Real-World Management of High Stool Output in Patients with Short Bowel Syndrome: An International Multicenter Survey.

BACKGROUND: International practice guidelines for high-stool-output (HSO) management in short bowel syndrome (SBS) are available, but data on implementation are lacking. This study describes the approach used to manage HSO in SBS patients across different global regions. METHODS: This is an international multicenter study evaluating medical management of HSO in SBS patients using a questionnaire survey. Thirty-three intestinal-failure centers were invited to complete the survey as one multidisciplinary team. RESULTS: Survey response rate was 91%. Dietary recommendations varied based on anatomy and geographic region. For patients without colon-in-continuity (CiC), clinical practices were generally consistent with ESPEN guidelines, including separation of fluid from solid food (90%), a high-sodium diet (90%), and a low-simple-sugar diet (75%). For CiC patients, practices less closely followed guidelines, such as a low-fat diet (35%) or a high-sodium diet (50%). First-line antimotility and antisecretory medications were loperamide and proton-pump inhibitors. Other therapeutic agents (e.g., pancreatic enzymes and bile acid binders) were utilized in real-world practices, and usage varied based on intestinal anatomy. CONCLUSION: Expert centers largely followed published HSO-management guidelines for SBS patients without CiC, but clinical practices deviated substantially for CiC patients. Determining the reasons for this discrepancy might inform future development of practice guidelines.

Effects of a peripherally acting µ-opioid receptor antagonist for the prevention of recurrent acute pancreatitis: study protocol for an investigator-initiated, randomized, placebo-controlled, double-blind clinical trial (PAMORA-RAP trial).

BACKGROUND: Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression. METHODS: The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis. DISCUSSION: This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. TRIAL REGISTRATION: EudraCT no. 2021-000069-34. CLINICALTRIALS: gov NCT04966559. Registered on July 8, 2021.

A multidisciplinary team evaluation of management guidelines for adult short bowel syndrome.

BACKGROUND & AIMS: An international, multidisciplinary management working group (MWG) convened to review clinically useful short bowel syndrome (SBS) literature and identify gaps and inconsistencies in the management of adults with SBS. METHODS: Using nominal group technique for literature review, key publications were identified, discussed, and ranked by importance related to management of SBS. Gaps in management recommendations for SBS were identified upon critical review of the selected publications. RESULTS: Five guidelines, seven review articles, one series of six articles, and one single center series were selected and prioritized for their importance to SBS management. Evaluation of the articles by the MWG identified ten gaps and opportunities to standardize and improve SBS management. CONCLUSION: The main practice areas in need of more definitive guidelines are the management of high stool output and strategies to improve absorption of medications, nutrients, and fluids. An understanding of current real-world clinical practices related to these gaps could allow for development of best practice standards and improve patient-focused care.

Characteristics of adult intestinal failure centers: An international multicenter survey.

BACKGROUND: Current guidelines recommend that patients with chronic intestinal failure (CIF) should be managed by a multidisciplinary team (MDT). However, the characteristics of real-world IF centers and the patients they care for are lacking. The study aims to describe IF center characteristics as well as characteristics of patients with CIF across different global regions. METHODS: This is an international multicenter study of adult IF centers using a survey. The questionnaire survey included questions regarding program and patient characteristics. Thirty-three investigational centers were invited to participate. Each center was asked to answer the survey questions as one MDT. RESULTS: The survey center response rate was 91%. The median number of patients with CIF per center was 128 (range, 30-380). The most common disciplines reported were gastroenterologist (93%), dietitian (90%), nurse (83%), and advanced practitioner (nurse practitioner and physician assistant, 77%). There were centers that did not have a pharmacist, surgeon, psychologist, and social worker (30%, 37%, 60%, and 70%, respectively). The median full-time equivalents (FTEs) per 100 patients were 1.1 for nurses, 1 for dietitians, 1 for advanced practitioners, and 0.9 for gastroenterologists. Short bowel syndrome was the most common cause of CIF (50%) followed by intestinal dysmotility (20%). CONCLUSION: The majority of centers were managing around 100 patients with CIF. Despite the widespread use of the MDT, there are some variances in team characteristics. Gastroenterologists were the most common physicians supporting MDTs. In IF centers, one FTE of each core discipline was supported to manage 100 patients with CIF.

Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Glepaglutide is a novel, long-acting, glucagon-like peptide-2 analogue in a stable aqueous formulation for subcutaneous dosing to treat patients with short bowel syndrome. This study was conducted primarily to characterise the pharmacokinetics of glepaglutide in healthy subjects. METHODS: In this open-label, partially randomised, parallel-group study, healthy subjects were evenly randomised to glepaglutide 5 or 10 mg dosed subcutaneously once weekly for 6 weeks or to a single intravenous infusion of glepaglutide 1 mg. Each group comprised 15 subjects. Blood samples were drawn to determine plasma concentrations of the parent drug and its two main metabolites. Concentrations of glepaglutide were calculated as the sum of these three analytes. Citrulline was included as a pharmacodynamic biomarker. Safety was assessed throughout the study. RESULTS: From a comparison of pharmacokinetic parameters following subcutaneous versus intravenous dosing, it is concluded that the pharmacokinetics of glepaglutide following subcutaneous dosing are primarily determined by slow release of the two main glepaglutide metabolites from a subcutaneous depot. For subcutaneous dosing once weekly, the two main metabolites accounted for >98% of the overall glepaglutide exposure at steady state, with the parent drug contributing to less than 1% of exposure. The estimated mean (95% confidence interval) effective half-life for glepaglutide 5 and 10 mg was 124 (73-185) h and 88 (31-146) h, respectively. There was an increase in the citrulline concentration for both glepaglutide subcutaneous dose levels. No safety issues were identified. CONCLUSIONS: Slow release of active metabolites following subcutaneous dosing leads to a significantly protracted pharmacokinetic profile for glepaglutide. These results support that once- or twice-weekly subcutaneous dosing of glepaglutide could be an efficacious therapy for intestinal rehabilitation. GOV IDENTIFIER: NCT03279302.

Characteristics of chronic intestinal failure in the USA based on analysis of claims data.

BACKGROUND: This study investigated the prevalence, characteristics, and management of patients with chronic intestinal failure (CIF) in the United States in 2012-2020, based on parenteral support (PS) prescription claims and healthcare utilization. METHODS: Patients with CIF were identified from the Integrated DataVerse® claims database if they had at least two PS prescriptions within 6 months and a relevant diagnosis. Analysis included prevalence and characteristics of patients with CIF, their travel distance to receive PS prescriptions, and the distribution of PS providers and their prescribing history. RESULTS: Up to 24,048 patients with CIF were identified, equivalent to 75 patients per million. CIF affected people of all ages, being more prevalent in women than in men. Many providers signed PS orders for small patient groups over short time periods, whereas few providers signed PS orders for large patient groups long term, indicating a lack of centralization. The distribution of PS providers suggested a disparity in healthcare coverage in rural vs urban areas, leading to patients traveling considerable distances to receive PS prescriptions. This may be exacerbated by a decline of providers with expertise in CIF and nutrition. CONCLUSIONS: Healthcare disparities for patients with CIF have likely been obscured by the lack of CIF-specific diagnostic and procedure codes, obliging providers to code for their patients under other codes. Effective policy changes, including centralized care, revision of reimbursement models, and expansion of nutrition-focused education in addition to the newly introduced International Classification of Diseases codes, are needed to provide the best care for patients.

Nanomolar EP4 receptor potency and expression of eicosanoid-related enzymes in normal appearing colonic mucosa from patients with colorectal neoplasia.

