Bile Acid Malabsorption Research Articles

The Underlying Causes of Secondary Bile Acid Diarrhea May Confound Cancer Risk.

The Underlying Causes of Secondary Bile Acid Diarrhea May Confound Cancer Risk.

When and What to Test for Diarrhea: Focus on Stool Testing.

To review stool diagnostic tests in acute and chronic diarrhea. Narrative review of published literature. (A). In acute diarrhea, stool tests are indicated when there is strong pre-test probability of infectious etiology or C. difficile infection (CDI) suggested by >3 unformed bowel movements per 24h, symptoms lasting >7 days, and circumstances that are suggestive of infection. Several commercially available rapid tests for bacterial, viral or protozoal infections may be offered in addition to traditional methods (e.g. culture, microscopy), and provide a result within 6 hours. For CDI infection, a highly sensitive test such as glutamate dehydrogenase test is required; however, this does not distinguish infection from carrier state. That differentiation requires specialized nucleic acid amplification test (for toxin B) or enzyme immunoassays for toxin A or B, which are unfortunately not generally offered by microbiology labs. (B). Chronic diarrhea may result from inflammatory, fatty, osmotic or secretory causes; the commonest causes are IBS-D/functional diarrhea. Current recommendations in societal guidelines or clinical practice updates regarding stool tests in IBS-D/functional diarrhea in the absence of alarm symptoms include testing for giardia, calprotectin, fecal immunochemical test (FIT), and bile acid diarrhea (BAD). Comprehensive stool biochemical analyses (osmolality, pH, electrolytes) differentiate osmotic from secretory diarrhea and identify laxative abuse. Specific stool diagnostic tests for BAD and exocrine pancreatic insufficiency can lead to specific diagnosis and treatments. Surrogate markers associated with high fecal output and rapid transit in chronic diarrhea are stool form and colonic transit. Fecal testing is still very relevant in the practice of gastroenterology and deserves introduction of advanced microbiological and biochemical tests.

Prevalence and Pathophysiology of Loose Stools and Their Impact on Clinical Severity and Quality of Life in Women With Fecal Incontinence.

To compare the impact of fecal consistency with anorectal sphincter dysfunctions on clinical severity and quality of life (QoL) in women with fecal incontinence (FI). FI affects up to 24% of middle-aged women, significantly impacting their QoL. Pathophysiological studies have focused more on sphincter and anorectal dysfunctions than on the role of fecal consistency. A cross-sectional observational study evaluating anorectal physiology, neurophysiology, and fecal consistency with regard to clinical severity and QoL. Patients with a Bristol Stool Chart (BSC) score of 5 or more (BSC ≥5) underwent a breath test to detect bacterial overgrowth (small intestinal bacterial overgrowth), lactose or fructose/sorbitol malabsorption, and/or a cholestyramine test to detect bile acid malabsorption. We compared anorectal physiology, clinical severity, and QoL of those with BSC ≥5 with BSC <5. The study included 150 women with an average age of 64.81 ± 11.96. FI types varied: 64.38% had urge FI, 15.06% had passive FI, and 19.18% had both. Among them, 56.2% had BSC ≥5, linked to bile acid malabsorption (20.5%), lactose malabsorption (17.9%), small intestinal bacterial overgrowth (14.3%), and fructose/sorbitol malabsorption (14.3%). Anorectal dysfunctions were highly prevalent, with 49.1% showing external anal sphincter insufficiency, 9.8% internal, and 34.7% both. Those with BSC ≥5 experienced significantly worse clinical severity and QoL (St. Mark 17.3 ± 2.69 vs 12.9 ± 3.27), and more pronounced issues in Fecal Incontinence Quality of Life Scale dimensions of lifestyle, coping, depression, and EuroQol 5-dimension of anxiety/depression and pain/discomfort. Fecal consistency of BSC ≥5 significantly worsens clinical severity and QoL in women with FI. Specific diagnostic and therapeutic approaches addressing loose stools are needed before any rehabilitation treatment.

Fecal Bile Acids in Canine Chronic Liver Disease: Results from 46 Dogs.

