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.

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.

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.

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.

Randomised study: effects of the 5-HT4 receptor agonist felcisetrag vs placebo on gut transit in patients with gastroparesis.

BACKGROUND: Gastroparesis is defined by delayed gastric emptying with associated symptoms in the absence of mechanical obstruction. AIM: To evaluate pharmacokinetics and pharmacodynamics of felcisetrag, a highly selective 5-HT4 receptor agonist, on total gut transit in patients with documented delayed gastric emptying of solids. METHODS: Single-centre, placebo-controlled study of 36 participants receiving placebo, 0.1mg, 0.3mg or 1.0mg of felcisetrag I.V. infusion, daily, for 3 days. At baseline, each participant completed a 4h, 99m Tc-egg meal (300 kcal, 30% fat) gastric emptying test. Following infusion (Day 2), gastric, small bowel and colonic transit of solids were measured over 48h (same meal plus 111 In-charcoal delivered in methacrylate-coated capsule). Samples were collected for pharmacokinetics. The primary endpoint was gastric emptying T1/2 . Statistical analysis used baseline parameters as covariates (ANCOVA). RESULTS: Patients (22 idiopathic, 14 diabetic gastroparesis) were randomised to felcisetrag (0.1 mg, n = 10; 0.3 mg, n = 9; 1.0 mg, n = 7) or placebo (n = 10). Compared to placebo, felcisetrag significantly accelerated gastric emptying T1/2 , colonic filling at 6h, and 10% small bowel transit time (overall P < 0.01; all three doses individually Bonferroni corrected P < 0.05) for all three measurements. Ascending colon emptying (T1/2 ) was significantly accelerated (all doses), and colonic transit at 48 hours was accelerated with 0.1 mg and 0.3 mg felcisetrag compared to placebo. Pharmacokinetic results were dose proportional. Felcisetrag was well tolerated with no clinically significant findings from clinical laboratory, vital signs or ECG. CONCLUSION: I.V. felcisetrag significantly accelerated gastric, small bowel and colonic transit in patients with gastroparesis, and should be further evaluated for short-term treatment of gastric and intestinal motility disorders. ClinicalTrials.gov #NCT03281577.

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.

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.

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.

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.

Systematic review with meta-analysis: efficacy and safety of treatments for opioid-induced constipation.

BACKGROUND: When opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of µ-opioid analgesia. This led to the development of peripherally acting µ-opioid receptor antagonists (PAMORAs). AIM: To evaluate the efficacy of available PAMORAs and other approved or experimental treatments for relieving constipation in patients with opioid-induced constipation, based on a systematic review and meta-analysis of published studies. METHODS: A search of MEDLINE, EMBASE and EBM Reviews Cochrane Central Register of Controlled Trials was completed in July 2019 for randomised trials compared to placebo. FDA approved doses or highest studied dose was evaluated. Efficacy was based on diverse endpoints, including continuous variables (the bowel function index, number of spontaneous bowel movements and stool consistency based on Bristol Stool Form Scale), or responder analysis (combination of >3 spontaneous bowel movements or complete spontaneous bowel movements plus 1 spontaneous bowel movement or complete spontaneous bowel movements, respectively, over baseline [so-called FDA endpoints]). Adverse effects evaluated included central opioid withdrawal, serious adverse events, abdominal pain and diarrhoea. RESULTS: We included 35 trials at low risk of bias enrolling 13 566 patients. All PAMORAs demonstrated efficacy on diverse patient response endpoints. There was greater efficacy with approved doses of the PAMORAs (methylnaltrexone, naloxegol and naldemidine), with lower efficacy or lower efficacy and greater adverse effects with combination oxycodone with naloxone, lubiprostone and linaclotide. CONCLUSIONS: Therapeutic response in opioid-induced constipation is best achieved with the PAMORAs, methylnaltrexone, naloxegol and naldemidine, which are associated with low risk of serious adverse events.

Clinical presentation and characteristics of pelvic floor myofascial pain in patients presenting with constipation.

