.03), but not with MTV or buffet meal kilocalorie ingestion. Regression analysis identified sex (P = 0.02, with males having significantly higher fasting gastric volume) and fasting gastric volume (0.04) as predictors of higher VTF. An increase in fasting gastric volume of 50 mL resulted in a 6-mL increase in VTF. Buffet meal intake was inversely related to the ability to resist the urge to eat; factors associated with ingestive behavior (increase in total WEL score) significantly correlated with satiety and gastric accommodation (P < 0.05). Gastric capacity during fasting is associated with calorie intake to the point of comfortable fullness; factors associated with ingestive behavior are associated with satiety and gastric accommodation.NEW & NOTEWORTHY Buffet meal intake was inversely related to the ability to resist the urge to overeat. Factors associated with ingestive behavior significantly correlated with satiety and gastric accommodation. Gastric capacity during fasting is associated with calorie intake to the point of comfortable fullness; factors associated with ingestive behavior are associated with satiety and gastric accommodation.

Effects of Promotility Agents on Gastric Emptying and Symptoms: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Studies have reported a lack of association between improvements in gastric emptying (GE) and upper gastrointestinal (UGI) symptoms with promotility drugs. However, GE test methods were suboptimal in some studies. We assessed improvements in GE and UGI symptoms in patients given promotility agents in studies with optimal or moderate test methods (scintigraphy or breath test, solid meal, >2 hours duration) compared to studies with suboptimal GE test methods. METHODS: With an expert librarian, we completed an extensive search of publications in the Ovid MEDLINE (1946 to present), EMBASE (1988 to January 2018), and EBM Reviews Cochrane Central Register of Controlled Trials, without restrictions on language or year. Two independent reviewers evaluated the following inclusion criteria: randomized, blinded, parallel, or crossover trials of 5HT4 agonists, D2 receptor antagonist, or ghrelin agonists; trials that measured change in GE (T1/2) or composite UGI symptoms; trials of patients with functional dyspepsia and gastroparesis; and trials of GE test methods. Standardized mean differences (units expressed as SD) were used to standardize symptom assessments that were not uniform across studies. Random effects model was used to analyze data and meta-regression was used to evaluate the association between change in GE and UGI symptoms. RESULTS: Of 899 studies considered, 22 studies assessed change in GE; 23 evaluated UGI symptoms; and 14 evaluated GE and UGI symptoms. Promotility agents significantly accelerated GE (T1/2) in all studies (mean reduction in T1/2, 16.3 minutes; 95% confidence interval, -22.1 to -10.6 minutes) and in studies that used optimal GE test methods (mean reduction in T1/2, 23.6 minutes; 95% confidence interval, -32.3 to -14.9 minutes). Promotility agents also significantly reduced UGI symptoms (mean reduction, 0.25 SD; 95% confidence interval, -0.37 to -0.13 SD). Meta-regression found no significant association between change in GE and UGI symptoms. However, when only studies with optimal GE test methods were evaluated, there was a significant positive association between improvement in GE and UGI symptoms (P = .02). CONCLUSIONS: In a meta-analysis of published trials, we found promotility agents to significantly accelerate GE (when optimal test methods were used) and to produce significant improvements in UGI symptoms.

Effects of Colesevelam on Bowel Symptoms, Biomarkers, and Colonic Mucosal Gene Expression in Patients With Bile Acid Diarrhea in a Randomized Trial.