The concentrations of fecal and serum bile acids (BAs) are known to be altered in human patients with chronic liver diseases (CLDs), especially those with biliary tract involvement (BTD). Scarce literature is available regarding fecal BA modifications during canine CLDs. This study aimed to evaluate fecal BAs in canine CLDs according to different clinical and clinicopathological variables. Forty-six dogs were enrolled. Canine feces were analyzed by HPLC. Cholic Acid (CA), Chenodeoxycholic Acid (CDCA), Ursodeoxycholic Acid (UDCA), Deoxycholic Acid (DCA), and Lithocholic Acid (LCA) were measured, and primary BAs (CA + CDCA), secondary BAs (UDCA + DCA + LCA), and the primary/secondary (P/S) ratio were calculated. Primary BAs (p < 0.0001), CA (p = 0.0003), CDCA (p = 0.003), the P/S ratio (p = 0.002), and total BAs (p = 0.005) were significatively higher in BTD dogs (n = 18) compared to in non-BTD dogs (n = 28). Fecal secondary BAs did not statistically differ between BTD and non-BTD dogs. Gastrointestinal clinical signs (p = 0.028) and diarrhea (p = 0.03) were significantly more prevalent in BTD dogs compared to in non-BTD dogs, supporting the hypothesis of some pathological mechanisms assimilable to bile acid diarrhea (BAD). Our results could reflect imbalances of the fecal BA metabolism in dogs with CLDs. Further studies involving gut microbiome and metabolomic assessment are needed to better understand the possible clinical implications of BA metabolism disruption and their potential role in canine CLDs.

Efficacy of Bile Acid Sequestrants in the Treatment of Bile Acid Diarrhea: A Meta-Analysis of Randomized Controlled Trials.

Bile acid sequestrants (BASs) have often been used for bile acid diarrhea (BAD) but carry a high risk of adverse events. New generations of BASs show promising results; however, their efficacy remains unclear. This systematic review and meta-analysis was conducted using PubMed, Cochrane, and Embase to assess randomized controlled trials (RCTs) published up to November 2023 to retrieve studies that measured the parameters before and after the administration of BASs. The outcomes assessed were cessation or improvement in diarrhea, fecal consistency, abdominal cramping, frequency of diarrhea, and adverse events. Risk ratios (RRs) and mean differences with 95% confidence intervals (CIs) were pooled using a random-effects model. Statistical analyses were conducted using RStudio version 4.1.2. The protocol was prospectively registered with PROSPERO (CRD42023445444). Seven RCTs with a total of 311 patients were included, of which 168 (54%) were randomized to BASs. Among BAS-treated patients, 101 (60.1%) received colesevelam, 40 (23.8%) received chenodeoxycholate, 18 (10.7%) received cholestyramine, and 9 (5.3%) received colestid. BASs were associated with a significant improvement in the cessation of diarrhea (RR 3.27; 95% CI 2.08 to 5.15; P ≤ .05) and liquid stool to normal fecal consistency (RR 2.69; 95% CI 1.56 to 4.65; P ≤ .05), as well as an increase in abdominal cramps (RR 5.27; 95% CI 1.21 to 22.93; P ≤ .05). There were no differences in urgency, adverse events, or nausea between groups. These findings indicate that BASs are effective in the treatment of BAD, as indicated by the improvement or cessation of diarrhea episodes.

The Effect of Colesevelam on the Microbiome in Postoperative Crohn's Disease.