BACKGROUND: Patients with pelvic floor myofascial pain (PFMP) have puborectalis tenderness on digital rectal examination (DRE). Little is known about its significance to anorectal function in patients presenting with constipation. AIM: To characterize demographics, clinical characteristics, findings on anorectal manometry (ARM), diagnosis of rectal evacuation disorder (RED), colonic transit [normal (NTC) or slow (STC)], and imaging in constipated patients with PFMP and compare these features to constipation without PFMP. METHODS: We performed an electronic medical records review of patients with constipation evaluated by a single gastroenterologist between January 2008 and February 2019. Patients with PFMP were compared to controls with constipation but without PFMP (1:2 ratio). KEY RESULTS: A total of 98 PFMP cases and 196 controls were identified. Constipated patients with PFMP were more likely to have RED [OR 7.59 (3.82-15.09), P < .01]; controls were more likely to have either NTC [OR 4.25 (1.45-12.42), P < .01] or STC [OR 3.57 (1.45-8.78), P < .01]. RED in patients with PFMP is supported by comparison to controls: On DRE, they had increased resting tone [OR 2.25 (1.33-3.83), P < .01] and paradoxical contraction of the puborectalis upon simulated evacuation [OR 3.41 (1.94-6.00), P < .01]; on ARM, they had higher maximum resting pressure (102.9 mmHg vs 90.7 mmHg, P < .01) and lower rectoanal pressure gradient (-39.4 mmHg vs -24.7 mmHg, P < .01). CONCLUSIONS/INFERENCES: In constipated patients, PFMP is highly associated with RED. Its presence provides a valuable clue regarding the etiology of a patient's constipation; it should be assessed in all patients with constipation and should also be an additional target for management.

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.

Increased fecal primary bile acids in multiple myeloma with engraftment syndrome diarrhea after stem cell transplant.

Autologous stem cell transplant (ASCT) for multiple myeloma (MM) is associated with diarrhea during the peri-transplant period. We aimed to appraise mechanisms of peri-ASCT diarrhea in a prospective, longitudinal study of patients with MM. We compared by repeated measures (RM)-ANOVA daily bowel movements (BMs) and consistency [7-point Bristol Stool Form Scale (BSFS)], fecal calprotectin (intestinal inflammation), 13C-mannitol excretion in urine 0-2 h (small intestinal permeability), fasting serum C4 (bile acid synthesis) and total and primary bile acid in stool samples during baseline, peri-transplant period (Days 5-7 after stem cell infusion), and after hematological recovery post-ASCT. The 12 (5F, 7M) patients' median age was 61 y (IQR 54.8-63.3). All participants reported increased BMs (increase of 2 and 1 per day with and without engraftment syndrome, respectively). There were no significant increases in serum C4, total fecal bile acids, or intestinal permeability. Relative to patients without engraftment syndrome, four participants with engraftment syndrome had looser stool consistency (mean 2.6 points higher BSFS compared to without engraftment syndrome), increased primary fecal bile acids relative to baseline (>33 µmol/L vs. 6 µmol/L without engraftment syndrome), and increased fecal calprotectin compared to baseline (313 µg/mL vs. 35.6 µg/mL without engraftment syndrome; p = 0.06). Engraftment syndrome post-ASCT is associated with increased fecal primary bile acids.

Use of prucalopride in adults with chronic idiopathic constipation.

Introduction: Prucalopride is a selective 5-HT4 receptor agonist with colonic prokinetic activity. It was recently approved by the FDA for the treatment of chronic idiopathic constipation. Before this approval, there were limited options to improve colonic motility in the treatment of chronic idiopathic constipation. Areas covered: We systematically searched PubMed, Embase, ClinicalTrials.gov, and international conference presentations, and we reviewed all studies that evaluated prucalopride for the treatment of chronic idiopathic constipation in adults. In this review, we discuss the pharmacokinetics, pharmacodynamics, receptor interactions, phase I-IV clinical trials, and safety outcomes of prucalopride in adults, including the elderly. Expert opinion: Prucalopride is an effective agent to improve colonic motility, decrease colonic transit time, and increase complete spontaneous bowel movements in patients with chronic idiopathic constipation. Unlike previously available 5-HT4 receptor agonists such as cisapride and tegaserod, prucalopride does not interact with the cardiac hERG potassium channels or other serotonergic receptors in blood vessels and is not associated with an increase in major adverse cardiovascular events. Additionally, prucalopride has demonstrated promise in the treatment of gastroparesis, post-operative ileus, and opioid-induced constipation. Prucalopride directly stimulates colonic motility, differentiating it from all other medications (exclusively osmotic or chloride secretagogues) approved for chronic constipation in the last decade.