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Current treatments for inflammatory bowel disease (IBD) treatment consist of anti-inflammatory products. In this study, we sought to induce the physiological secretion of glucagon-like peptide 2, a peptide with intestinal growth-promoting activity, via nanoparticles while simultaneously providing with immunomodulation by tailoring the nanoparticle surface. To this end, we developed hybrid lipid hyaluronate-KPV conjugated nanoparticles loaded with teduglutide for combination therapy in IBD. The nanocarriers induced (or did not induce) immunosuppression depending on the presence (or absence) of a hyaluronan-KPV functionalization. This strategy holds promise as a nanoparticle platform for combined mucosal healing and immunomodulation in IBD treatment. [Display omitted] •As proof-of -concept, we have demonstrated that lipid nanocapsules per se increased GLP-2 secretion in vitro and in vivo in a murine acute colitis model (DSS) while increasing citrulline (mucosal healing marker) and decreasing the colon weight/length ratio (hallmark of this model).•We encapsulated teduglutide within lipid nanocapsules and tested in vivo in two acute models of colitis (DSS and TNBS) the mucosal healing and anti-inflammatory properties of the formulation, demonstrating no immunomodulatory effect of the nanocarriers per se with increased GLP-2 levels.•We synthesized hyaluronan-KPV conjugates and functionalized our teduglutide-loaded nanocarriers demonstrating combined anti-inflammatory and mucosal healing properties in an acute DSS model and in a chronic DSS model (50 days) upon intermittent administration.•The pharmacological effect exerted by our nanocarriers induced sufficient stimulus as per providing with mucosal healing upon intermittent administration of our formulation during 3 consecutive days, 3 times over 50 days, 9 doses in total.

Teduglutide has been described as an effective treatment for parenteral support (PS) reduction in patients with short bowel syndrome (SBS). However, a quantitative summary of the available evidence is still lacking. PubMed/Medline, EMBASE, Cochrane library, OVID, and CINAHL databases were systematically searched up to July 2021 for studies reporting the rate of response (defined as a ≥20% reduction in PS) to teduglutide among PS-dependent adult patients. The rate of weaning (defined as the achievement of PS independence) was also evaluated as a secondary end-point. Ten studies were finally considered in the meta-analysis. Pooled data show a response rate of 64% at 6 months, 77% at 1 year and, 82% at ≥2 years; on the other hand, the weaning rate could be estimated as 11% at 6 months, 17% at 1 year, and 21% at ≥2 years. The presence of colon in continuity reduced the response rate (−17%, 95%CI: (−31%, −3%)), but was associated with a higher weaning rate (+16%, 95%CI: (+6%, +25%)). SBS etiology, on the contrary, was not found to be a significant predictor of these outcomes, although a nonsignificant trend towards both higher response rates (+9%, 95%CI: (−8%, +27%)) and higher weaning rates (+7%, 95%CI: (−14%, +28%)) could be observed in patients with Crohn’s disease. This was the first meta-analysis that specifically assessed the efficacy of teduglutide in adult patients with SBS. Our results provide pooled estimates of response and weaning rates over time and identify intestinal anatomy as a significant predictor of these outcomes.

Safety and usefulness of double-balloon enteroscopy (DBE) in patients with short bowel syndrome (SBS) are unknown. DBE could be effective in exploring the residual small bowel (SB) entirely, in monitoring patients receiving teduglutide (TED) treatment and, if necessary, could be operative. This study aimed to assess the safety, feasibility, and efficacy of enteroscopy in SBS patients. Single center, retrospective. We collected data on patients with SBS patients undergoing DBE from December 2019 to October 2023. We analyzed the technical success total enteroscopy rates, adverse events, diagnostic yield, and residual SB length measurement. A total of 12 SBS patients (8 females, median age at first enteroscopy, 66 years, interquartile range (IQR) 58-79) were included; among them, 10 received TED therapy (median interval from TED prescription to DBE surveillance 9.1 months (IQR 3.2-32.9)). Overall, 15 DBE procedures (3 retrograde) were performed, all of which were technically successful and completed without adverse events. The overall diagnostic yield was 60% for relevant findings, defined as conditions unknown before DBE. No SB malignancies were detected during the study period. In 80% of cases, a complete visualization of the SB was obtained with a reevaluation of the SB length. The median depth of maximal insertion was 85 cm (IQR 50-187). DBE is feasible, safe, and effective in SBS patients. Total enteroscopy can be frequently achieved with a single approach in these patients, allowing easy diagnostic and oncologic surveillance for SB and colonic malignancy.