BACKGROUND: Aberrations in cyclooxygenase and lipoxygenase (LOX) pathways in non-neoplastic, normal appearing mucosa from patients with colorectal neoplasia (CRN), could hypothetically qualify as predisposing CRN-markers. METHODS: To test this hypothesis, biopsies were obtained during colonoscopy from macroscopically normal colonic mucosa from patients with and without CRN. Prostaglandin E2 (PGE2) receptors, EP1-4, were examined in Ussing-chambers by exposing biopsies to selective EP receptor agonists, antagonists and PGE2. Furthermore, mRNA expression of EP receptors, prostanoid synthases and LOX enzymes were evaluated with qPCR. RESULTS: Data suggest that PGE2 binds to both high and low affinity EP receptors. In particular, PGE2 demonstrated EP4 receptor potency in the low nanomolar range. Similar results were detected using EP2 and EP4 agonists. In CRN patients, mRNA-levels were higher for EP1 and EP2 receptors and for enzymes prostaglandin-I synthase, 5-LOX, 12-LOX and 15-LOX. CONCLUSIONS: In conclusion, normal appearing colonic mucosa from CRN patients demonstrates deviating expression in eicosanoid pathways, which might indicate a likely predisposition for early CRN development and furthermore that PGE2 potently activates high affinity EP4 receptor subtypes, supporting relevance of testing EP4 antagonists in colorectal neoplasia management.

Dapiglutide, a novel dual GLP-1 and GLP-2 receptor agonist, attenuates intestinal insufficiency in a murine model of short bowel.

BACKGROUND: Extensive intestinal resection may lead to short bowel (SB) syndrome, resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon-derived hormones glucagon-like peptide-1 (GLP-1) and GLP-2. Two major problems of SB are epithelial surface loss and accelerated transit. Standard treatment now targets intestinal adaptation with a GLP-2 analogue to enlarge absorptive surface area. It is possible that additional benefit can be gained from a combination of GLP-1 and GLP-2 activity, with the aim to enlarge intestinal surface area and slow intestinal transit. METHODS: The GLP-1- and GLP-2-specific effects of the novel dual GLP-1 receptor (GLP-1R) and GLP-2 receptor (GLP-2R) agonist dapiglutide (rINN) were characterized in rodents. Furthermore, in a murine SB model of intestinal insufficiency with 40% ileocecal resection, the influence of dapiglutide on intestinal growth, body weight, food intake, volume status, and stool water content was tested against vehicle and sham-operated male mice. RESULTS: Dapiglutide significantly improves oral glucose tolerance, reduces intestinal transit time, and promotes intestinal growth. In the SB mouse model, dapiglutide promotes body weight recovery, despite unchanged intake of liquid diet. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Furthermore, dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. CONCLUSION: Dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents. In the murine SB model, combined unimolecular GLP-1R and GLP-2R stimulation with dapiglutide potently attenuates intestinal insufficiency and potentially also IF.

Decreased number of colonic tuft cells in quiescent ulcerative colitis patients.

BACKGROUND: Colonic tuft cells are epithelial chemosensory cells involved in barrier integrity, modulation of inflammatory responses and gut homeostasis. Recent evidence indicates an involvement of tuft cells in ulcerative colitis pathogenesis, though mechanisms remain largely unknown.Here, we quantified the colonic tuft cell population in patients with quiescent ulcerative colitis as compared to patients without identified colonic disease (controls). METHODS: In this retrospective study, we obtained endoscopic colonic sigmoid biopsies from 14 patients with quiescent ulcerative colitis and from 17 controls. In a blinded central-reading design, we identified tuft cells by immunohistochemistry using a cyclooxygenase-1 antibody as a marker and performed a simple counting by visual inspection. Poisson regression was employed for statistics and results were adjusted for gender, age and smoking status. RESULTS: Ulcerative colitis patients demonstrated a 55% reduced tuft cell count in colonic mucosa compared with the control group (95% confidence limit: range 31-71%, P = 0.0002). Ulcerative colitis patients had a mean tuft cells count of 46 tuft cells/mm2 (95% CI, 36-59), while controls demonstrated a mean of 104 tuft cells/mm2 (95% CI, 79-136). No interactions of other covariates, such as age, smoking status, total duration of ulcerative colitis disease and duration of clinical remission prior to study inclusion were detected between ulcerative colitis patients and controls. CONCLUSION: Quiescent ulcerative colitis patients have a relatively low number of colonic tuft cells. Further studies are warranted to explore the potential involvement of tuft cells in ulcerative colitis pathogenesis.