BACKGROUND & AIMS: Approximately one-third of patients with IBS-diarrhea (IBS-D) have increased bile acid (BA) synthesis or excretion. An open-label study showed benefits of colesevelam on bowel functions, consistent with luminal BA sequestration by colesevelam. We compared the effects of colesevelam vs placebo on symptoms and gene expression patterns in the sigmoid colon mucosa in patients with BA diarrhea associated with IBS-D. METHODS: We performed a double-blind, parallel-group study of 30 adults with IBS-D and evidence of increased BA synthesis or fecal excretion, from December 2017 through December 2018 at a single center. Patients were randomly assigned (1:1) to groups given colesevelam (3 tablets, 625 mg each) or matching placebo, orally twice daily for 4 weeks. Stool diaries documented bowel functions for 8 days before and 28 days during colesevelam or placebo. Stool and fasting serum samples were collected for analyses of fecal BAs and serum levels of C4 and FGF19. We measured colonic transit by scintigraphy, mucosal permeability by in vivo excretion of saccharide probes, and mRNA levels in rectosigmoid biopsies. All measurements were made at baseline and on the last days of treatment. The primary endpoints were change in total fecal BA concentration and stool consistency. RESULTS: Compared with placebo, colesevelam was associated with significant changes in sequestered fecal total BA excretion (P < .001) and serum levels of C4 and FGF19 (both P < .001), and with a mean increase in fecal level of deoxycholic acid (10%; P = .07) compared to placebo. Colesevelam decreased colon mucosal expression of NR1H4 and P2RY4 and increased expression of GPBAR1, compared with baseline. Stool frequency and consistency, colonic transit, and permeability did not differ significantly between groups. Colesevelam was well tolerated. CONCLUSIONS: In a randomized trial, we found that colesevelam increases delivery of total and secondary BAs to stool, hepatic BA synthesis, and colonic mucosal expression of genes that regulate BA, farnesoid X, and GPBAR1 receptors. Larger studies are needed to determine the effects on clinical responses. ClinicalTrials.gov no: NCT03270085.

The Role of Bile Acids in Chronic Diarrhea.

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.

Fecal Bile Acid Testing in Assessing Patients With Chronic Unexplained Diarrhea: Implications for Healthcare Utilization.

INTRODUCTION: Bile acid (BA) diarrhea is the cause in ∼26% of chronic unexplained (nonbloody) diarrhea (CUD) based on SeHCAT testing. To assess fecal BA excretion and healthcare utilization in patients with CUD. METHODS: In a retrospective review of 1,071 consecutive patients with CUD who completed 48-hour fecal BA testing, we analyzed the symptoms, diagnostic tests performed, and final diagnoses. RESULTS: After 135 patients were excluded because of mucosal diseases, increased BA excretion was identified in 476 (51%) of the 936 patients with CUD: 29% with selective increase in primary BA and 22% with increased total BA excretion (35% with normal primary BA excretion). There were no differences in demographics, clinical symptoms, or history of cholecystectomy in patients with elevated total or selective primary fecal BA excretion compared with patients with normal excretion. Before the 48-hour fecal BA excretion test was performed, patients completed on average 1.2 transaxial imaging, 2.6 endoscopic procedures, and 1.6 miscellaneous tests/person. Less than 10% of these tests identified the etiology of CUD. Total fecal BAs >3,033 µmol/48 hour or primary BAs >25% had a 93% negative predictive value to exclude mucosal disease. Among patients with increased fecal BA excretion, >70% reported diarrhea improved with BA sequestrant compared with 26% with normal fecal BA excretion. Patients with selective elevation in primary fecal BAs were 3.1 times (95% confidence interval, 1.5-6.63) more likely to respond to BA sequestrant therapy compared with those with elevated total fecal BAs. DISCUSSION: Increased fecal BA excretion is frequent (51%) in patients with CUD. Early 48-hour fecal BA evaluation has the potential to decrease healthcare utilization in CUD.

Clinical Features and Associations of Descending Perineum Syndrome in 300 Adults with Constipation in Gastroenterology Referral Practice.

BACKGROUND: Outlet obstruction constipation accounts for about 30% of chronic constipation (CC) cases in a referral practice. AIMS: To assess the proportion of patients with CC diagnosed with descending perineum syndrome (DPS) by a single gastroenterologist and to compare clinical, radiological, and associated features in DPS compared to patients with constipation. METHODS: We conducted a review of records of 300 consecutive patients evaluated for constipation by a single gastroenterologist from 2007 to 2019, including medical, surgical, and obstetrics history, digital rectal examination, anorectal manometry, defecation proctography (available in 15/23 with DPS), treatment, and follow-up. DPS was defined as > 3 cm descent of anorectal junction on imaging or estimated perineal descent on rectal examination. Logistic regression with univariate and multivariate analysis compared factors associated with DPS to non-DPS patients. RESULTS: Twenty-three out of 300 (7.7%, all female) patients had DPS; these patients were older, had more births [including more vaginal deliveries (84.2% vs. 31.2% in non-DPS, p < 0.001)], more instrumental or traumatic vaginal deliveries, more hysterectomies, more rectoceles on proctography (86.7% vs. 28.6% non-DPS, p = 0.014), lower squeeze anal sphincter pressures (p < 0.001), and lower rectal sensation (p = 0.075) than non-DPS. On univariate logistic regression, history of vaginal delivery, hysterectomy, and Ehlers-Danlos syndrome increased the odds of developing DPS. Vaginal delivery was confirmed as a risk factor on multivariate analysis. CONCLUSIONS: DPS accounts for almost 10% of tertiary referral patients presenting with constipation. DPS is associated with age, female gender, and number of vaginal (especially traumatic) deliveries.