While surgery plays a pivotal role in the management of ileal Crohn's disease, the risk of endoscopic recurrence following an ileocaecal resection can be greater than 65% within 12 months of surgery. More than 90% of patients with Crohn's disease have a concomitant diagnosis of bile acid diarrhea following an ileal resection. This pilot study aimed to assess whether the use of bile acid sequestrants in patients with Crohn's disease who have undergone a primary terminal ileal resection with concomitant bile acid diarrhea can alter the microbiome and prevent disease recurrence. Patients with Crohn's disease who underwent a primary terminal ileal resection and had symptoms of diarrhea within 1-3 months of surgery underwent 75SeHCAT testing for bile acid diarrhea. If positive (75SeHCAT ≤ 15%), patients were treated with colesevelam and stool samples were collected at 4 weeks, 8 weeks, and 6-12 months posttreatment. If negative (75SeHCAT > 15%), treatment was not given and were reviewed in the clinic as per local guidelines. All patients underwent a 6-12 month postoperative colonoscopy where further stool samples and mucosal biopsies were taken. Disease activity was established using the endoscopic Rutgeert's score, with disease remission defined as Rutgeert's score <i2 and disease recurrence ≥i2. 16S ribosomal RNA gene analysis was undertaken for the collected fecal and mucosal samples to assess α/β-diversity and microbial composition. A total of 14 patients who completed the study, 10 of whom had a 75SeHCAT positive diagnosis of bile acid diarrhea and were started on treatment with colesevelam. Four patients did not require treatment as 3 were asymptomatic and 1 had a negative 75SeHCAT scan. Three of the fourteen patients had disease recurrence at their 6-12 month postoperative colonoscopy assessment, of which 1 patient was taking colesevelam and 2 patients were not taking colesevelam. A total of 44 fecal samples and 44 mucosal biopsies underwent 16S ribosomal RNA gene analysis to assess α/β-diversity and microbial composition. In the colesevelam treated patients there was no significant difference in α/β-diversity pre- and posttreatment. Pretreatment, the 3 most abundant bacterial classes in all patients were Bacteroidia, Clostridia, and Gammaproteobacteria. Following 6-12 months of treatment, out of the 9 patients on colesevelam, 5/9 (55.6%) had a reduction in Bacteroidia, 9/9 (100%) had an increase in Clostridia, and 7/9 (77.8%) had a reduction in Gammaproteobacteria. Of the 2 patients not given colesevelam, one showed a reduction in Bacteroidia, increase in Clostridia and a reduction in Gammaproteobacteria. This small pilot study demonstrated that patients who were given colesevelam, were more likely to be in disease remission at their 6-12 months colonoscopy review compared with those not treated. Furthermore, treatment with colesevelam may have a role in altering the microbiome to help maintain remission states in postoperative Crohn's disease. Larger mechanistic studies are now needed to confirm these findings and demonstrate statistical significance as well as investigate whether this benefit may be present even in those patients with 75SeHCAT negative disease.

Paclitaxel chemotherapy disrupts microbiota-enterohepatic bile acid metabolism in mice

ABSTRACT Balanced interactions between the enteric microbiota and enterohepatic organs are essential to bile acid homeostasis, and thus normal gastrointestinal function. Disruption of these interactions by cancer treatment instigates bile acid malabsorption, leading to treatment delays, malnutrition, and decreased quality of life. However, the nature of chemotherapy-induced bile acid malabsorption remains poorly characterized with limited treatment options. Therefore, this study sought to characterize changes in hepatic, enteric, and microbial bile acid metabolism in a mouse model of chemotherapy-induced toxicity. Consistent with clinical bile acid malabsorption, chemotherapy increased fecal excretion of primary bile acids and water, while diminishing microbiome diversity, secondary bile acid formation, and small intestinal bile acid signaling. We identified new contributors to pathology of bile acid malabsorption in the forms of lipopolysaccharide-induced cholestasis and colonic crypt hyperplasia from reduced secondary bile acid signaling. Chemotherapy reduced markers of hepatic bile flow and bile acid synthesis, elevated markers of fibrosis and endotoxemia, and altered transcription of genes at all stages of bile acid metabolism. Primary hepatocytes exposed to lipopolysaccharide (but not chemotherapy) replicated chemotherapy-induced transcriptional differences, while gut microbial transplant into germ-free mice replicated very few differences. In the colon, chemotherapy-altered bile acid profiles (particularly higher tauromuricholic acid and lower hyodeoxycholic acid) coincided with crypt hyperplasia. Exposing primary colonoids to hyodeoxycholic acid reduced proliferation, while gut microbiota transplant enhanced proliferation. Together, these investigations reveal complex involvement of the entire microbiota-enterohepatic axis in chemotherapy-induced bile acid malabsorption. Interventions to reduce hepatic lipopolysaccharide exposure and enhance microbial bile acid metabolism represent promising co-therapies to cancer treatment.

