AbstractStress-induced intestinal epithelial injury (IEI) and a delay in repair in infancy are predisposing factors for refractory gut diseases in adulthood, such as irritable bowel syndrome (IBS). Hence, it is necessary to develop appropriate mitigation methods for mammals when experiencing early-life stress (ELS). Weaning, as we all know, is a vital procedure that all mammalian newborns, including humans, must go through. Maternal separation (MS) stress in infancy (regarded as weaning stress in animal science) is a commonly used ELS paradigm. Drinking silicon-rich alkaline mineral water (AMW) has a therapeutic effect on enteric disease, but the specific mechanisms involved have not been reported. Herein, we discover the molecular mechanism by which silicon-rich AMW repairs ELS-induced IEI by maintaining intestinal stem cell (ISC) proliferation and differentiation through the glucagon-like peptide (GLP)2–Wnt1 axis. Mechanistic study showed that silicon-rich AMW activates GLP2-dependent Wnt1/β-catenin pathway, and drives ISC proliferation and differentiation by stimulating Lgr5+ ISC cell cycle passage through the G1–S-phase checkpoint, thereby maintaining intestinal epithelial regeneration and IEI repair. Using GLP2 antagonists (GLP23−33) and small interfering RNA (SiWnt1) in vitro, we found that the GLP2–Wnt1 axis is the target of silicon-rich AMW to promote intestinal epithelium regeneration. Therefore, silicon-rich AMW maintains intestinal epithelium regeneration through the GLP2–Wnt1 axis in piglets under ELS. Our research contributes to understanding the mechanism of silicon-rich AMW promoting gut epithelial regeneration and provides a new strategy for the alleviation of ELS-induced IEI.

01 Dec 2024·Clinical Nutrition ESPEN

Real-world experience with glucagon-like peptide 2 analogues in patients with short bowel syndrome and chronic intestinal failure: Results from an international survey in expert intestinal failure centers

Article

Author: Berner-Hansen, Mark ; Mercer, David ; Herlitz, Jean ; Greif, Sophie ; Wall, Elizabeth ; Gramlich, Leah ; Catron, Hilary ; Vanuytsel, Tim ; Moccia, Lisa ; Kumpf, Vanessa ; Lakananurak, Narisorn

BACKGROUND AND AIMSGlucagon-like peptide 2 (GLP-2) analogues are the first available disease-modifying treatments for patients with intestinal failure (IF) due to short bowel syndrome (SBS). Efficacy in terms of reduction of parenteral support (PS) has been demonstrated in multiple studies and real-world reports. However, it remains unclear how many patients are eligible to receive the treatment, when treatment is started after intestinal resection, how treatment efficacy is assessed outside of clinical trials, and how the treatment is modified in case of non-response or adverse events. The aim of this study was to investigate the real-world management of patients treated with GLP-2 analogues in expert centers around the world.METHODSA survey questionnaire was developed by a multidisciplinary working group consisting of 52 questions related to various aspects of multidisciplinary care of SBS-IF patients. The 17 questions related to the use of GLP-2 analogues in clinical practice were analyzed for this study. The online survey was sent to 33 participating centers in a phase 3 study of a long-acting GLP-2 analogue. Only responses from countries with access to commercially available GLP-2 analogues were included in the study. A descriptive analysis was performed for each question. Results are presented as median (interquartile range).RESULTSThe responses from the 19 expert IF centers with access to GLP-2 analogues indicated that 10 (10-20) % of patients with SBS-IF were treated with a GLP-2 analogue, which was less than the number of eligible patients (30 (25-40) %). In most centers (10 centers, 53%), GLP-2 therapy was started 6-12 months after the last intestinal resection, with 5 centers (26%) starting later (12-24 months). Multiple parameters were used in combination to determine the response to GLP-2 analogues of which the three most common were >20% decrease in PS (95%), at least 1 day of PS reduction per week (84%) and increased urinary output (68%). In non-responders GLP-2 therapy was stopped within the first year by 67% of the centers. Finally, strategies in case of significant adverse events include stopping the GLP-2 analogue (used by 79% of experts), dose reduction (67%) and temporary treatment interruption (62%).CONCLUSIONThe results of this survey completed by expert IF centers show the real-life use of GLP-2 analogues in clinical practice. Key learning points identified include the accounting for a period of intestinal adaptation before starting GLP-2 analogues and not stopping the treatment too early in case of non-response. The best strategy in case of adverse effects should be studied further.

29 Aug 2024·Cureus

Pancreatitis Associated With Teduglutide: A Disproportionality Analysis via the Food and Drug Administration Adverse Event Reporting System (FAERS) Database

Article

Author: Samarneh, Mark ; Sheingold, Zachary ; Gu, Joyce H

Introduction Teduglutide is a glucagon-like peptide-2 analog that is indicated for the treatment of short bowel syndrome (SBS) by reducing patient dependence on parenteral support. Due to the rarity of SBS as well as the recent timeline of the adoption of teduglutide, the safety of teduglutide is relatively poorly understood. Several recent clinical case reports have highlighted elevated pancreatic enzymes and pancreatitis as a concerning complication of teduglutide. This prompts a systematic study of the association between pancreatitis and teduglutide. Methods This study conducts a case-control design disproportionality analysis by using data from the US Food and Drug Administration Adverse Event Reporting System (FAERS). Reports from the first quarter of 2020 through the first quarter of 2024 were retrieved from this database, and a disproportionality analysis was conducted. The analysis consisted of traditional methods of analyzing adverse drug events such as the reporting odds ratio (ROR) and proportional reporting ratio (PRR), as well as Bayesian methods such as the empirical Bayes geometric mean (EBGM) and information component (IC). A confidence interval for ROR and PRR that excludes a ratio of 1 or a confidence interval for IC that excludes a score of 0 was used as the criterion for a statistically significant association between pancreatitis risk and teduglutide use. Results Out of 11,696 reports of teduglutide adverse effects in over four years of adverse effects data drawn from the FAERS database, 79 cases of pancreatitis were identified. The disproportionality analysis revealed an ROR of 3.73 (95% CI (2.99, 4.66)), a PRR of 3.71 (95% CI (2.97, 4.63)), an EBGM of 3.70, and an IC of 1.84 (95% CI (1.51, 2.16)). All of these statistics indicate a statistically significant association between pancreatitis risk and teduglutide use. Conclusion The results reveal a statistically significant association between pancreatitis risk and teduglutide use. Our findings highlight the necessity for the careful monitoring of pancreatitis in patients undergoing teduglutide therapy going forward.

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Indication	Highest Phase	Country/Location	Organization	Date
Gastrointestinal Diseases	Preclinical	IL	Entera Bio Ltd.	-

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