Association between delayed gastric emptying and upper gastrointestinal symptoms: a systematic review and meta-analysis.

BACKGROUND: The relationship between delayed gastric emptying and upper GI symptoms (UGI Sx) is controversial. OBJECTIVE: To assess association between gastric emptying and UGI Sx, independent of treatment. DESIGN: We performed a systematic review and meta-analysis of the literature from 2007 to 2017, review of references and additional papers identified by content expert. We included studies evaluating the association between gastric emptying and nausea, vomiting, early satiety/postprandial fullness, abdominal pain and bloating. Covariate analyses included optimal gastric emptying test method, gastric emptying type (breath test or scintigraphy) and patient category. Meta-regression compared the differences based on type of gastric emptying tests. RESULTS: Systematic review included 92 gastric emptying studies (26 breath test, 62 scintigraphy, 1 ultrasound and 3 wireless motility capsule); 25 of these studies provided quantitative data for meta-analysis (15 scintigraphy studies enrolling 4056 participants and 10 breath test studies enrolling 2231 participants). Meta-regression demonstrated a significant difference between optimal and suboptimal gastric emptying test methods when comparing delayed gastric emptying with nausea and vomiting. On evaluating studies using optimal gastric emptying test methodology, there were significant associations between gastric emptying and nausea (OR 1.6, 95% CI 1.4 to 1.8), vomiting (OR 2.0, 95% CI 1.6 to 2.7), abdominal pain (OR 1.5, 95% CI 1.0 to 2.2) and early satiety/fullness (OR 1.8, 95% CI 1.2 to 2.6) for patients with UGI Sx; gastric emptying and early satiety/fullness in patients with diabetes; gastric emptying and nausea in patients with gastroparesis. CONCLUSIONS: The systematic review and meta-analysis supports an association between optimally measured delayed gastric emptying and UGI Sx.

Analysis of Fecal Primary Bile Acids Detects Increased Stool Weight and Colonic Transit in Patients With Chronic Functional Diarrhea.

BACKGROUND & AIMS: Patients with bile acid diarrhea (BAD) are identified based on increased levels of BAs in fecal samples collected over a 48-hr period while on a 100-gram fat diet (48-hr BA), retention of 75Se-labeled homocholic acid taurine, or serum levels of C4 or FGF19. BAD increases fecal weight and colonic transit. We investigated whether results of tests for BAD associate with increased fecal weight and more rapid colonic transit over a 24- or 48-hr period in patients with irritable bowel syndrome with diarrhea (IBS-D). We also estimated the prevalence of increased 48-hr fecal BAs in patients with chronic diarrhea. METHODS: We performed a retrospective study of 64 patients with IBS-D, 30 patients with IBS-constipation, 30 healthy volunteers (controls). We collected data on fecal weights (measured over a 48-hr period), colonic transit over a 24-hr period (measured by scintigraphy), and percentages of different BAs in stool samples. Colonic transit was measured as the geometric center (weighted average) of colonic counts on a scale of 1 (100% in ascending colon) to 5 (100% in stool). We performed area under the curve (AUC) analyses to assess the association between result of serum and stool tests and high fecal weight (>400g/48 hrs) or rapid colonic transit (>3.34, corresponding to isotope geometric center in sigmoid colon). We estimated the prevalence of increased 48-hr fecal BAs among 938 patients with chronic diarrhea. RESULTS: Total fecal 48-hr BA alone, or in combination with percentage of primary fecal BAs, identified patients with increased fecal weight with an AUROC of 0.86. Percentage of primary fecal BA alone identified patients with increased fecal weight with an AUROC of 0.73. Total fecal 48-hr BA alone identified patients with increased colonic transit with an AUROC of 0.65 and percentage of primary fecal BA alone identified patients with increased colonic transit with an AUROC of 0.69; combined data on these features identified patients with increased colonic transit with an AUROC of 0.70. Serum level of C4 identified patients with increased colonic transit with an AUROC of 0.60. Primary BAs >10% identified patients with increased fecal weight (sensitivity 49% and specificity 91%) and rapid colonic transit (sensitivity 48% and specificity 87%). Among the patients with chronic diarrhea, 45.6% had fecal primary BAs >10% and 27% had increased total fecal BAs (>2337 µmol/48 hrs). CONCLUSIONS: In a retrospective analysis of patients with IBS-D, we found percentage of primary BAs in fecal samples to provide an alternative to total fecal BAs in identification of patients with BAD or chronic diarrhea.