S822 Prevalence of Bile Acid Malabsorption in IBS-D Patients: Systematic Review and Meta-Analysis

S822 Prevalence of Bile Acid Malabsorption in IBS-D Patients: Systematic Review and Meta-Analysis

Microscopic Colitis: An Underestimated Disease of Growing Importance

The aim of this paper is to raise awareness of MC as a clinically significant condition and to highlight its under-recognition, risk factors, diagnosis, management, and complications. This paper underlines the diagnostic and therapeutic challenges associated with the often nonspecific symptoms of MC. In order to create this article, we reviewed available articles found in the PubMed database and searched for articles using the Google Scholar platform. Microscopic colitis (MC) is a chronic inflammatory bowel disease, classified into three types: lymphocytic, collagenous, and unspecified. The average age of onset of MC is around 62–65 years and the disease is more common in women than men (nine times more common). The main symptom of MC is watery diarrhoea without blood, other symptoms include defecatory urgency, faecal incontinence, abdominal pain, nocturnal bowel movements, and weight loss. Once considered a rare disease, MC is now being diagnosed with increasing frequency, but diagnosis remains difficult. To date, a number of causative factors for MC have been identified, including smoking, alcohol consumption, medications (including NSAIDs, PPIs, SSRIs, and ICPIs), genetic factors, autoimmune diseases, bile acid malabsorption, obesity, appendicitis, and intestinal dysbiosis. It may be difficult to recognize and should be differentiated from inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), irritable bowel syndrome (IBS), coeliac disease, infectious bowel disease, and others. Diagnosis involves biopsy at colonoscopy and histopathological evaluation of the samples. Treatment consists of budesonide oral (the gold standard) or enema. Alternatives include bile acid sequestrants (cholestyramine, colesevelam, and colestipol), biologics (infliximab, adalimumab, and vedolizumab), thiopurines, methotrexate, and rarely, surgery.

Liraglutide and Colesevelam Changes Serum and Fecal Bile Acid Levels in a Randomized Trial with Patients with Bile Acid Diarrhea.

Both liraglutide and colesevelam improve bile acid diarrhea (BAD) symptoms. Colesevelam binds excess amounts of diarrhea-causing bile acids in the colon whereas the mode of action for liraglutide remains elusive. Here, we examined the impact of colesevelam and liraglutide treatment on the concentrations of bile acids in serum and feces and the fecal microbiota composition to better understand the two drugs' modes of action. Bile acid species were analyzed in serum and fecal samples from a randomized, double-blind, double-dummy trial at baseline and after three and six weeks of orally administered colesevelam (1,875 mg twice daily, n = 26) or subcutaneously administered liraglutide (uptitrated by weekly increments of 0.6 mg from 0.6 to 1.8 mg daily, n = 26) in patients with 75selenium-homotaurocholic acid test-verified, idiopathic, or post-cholecystectomy BAD. Fecal microbiota composition was analyzed by 16S rRNA gene amplicon sequencing at the same time points. Colesevelam increased the fecal concentrations of all bile acid species while it decreased serum concentrations of secondary bile acids. Liraglutide induced a small increase in serum unconjugated bile acid concentrations without affecting fecal bile acid concentrations. No changes in fecal microbiota composition were observed with either treatment. Colesevelam and liraglutide exhibit distinct effects on serum and fecal bile acid concentrations with colesevelam reducing serum concentrations of secondary bile acids and promoting fecal bile acid excretion while liraglutide enhances serum concentrations of unconjugated bile acids, potentially through deceleration of small intestinal transit time allowing more time for passive absorption of bile acids.

Additional criteria on scintigraphic testing for diagnosis of rapid colonic transit in patients with chronic diarrhea.

Colonic transit (CT) measured by validated scintigraphy using 111In-labeled activated charcoal particles is summarized using geometric center (GC) of isotopic distribution in four colonic regions and stool at 24 and 48 h. Diagnosis of rapid CT is currently based on GC24 ≥4.4 in females and >4.7 in males, which lack sensitivity. Our aim was to evaluate, in patients with chronic diarrhea with normal CT by GC24 and GC48, the diagnostic utility of CT change (∆GC) relative to sex-matched normal values. We evaluated two adult patient cohorts: 701 clinical patients (1994-2023) with chronic diarrhea and 76 research participants with irritable bowel syndrome with diarrhea (N = 63) or bile acid diarrhea (BAD, N = 13). Results of ∆GC were compared to 220 healthy controls' 95th percentiles (%ile) (≥2.0 females and ≥2.2 males). In the research cohort, we also analyzed (Spearman correlation) colonic ∆GC with ascending colon emptying T1/2 (AC T1/2), average stool frequency and consistency based on a daily diary, total fecal bile acid (BA) concentration, and % primary BA in a single stool sample. Among 701 clinical patients with normal GC24, 160 (22.3%) had rapid CT based on ∆GC 95th %ile in health. Among 76 research participants, an additional 20.6% IBS-D and 23% BAD had rapid CT ∆GC. Younger age and absence of diabetes mellitus were predictive of rapid ∆GC. ∆GC significantly correlated with AC T1/2 and with fecal BA. ∆GC identified an additional 21%-23% patients with rapid colonic transit among patients with diarrhea and normal GC24.