Background and aimsTeduglutide, a GLP-2 analogue, may restore intestinal structural and functional integrity by promoting repair and growth of the mucosa and reducing gastric emptying and secretion, thereby increasing fluid and nutrient absorption in patients with short bowel syndrome (SBS). This 24-week placebo-controlled study evaluated the ability of teduglutide to reduce parenteral support in patients with SBS with intestinal failure.MethodsIn 83 patients randomised to receive subcutaneous teduglutide 0.10 mg/kg/day (n=32), 0.05 mg/kg/day (n=35) or placebo (n=16) once daily, parenteral fluids were reduced at 4-week intervals if intestinal fluid absorption (48 h urine volumes) increased ≥10%. Responders were subjects who demonstrated reductions of ≥20% in parenteral volumes from baseline at weeks 20 and 24. The primary efficacy end point, a graded response score (GRS), took into account higher levels and earlier onset of response, leading to longer duration of response. The intensity of the response was defined as a reduction from baseline in parenteral volume (from 20% to 100%), and the duration of the response was considered the response at weeks 16, 20 and 24. The results were tested according to a step-down procedure starting with the 0.10 mg/kg/day dose.ResultsUsing the GRS criteria, teduglutide in a dose of 0.10 mg/kg/day did not have a statistically significant effect compared with placebo (8/32 vs 1/16, p=0.16), while teduglutide in a dose of 0.05 mg/kg/day had a significant effect (16/35, p=0.007). Since parenteral volume reductions were equal (353±475 and 354±334 ml/day), the trend towards higher baseline parenteral volume (1816±1008 vs 1374±639 ml/day, p=0.11) in the 0.10 mg/kg/day group compared with the 0.05 mg/kg/day group may have accounted for this discrepancy. Three teduglutide-treated patients were completely weaned off parenteral support. Serious adverse events were distributed similarly between active treatment groups and placebo. Villus height, plasma citrulline concentration and lean body mass were significantly increased with teduglutide compared with placebo.ConclusionsTeduglutide was safe, well tolerated, intestinotrophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS with intestinal failure.ClinicalTrials.gov numberNCT00172185.

Background: In multiple clinical studies, teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome–associated intestinal failure (SBS–IF). The objective of this study was to assess adverse events (AEs) from a pooled data set. Methods: Safety data from four prospective clinical trials of teduglutide in patients with SBS–IF were assimilated. AEs were evaluated in patient groups based on treatment received in each study and in populations stratified to create distinct subgroups based on aetiology, bowel anatomy and baseline PS volume requirements. Results: Safety data are reported for up to 2.5 years, totalling 222 person-years exposure to teduglutide. In most patients, AEs were reported as mild or moderate in severity in all patient groups and occurred at comparable rates between patients who received teduglutide or placebo. Several common gastrointestinal AEs, including abdominal pain, nausea and abdominal distension, were reported more frequently earlier in the course of treatment, with their frequency declining over time. Fewer gastrointestinal AEs were reported in patients with vascular causes of SBS–IF and patients with most of their colon-in-continuity than in other patient subgroups. Across the patient stratification subgroups, the predominant treatment-emergent AEs for which patients receiving teduglutide had a significantly increased relative risk were abdominal distension and gastrointestinal stoma complication compared with patients receiving placebo. Conclusions: Teduglutide had a safety profile consistent with prior adult data and no new safety concerns were identified. The most frequently reported AEs were gastrointestinal in origin, consistent with the underlying disease condition and intestinotrophic actions of teduglutide. Clinical Trial Registry information: NCT00081458/EudraCT, 2004-000438-35; NCT00798967/EudraCT, 2008-006193-15; NCT00172185/EudraCT, 2004-000439-27; NCT00930644/EudraCT, 2009-011679-65