Characterization of Upper Gastrointestinal Symptoms, Gastric Motor Functions, and Associations in Patients with Diabetes at a Referral Center.

OBJECTIVES: Our aim was to characterize upper gastrointestinal (UGI) symptoms and associations in individuals with diabetes mellitus (DM) who had undergone evaluation of gastric emptying (GE) and accommodation (GA) at a referral center. METHODS: From the Mayo Clinic Rochester electronic medical records of adults with diabetes types 1 and 2 (DM1 and DM2) evaluated between January 1997 and December 2015, we extracted demographics, UGI symptoms, current medications, treatments for diabetes, GE solids by scintigraphy, GA by single photon emission computed tomography (SPECT), and diabetes complications. We compared subgroups with delayed (GE at 2 h <25% or GE at 4 h <75%), rapid (GE at 1 h > 35%), and normal GE, as well as reduced (<428 mL) and normal GA. RESULTS: We reviewed 108 patients (60.2% females, median age 49.0 years). Overall, 71.3% had DM2; one-third of these were insulin dependent and had fairly well-controlled diabetes (median HbA1c 6.7% (IQR 6.2; 7.9)). Manifestations of diabetic triopathy (peripheral neuropathy, nephropathy, and retinopathy) were uncommon at presentation with UGI symptoms. Nausea was the most common symptom (80.6%). There were single or combined GE (total 56%: rapid in 37%, slow in 19%) and GA (total 39%) abnormalities; there was normal GA and GE in 28%; 40.3% of the DM2 patients had accelerated GE at 1 h. GE at 1 h is associated with nausea/vomiting, and fasting gastric volume is associated with bloating. CONCLUSIONS: Among referred diabetic patients with UGI symptoms, GE and GA testing identifies potential targets for individualizing treatment and avoidance of empirical trials for the 28% with no disturbance of GE and GA.

Bile Acid Deficiency in a Subgroup of Patients With Irritable Bowel Syndrome With Constipation Based on Biomarkers in Serum and Fecal Samples.

BACKGROUND & AIMS: Short-term administration of delayed-release chenodeoxycholic acid to patients with irritable bowel syndrome with constipation (IBS-C) accelerates colonic transit and reduces symptoms. A preliminary study has shown that patients with IBS-C have reduced levels of bile acids (BAs) in feces and reduced synthesis of BA. We compared the levels of primary and secondary BAs in fecal samples collected over a 48-hour period from patients with IBS-C on a diet that contained 100 g fat per day, and compared them with levels in samples from healthy volunteers (controls). We also examined the relationship between overall colonic transit and biomarkers of BAs in patients with IBS-C. METHODS: We performed a retrospective study of 45 patients with IBS-C and 184 controls. For controls, we estimated the 10th percentile of fasting serum levels of 7α-hydroxy-4-cholesten-3-one (C4, n = 184) and 48-hour fecal BAs (n = 46), and the 90th percentile of the fasting serum level of fibroblast growth factor 19 (FGF19, n = 50). Colonic transit was measured in patients using a validated scintigraphic method. Data from patients with IBS-C were analyzed using Spearman correlations to determine the relationships among levels of C4, FGF19, fecal BAs, and colonic transit. RESULTS: Among the patients with IBS-C, 2 of 45 had low serum levels of C4, 4 of 43 had increased serum levels of FGF19, and 6 of 39 had low levels of BAs in feces collected over 48 hours. Patients with IBS-C had a significant increase in the proportions of fecal lithocholic acid compared with controls (P = .04), and a decrease in deoxycholic acid compared with controls (P = .03). In patients with IBS-C, there were inverse relationships between serum levels of C4 and FGF19 and correlations among levels of 48-hour fecal BAs, colonic transit, and serum C4 and FGF19. CONCLUSIONS: Approximately 15% of patients with IBS-C have reduced total BAs and level of deoxycholic acid in fecal samples collected over 48 hours on a 100 g fat diet. In these patients, lower levels of excretion of BAs into feces correlated with slower colonic transit.