SeHCAT retention measurements may be compromised by traces of 177 Lu/ 177m Lu more than 90 days after 177 Lu-DOTATATE was administered.

[ 75 Se]tauroselcholic acid (SeHCAT) retention measurement provides a noninvasive test for bile acid diarrhea (BAD); however, it is sensitive to the presence of other radionuclides. Two SeHCAT patients at the Royal Free Hospital (RFH) had significant discrepancies between the lower photopeak (111-159 keV) and central photopeak (242-296 keV) windows, indicating contamination with a radionuclide other than 75 Selenium. These patients had received lutetium-177 oxodotreotide ( 177 Lu-DOTATATE) therapy 98 and 151 days before their SeHCAT tests. Traces of 177 Lu may be retained longer than typically modeled, along with the contaminant 177m Lu. This work includes a retrospective audit to examine the prevalence of SeHCAT tests being affected by 177 Lu and phantom measurements to investigate the potential impact. Of 579 patients who received 177 Lu-DOTATATE therapy at our center, 11 subsequently attended for a SeHCAT test. The two previously identified patients may have had compromised SeHCAT results; however, the other patients had longer intervals between their therapy and test, and their tests are believed to be valid. Spectra were acquired from a phantom containing either a SeHCAT capsule or a mixture of 177 Lu/ 177m Lu representative of a patient >90 days after their treatment. The SeHCAT spectrum was scaled to produce simulated day-7 spectra, and the SeHCAT retention that would have been calculated if 177 Lu/ 177m Lu were present was determined. All SeHCAT measurement windows are affected by the 177 Lu/ 177m Lu, producing clinically significant errors. Patients requiring SeHCAT testing should be asked whether they have ever received 177 Lu-DOTATATE. Patient-specific background measurements may be useful for checking for significant levels of other radionuclides.

443. IMPLEMENTATION OF A PROTOCOL FOR THE DIAGNOSIS AND MANAGEMENT OF LONG-TERM COMPLICATIONS FOLLOWING ESOPHAGECTOMY AND GASTRECTOMY

Abstract Background Surgery remains the mainstay of curative pathway treatment for most patients with esophageal and gastric cancer. Both esophagectomy and gastrectomy carry a significant risk of early post-operative morbidity. The gastrointestinal, nutritional, and endocrine effects of surgery can have a significant impact on patients’ quality of life and include small intestinal bacterial overgrowth, pancreatic exocrine insufficiency, bile acid malabsorption, hypoglycaemia, dumping, and others. Early diagnosis and treatment for these consequences of surgery can significantly improve quality of life. We developed a protocol for the investigation and management of patients with symptoms post-esophagogastric resection and implemented this within a nurse-led follow-up clinic. Methods A multi-disciplinary team was involved in the design of a protocol for the investigation and management of late effects following esophagectomy or gastrectomy. The protocol was implemented within a nurse-led clinic with prospective follow-up of all patients following resection. Following the introduction of the protocol, patients were divided into two groups; those with symptoms undergoing investigation prior to introduction of the protocol and all patients prospectively following introduction of the protocol in October 2022 to December 2023. The prevalence of patients undergoing investigation and the time from documentation of symptoms to diagnosis and the prevalence of each diagnosis were assessed. Results A total of 217 patients were studied, of whom 93 were part of the pre-protocol (symptomatic) group and the remaining 124 were part of the post-protocol prospective group. Within the pre-protocol group, 67 (72.0%) patients underwent investigation for late effects following surgery. The median time between the presentation of symptoms to diagnosis in the pre-protocol group was 7 months. Within the post-protocol prospective group, 33 (26.6%) patients underwent investigation for late effects following surgery. The median time between the presentation of symptoms to diagnosis in the post-protocol group was 2 months, representing a 71.4% reduction compared to the pre-protocol group. Conclusion Gastrointestinal, nutritional, and endocrine effects of esophagectomy and gastrectomy remain common. In symptomatic patients, a protocolised approach to investigation shortened the time to diagnosis and treatment by a median of 5 months. This approach can be successfully employed within a nurse-led follow-up pathway supported by a multidisciplinary team.