Glucagon-Like Peptide-2 Analogue ZP1849 Augments Colonic Anastomotic Wound Healing.

BACKGROUND: The enteroendocrine hormone glucagon-like peptide- (GLP-) 2 is a potent trophic factor in the gastrointestinal tract. The GLP-2 receptor (GLP-2R) is expressed in the stroma of the large bowel wall, which is the major therapeutic target area to prevent anastomotic leakage. We investigated the efficacy of the long-acting GLP-2 analogue ZP1849 on colonic anastomotic wound healing. METHODS: Eighty-seven male Wistar rats were stratified into four groups and received daily treatment with vehicle or ZP1849 starting one day before (day -1) end-to-end anastomosis was constructed in the left colon on day 0, and on days 0 (resected colon segment), 3, and 5, gene expressions of GLP-2R, Ki67, insulin-like growth factor- (IGF-) 1, type I (COL1A1) and type III (COL3A1) procollagens, cyclooxygenase- (COX-) 1, COX-2, and matrix metalloproteinase- (MMP-) 7 were quantified by RT-qPCR. Breaking strength, myeloperoxidase (MPO), transforming growth factor- (TGF-) ß1, and soluble collagen proteins were measured on days 3 and 5. RESULTS: ZP1849 treatment increased Ki67 (P < 0.0001) and IGF-1 (P < 0.05) mRNA levels in noninjured colon day 0, and postoperatively in the anastomotic wounds compared to vehicle-treated rats. ZP1849-treated rats had increased (P = 0.042) anastomotic breaking strength at day 5 compared with vehicle. COL1A1 and COL3A1 mRNA levels (P < 0.0001) and soluble collagen proteins (P < 0.05) increased from day 3 to day 5 in ZP1849-treated rats, but not in vehicle-treated rats. COX-2 mRNA and MPO protein levels decreased from day 3 to day 5 (P < 0.001) in both groups. ZP1849 treatment reduced TGF-ß1 protein levels on day 5 (P < 0.001) but did not impact MMP-7 transcription. CONCLUSIONS: The GLP-2 analogue ZP1849 increased breaking strength, IGF-1 expression, and cell proliferation, which may be beneficial for colonic anastomotic wound healing.

Indications and diagnostic yield of small-bowel capsule endoscopy in a real-world setting.

BACKGROUND: Indications and diagnostic yield of small-bowel video capsule endoscopy (SB-VCE) are communicated in recent clinical academic guidelines. However, guidelines are based mainly on relatively few, small, selection-biased studies at experienced centers, and thus we lack information on indications and diagnostic yield of SB-VCE in the real-world community setting. The aim of the study was to evaluate indications and diagnostic yield of SB-VCE in the real-world community setting. METHODS: Our local VCE clinical database was used to identify patients undergoing SB-VCE procedures over a 7-year period (2011-2018). Patients were broadly referred and underwent SB-VCE using PillCam™ SB 2 and SB 3 capsule systems. Procedures were reviewed by local endoscopists, who had undergone similar formal SB-VCE review training. Medical reports of the procedures were composed as such. We retrospectively reviewed all reports and gathered data regarding indications and findings. Diagnostic yield was considered positive if SB-VCE visualized any type of clinically significant pathological finding. RESULTS: 536 SB-VCE procedures in 516 patients were included in final assessment. Patient mean (± SD) age was 50 ± 20 years with approximately even female/male ratio (275:241). The overall proportion of positive findings was 42% (225/536). The two main indications were obscure gastrointestinal bleeding (occult/anemia or overt/active, OGIB) of 46% (246/536) and definite/suspected Crohn's disease (CD) of 39% (210/536). Positive SB-VCE findings were obtained in 44% (108/246) of procedures with indication of OGIB and in 50% (104/210) of procedures with indication of CD. CONCLUSIONS: The indications for SB-VCE are largely consistent with guidelines but with an apparently relatively low diagnostic yield in our real-world community setting.