Update on Bile Acid Malabsorption: Finally Ready for Prime Time?

PURPOSE OF REVIEW: To provide an update on the prevalence, pathophysiology, disease associations, and treatment options for bile acid malabsorption (BAM). RECENT FINDINGS: •Molecular mechanisms-BAs prevent water reabsorption and increase water secretion by intracellular mediators, increasing aquaporin channels and intracellular permeability. •Inflammatory bowel disease-new molecular mechanisms of BAM are identified in patients without ileal disease, including changes in expression of ileal BA transporter and nuclear receptors involved in BA homeostasis. •Microscopic colitis-BAM is one of the mechanisms leading to microscopic colitis. •Diagnostic testing-new diagnostic tests have been launched in the USA (serum C4 and fecal 48-h BA excretion); stimulated FGF19 has higher detection of BAM compared to fasting sample alone. •Treatment-investigational FXR agonists may provide a daily, oral option for treatment of BAM instead of BA sequestrants. There is a greater appreciation of the biological role of bile acids across multiple fields of medicine, including gastrointestinal indications.

Comparison of efficacy of pharmacological treatments for chronic idiopathic constipation: a systematic review and network meta-analysis.

OBJECTIVE: To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis. DATA SOURCES: We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane Central, as well as original data from authors or drug companies for the medications used for CIC. STUDY SELECTION: Phase IIB and phase III randomised, placebo-controlled trials (RCT) of ≥4 weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least one of four end points. DATA EXTRACTION AND SYNTHESIS: Two investigators independently evaluated all full-text articles that met inclusion criteria and extracted data for primary and secondary end points, risk of bias and quality of evidence. OUTCOMES: Primary end points were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary end points were change from baseline (Δb) in the number of SBM/week and Δb CSBM/week. RESULTS: Twenty-one RCTs (9189 patients) met inclusion and end point criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All prespecified end points were unavailable in four polyethylene glycol studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 CSBM/week end point. No drug was superior at improving the primary end points on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary end point, Δb in number of SBM/week. CONCLUSIONS: Current drugs for CIC show similar efficacy. Bisacodyl may be superior to prescription medications for Δb in the number of SBM/week in CIC.

Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-analysis.

There is no universally available laboratory test to diagnose bile acid diarrhoea (BAD). OBJECTIVE: To conduct a systematic review and meta-analysis to identify a biomarker for idiopathic BAD in patients with functional bowel disorder (FBD) with diarrhoea. DESIGN: We searched multiple databases through 15 May 2015. Data were only available to estimate the diagnostic yield of each test (the prevalence of a positive test). Estimates were pooled across studies using the random effects model. RESULTS: We included 36 studies, enrolling 5028 patients (24 using 75selenium homotaurocholic acid test (75SeHCAT) retention of <10%, 6 using fasting serum C4, 3 using fasting serum fibroblast growth factor 19 (FGF19) and 2 based on total faecal bile acid (BA) excretion over 48 h). The diagnostic yields (and 95% CI) of abnormal tests were: 0.308 (0.247 to 0.377) for 75SeHCAT retention (<10%), 0.171 (0.134 to 0.217) for serum C4, 0.248 (0.147 to 0.385) for serum FGF19 and 0.255 (0.071 to 0.606) for total faecal BA excretion over 48 h. The majority of the analyses were associated with substantial heterogeneity. Performance characteristics relative to a gold standard test could not be estimated. CONCLUSIONS: Overall, the test with the highest diagnostic yield conducted in the largest number of studies was 75SeHCAT retention, which is not widely available in many countries outside Europe and Canada. Using different diagnostic tests, 25% (average) of patients with lower FBD with diarrhoea has evidence of idiopathic BAD. These tests serve to identify idiopathic BAD among patients with FBD with diarrhoea. Further studies are required to appraise the performance characteristics of tests for idiopathic BAD.