Teduglutide is a glucagon-like-peptide-2 analogue that reduces the need for parenteral support in patients with short bowel syndrome (SBS). Nevertheless, data about long-term therapy with teduglutide in children are still scarce. Our objective was to describe the real-life experience with teduglutide in children with SBS over the last 5 years in Spain. This was a national multicentre and prospective study of paediatric patients with intestinal failure (IF) treated with teduglutide for at least 3 months. The data included demographic characteristics, medical background, anthropometric data, laboratory assessments, adverse events, and parenteral nutrition (PN) requirements. Treatment response was defined as a > 20% reduction in the PN requirement. The data were collected from the Research Electronic Data Capture (REDCap) database. Thirty-one patients from seven centres were included; the median age at the beginning of the treatment was 2.3 (interquartile range (IQR) 1.4–4.4) years; and 65% of the patients were males. The most frequent cause of IF was SBS (94%). The most common cause of SBS was necrotizing enterocolitis (35%). The median residual bowel length was 29 (IQR 12–40) cm. The median duration of teduglutide therapy was 19 (IQR 12–36) months, with 23 patients (74%) treated for > 1 year and 9 treated for > 3 years. The response to treatment was analysed in 30 patients. Twenty-four patients (80%) had a reduction in their weekly PN energy > 20% and 23 patients (77%) had a reduction in their weekly PN volume > 20%. Among the responders, 9 patients (29%) were weaned off PN, with a median treatment duration of 6 (IQR 4.5–22) months. The only statistically significant finding demonstrated an association between a > 20% reduction in the weekly PN volume and a younger age at the start of treatment ( p  = 0.028).    Conclusions : Teduglutide seems to be an effective and safe treatment for paediatric patients with IF. Some patients require a prolonged duration of treatment to achieve enteral autonomy. Starting treatment with teduglutide at a young age is associated with a higher response rate. What is Known: •  Glucagon-like peptide-2 (GLP-2) plays a crucial role in the regulation of intestinal adaptation in short bowel syndrome (SBS). Teduglutide is a GLP-2 analog that reduces the need for parenteral support in patients with SBS. • Data about long-term therapy with teduglutide in children in real life are still scarce. What is New: • Most pediatric patients with SBS respond in a satisfactory manner to teduglutide treatment. The occurrence of long-term adverse effects is exceptional. • Starting treatment with the drug at a young age is associated with a greater response rate.

Teduglutide, a GLP-2 analogue, has been available in France since 2015 to treat short-bowel-syndrome (SBS)-associated chronic intestinal failure (CIF) but it remains very expensive. No real-life data on the number of potential candidates are available. The aim of this real-life study was to assess teduglutide initiation and outcomes in SBS-CIF patients. All SBS-CIF patients cared for in an expert home parenteral support (PS) center between 2015 and 2020 were retrospectively included. Patients were divided into two subpopulations: prevalent patients, already cared for in the center before 2015, and incident patients, whose follow-up started between 2015 and 2020. A total of 331 SBS-CIF patients were included in the study (156 prevalent and 175 incident patients). Teduglutide was initiated in 56 patients (16.9% of the cohort); in 27.9% of prevalent patients and in 8.0% of incident patients, with a mean annual rate of 4.3% and 2.5%, respectively. Teduglutide allowed a reduction in the PS volume by 60% (IQR: 40–100), with a significantly higher reduction in incident versus prevalent patients (p = 0.02). The two- and five-year treatment retention rates were 82% and 64%. Among untreated patients, 50 (18.2%) were considered ineligible for teduglutide for non-medical reasons. More than 25% of prevalent SBS patients were treated with teduglutide compared to 8% of incident patients. The treatment retention rate was >80% at 2 years, which could be explained by a careful selection of patients. Furthermore, this real-life study confirmed the long-term efficacy of teduglutide and showed a better response to teduglutide in incident patients, suggesting a benefit in early treatment.