590. RESOLUTION OF SYMPTOMS AFTER OESOPHAGO-GASTRIC CANCER RESECTION (RESTORED)–STANDARDISING GASTROINTESTINAL SYMPTOMS AND CONDITIONS AFTER SURGERY: A MULTI-DISCIPLINARY EXPERT DELPHI STUDY

Abstract Background Oesophago-gastric cancer surgery negatively affects quality of life with a high post-operative symptom burden. Several conditions that may be diagnosed and treated after surgery are recognised. However, consensus regarding their definition and management is lacking. We aimed to develop consensus regarding the definition, investigation and management of the common symptoms and conditions, and triggers to consider disease recurrence, as a foundation for improving management and quality of life in these patients. Design Modified 2-round Delphi consensus study of a multidisciplinary expert panel. Results 86/127(67.7%) and 77/100(77.0%) responses were received in rounds 1 and 2. Consensus was achieved in defining 26 symptoms. For 10 conditions (anastomotic stricture, acid reflux, non-acid reflux, biliary gastritis, delayed gastric emptying, dumping syndrome, exocrine pancreatic insufficiency, bile acid diarrhoea, small intestinal bacterial overgrowth and carbohydrate malabsorption), definitions, diagnostic criteria, first and second-line investigation and first-line treatments were agreed. Consensus was not reached for third line investigation of some conditions, nor for second, third or fourth-line treatments for others. 12 of 14(85.7%) symptoms were agreed as triggers to consider cancer recurrence, during the early (&amp;lt; 1 year) and late (&amp;gt; 1 year) post-operative periods. Conclusion Expert consensus regarding symptoms, conditions and triggers to consider investigation for recurrence after oesophago-gastric cancer surgery was achieved. This will allow standardisation and timely diagnosis and treatment of post-operative conditions, reducing variation in care. It will facilitate comparative, prospective research to establish the incidence and response to treatment of these conditions, helping develop robust evidence to optimise patients’ quality of life.

Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023.

The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and antidiarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogues, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide.

Bile acid diarrhoea and metabolic changes after cholecystectomy: a prospective case-control study

IntroductionBile acid diarrhoea (BAD) can occur due to disruption to the enterohepatic circulation such as following cholecystectomy. However, the mechanism behind this is as yet unknown. The aim of this study was to determine the rate of post-cholecystectomy diarrhoea and to assess whether FGF19 within the gallbladder was associated with the development of BAD.MethodsThis was a prospective case-control study in which patients were assessed pre- and post- cholecystectomy (study group) and compared with patients also having laparoscopic surgery but not cholecystectomy (control group). Their bowel habits and a GIQLI questionnaire was performed to compare the pre- and post-operative condition of the two groups. Gallbladder tissue sample was tested for FGF19 and PPARα in the study group patients. A subset had serum lipid levels, FGF19 and C4 measurements.ResultsGallbladder PPAR α was found to have a significant correlation with stool consistency, with the lower the PPARα concentration the higher the Bristol stool chart number (i.e. looser stool). There were no significant correlation when assessing the effect of gallbladder FGF19 concentration on bowel habit, stool consistency, lipid levels, BMI or smoking. The study group showed a significant increase in triglycerides post-operatively, however there were no changes in cholesterol, HDL and LDL levels. Correlation of the increased triglyceride levels with stool consistency and frequency showed no significant resultsDiscussion and conclusionWe did not find any direct evidence that FGF19 levels within the gallbladder impact the development of post-cholecystectomy diarrhoea. There was however a significant increase in triglycerides postoperatively. There was also no correlation of bowel habits with PPARα suggesting the observed rise is independent of this pathway. Further work is required particularly relating to the gut microbiome to further investigate this condition.

Development and validation of a novel 7α-hydroxy-4-cholesten-3-one (C4) liquid chromatography tandem mass spectrometry method and its utility to assess pre-analytical stability.