Standardisation of diet and exercise in clinical trials of NAFLD-NASH: Recommendations from the Liver Forum.

Lifestyle modification is the foundation of treatment recommendations for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The design of clinical trials in NASH may be impeded by the lack of a systematic approach to identify and evaluate how lifestyle changes and/or modifications influence clinical trial outcomes and associated endpoints. Furthermore, there are additional uncertainties regarding the methods that can be utilised to better characterise and quantify lifestyle variables - which can influence disease activity and alter trial endpoints - to allow for comparisons of trial outcomes across different phases of research and/or within drug-classes. This summary by the Liver Forum's Standard of Care Working Group reviews currently available clinical data, identifies the barriers and challenges associated with the standard of care in NAFLD/NASH clinical trials, defines available assessments of lifestyle changes, and proposes approaches to better understand and define the influence of diet and exercise on NASH treatment in the context of different pharmacologic interventions. The ultimate objective is to propose tangible solutions which enable investigators, sponsors, and regulatory authorities to meaningfully interpret clinical trial outcomes and the impact of lifestyle modification on such outcomes as they pertain to phase I-IV clinical trials.

Serotonin, calcitonin and calcitonin gene-related peptide in acute pancreatitis.

OBJECTIVE: The aim of this study was to investigate plasma levels of serotonin, calcitonin and calcitonin gene-related peptide (CGRP) in the course of acute pancreatitis (AP) taking organ failure, etiology and severity into consideration. MATERIAL AND METHODS: Sixty consecutive patients with alcohol- or gallstone-induced AP were included over a 15-month period. Patients were treated according to a standardized algorithm and monitored for organ specific morbidity and mortality. Organ functions and blood samples were assessed on days 0, 1, 2 and 14 after hospital admission. Twenty healthy volunteers, matched for age and gender, comprised the reference group. RESULTS: Lower levels of serotonin were observed in patients at admission compared to healthy volunteers (p = .021). Serotonin levels increased from day 2 to 14 (p < .001), but with no relation to severity, etiology or organ failure. No difference in calcitonin levels was found in patients at admission compared to healthy volunteers. However, calcitonin levels decreased over time (p < .001) and higher levels were found in patients with respiratory failure (p = .039). No difference was observed in relation to severity or etiology. CGRP levels in patients at admission did not differ from healthy volunteers, nor did CGRP change over time or show any relationship to severity, etiology or organ failure. CONCLUSION: Our data suggest serotonin and calcitonin levels to be associated to time-course of AP, and calcitonin levels to organ dysfunction. We hypothesize that serotonin plays a pathogenic role in the compromised pancreatic microcirculation, and calcitonin a role as a biomarker of severity in AP.

Neutrophils in ulcerative colitis: a review of selected biomarkers and their potential therapeutic implications.

OBJECTIVES: This review article describes the role of neutrophils in mucosal injury and the resulting crypt abscesses characteristic of ulcerative colitis. We also review selected biomarkers for monitoring neutrophil presence and activity in the mucosa as well as their potential as therapeutic targets. MATERIAL: We have collated and selectively reviewed data on the most prominent well-established and emerging neutrophil-related biomarkers and potential therapeutic targets (calprotectin, lactoferrin, CXCR1, CXCR2, MMP-9, NGAL, elafin, HNE, pANCAs, MPO, CD16, CD177, CD64, HNPs, SLPI and PTX3) in ulcerative colitis. RESULTS: Systemic and intestinal neutrophil activity increases substantially in active ulcerative colitis, driving tissue damage and extra-intestinal manifestations. Calprotectin is a robust neutrophil and disease biomarker, and a few neutrophil-related targets are being clinically explored as therapeutic targets. CONCLUSION: We propose that targeting neutrophils and their inflammatory mediators per se is an opportunity that should be explored to identify new effective medical therapies. The overall clinical goal for neutrophil-targeted therapy will be to modulate, but not completely silence, neutrophil activity, thereby abolishing the destructive inflammation with associated acute and chronic tissue damage without compromising host-defense.