Purpose The short- and long-term efficacy, safety, and pharmacokinetics of teduglutide were analyzed in adult Japanese patients with short bowel syndrome and intestinal failure (SBS-IF). Methods Patients received teduglutide 0.05 mg/kg/day in clinical trials (TED-C14-004, SHP633-306, and extension SHP633-307). Data were analyzed at 24 weeks and an interim data cut-off of 4.5 years. Results The parenteral support (PS) volume decreased by ≥ 20% for 9/18 patients at 24 weeks and in all 11 patients by data cut-off in SHP633-307. The mean (standard deviation) PS volume decreased from baseline at 24 weeks in TED-C14-004 (−30.1 ± 25.9%) and SHP633-306 (−25.6 ± 25.5%), and at data cut-off in SHP633-307 (−57.08 ± 28.49%). Teduglutide was absorbed quickly. The adverse events were consistent with the underlying disease and known adverse drug reactions. Anti-teduglutide antibody titers declined with long-term treatment. Conclusions In Japanese adults with SBS-IF, teduglutide treatment was associated with clinically meaningful reductions in PS requirements, similar to findings in prior international studies. No new safety concerns specific to the Japanese SBS-IF patient population were identified with short- or long-term teduglutide treatment. Anti-teduglutide antibody titers disappeared in most Japanese adults with long-term treatment. These results constitute the longest evaluation of teduglutide treatment within clinical trials reported to date.

Short bowel syndrome (SBS) is a chronic disease whose natural history requires a changing array of management strategies over time. Chief amongst these is the chronic use of parenteral nutrition (PN) to ensure adequate nutritional intake. With time and appropriate management, approximately half of all SBS patients will successfully regain a functional, baseline level of intrinsic bowel function that will allow for them to achieve PN independence. However, the other half of SBS patients will progress into chronic intestinal failure which warrants a change in therapy to include more aggressive medical and potentially surgical measures. This review examines the evolving treatment strategies involved in the management of SBS as well as intestinal failure.

Glucagon-like peptide-2 (GLP-2) is a gut hormone that plays a pivotal role in regulating intestinal epithelial cell growth and function, making it a promising therapeutic agent for intestinal damage and bone-related diseases. Nonetheless, the therapeutic potential of GLP-2 is substantially diminished due to its inactivation by dipeptidyl peptidase 4 (DPP-4). In recent years, advancements have been made in developing dipeptidyl peptidase 4 (DPP-4) resistant GLP-2 analogues with an extended half-life. The murine model with extensive experimental bowel resection maintained on parenteral nutrition has been used for assessing the physiology and pharmacology of GLP-2, and for the preclinical validation of GLP-2 analogues. However, it possesses certain limitations, such as complex procedure, considerable variability, and time-consuming nature. Consequently, there is a pressing need for the development of a cell-based bioassay to assess GLP-2 analogues. Here, we successfully developed a mechanism-of-action (MOA)-reflective cell-based reporter gene assay (RGA), utilizing a stable HEK293 cell line expressing the GLP-2 receptor and a luciferase reporter gene. This innovative approach allows for precise quantification of the potency of GLP-2 analogues. The RGA demonstrated good accuracy, linearity, precision, and specificity, with potential applications in stability testing, drug screening, and therapeutic monitoring of GLP-2 analogues. Moreover, RNA sequencing reveals the multi-target regulatory effect of GLP-2 analogues. The establishment of this RGA provides a valuable tool for evaluating the potency of GLP-2 analogues and the screening of potential therapeutic drugs targeting to GLP-2 receptor.