7α-Hydroxy-4-cholesten-3-one (C4) is the common intermediary of both primary bile acids. C4 is recommended by the British Society of Gastroenterology for the investigation of bile acid diarrhoea (BAD) in patients with chronic diarrhoea. This project aimed to develop and validate an assay to quantitate C4 in serum and assess the stability of C4 in unseparated blood. Accuracy was underpinned by calibrating to quantitative nuclear magnetic resonance analysis. C4 was analysed in a 96-well plate format with a deuterated C4 internal standard and liquid-liquid extraction. Validation followed the 2018 Food and Drug Administration guidelines. To assess C4 stability, healthy volunteers (n=12) donated 8 fasted samples each. Samples were incubated at 20 °C for up to 72 h and retrieved, centrifuged, aliquoted and frozen for storage at different time points prior to C4 analysis. The C4 method demonstrated excellent analytical performance and passed all validation criteria. The method was found to be accurate, precise, free from matrix effects and interference. After 72 h of delayed sample separation, C4concentration gradually declined by up to 14 % from baseline. However, the change was not significant for up to 12 h. We present a robust method of analysing serum C4, offering a convenient alternative to 75SeHCAT for BAD investigation. C4 was found to decline in unseparated blood over time; however, after 12 h the mean change was <5 % from baseline. Our results suggest C4 is suitable for collection from both primary and secondary care prior to gastroenterology referral.

Comment on Yang et al. Bile Acid Diarrhea: From Molecular Mechanisms to Clinical Diagnosis and Treatment in the Era of Precision Medicine. Int. J. Mol. Sci. 2024, 25, 1544.

We have with great interest read the recent review on the molecular mechanisms underlying bile acid diarrhea (BAD) by Yang et al [...].

The GLP-1 Receptor Agonist Liraglutide Decreases Primary Bile Acids and Serotonin in the Colon Independently of Feeding in Mice.

Liraglutide, a glucagon-like peptide 1 analog used to treat type 2 diabetes and obesity, is a potential new treatment modality for bile acid (BA) diarrhea. Here, we show that administration of liraglutide significantly decreased total BAs, especially the primary BAs, including cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, and β-muricholic acid, in the liver and feces. In addition, liraglutide significantly decreased tryptophan metabolites, including L-tryptophan, serotonin, 5-hydroxy indole-3-acetic acid, L-kynurenine, and xanthurenic acid, in the colon, whereas it significantly increased indole-3-propionic acid. Moreover, the administration of liraglutide remarkably decreased the expression of apical sodium-dependent bile acid transporter, which mediates BA uptake across the apical brush border member in the ileum, ileal BA binding protein, and fibroblast growth factor 15 in association with decreased expression of the BA-activated nuclear receptor farnesoid X receptor and the heteromeric organic solute transporter Ostα/β, which induces BA excretion, in the ileum. Liraglutide acutely decreased body weight and blood glucose levels in association with decreases in plasma insulin and serotonin levels in food-deprived mice. These findings suggest the potential of liraglutide as a novel inhibitor of primary BAs and serotonin in the colon.

Algorithms or biomarkers in patients with lower DGBI?

Several organizations have proposed guidelines or clinical decision tools for the management of patients with disorders of gut-brain interactions (DGBI) affecting the lower digestive tract including irritable bowel syndrome and chronic idiopathic constipation. Such algorithms are based on sequential therapeutic trials and modifying the treatment strategy based on efficacy and adverse events. The aims of this review are to evaluate the evidence for efficacy of second- and third-line pharmacotherapies and to assess the evidence for the alternative option to manage subgroups of patients with symptoms suggestive of lower DGBI based on diagnostic tests or documented dysfunctions. The preeminent tests to identify such subgroups that present with symptoms that overlap with lower DGBI are detailed: digital rectal examination as well as anorectal manometry and balloon expulsion for evacuation disorders, detailed measurements of colonic transit, and diagnosis of bile acid diarrhea or carbohydrate malabsorption based on biochemical measurements. The review also addresses the cost implications of screening to exclude alternative diagnoses and the costs of therapy associated with the therapeutic options following an algorithmic approach to treatment from the perspective of society, insurer, or patient. Finally, the costs of the diagnostic tests to identify actionable biomarkers and the evidence of efficacy of individualized therapy based on formal diagnosis or documentation of abnormal functions are detailed in the review.