Beyond intestinal failure: Expanding therapeutic frontiers of glucagon-like peptide-2 in gastrointestinal disease

This minireview examines glucagon-like peptide-2 (GLP-2), a gut hormone secreted after meals, and its growing role as a drug target well beyond its established use in short bowel syndrome (SBS). GLP-2 and its longer-acting synthetic analogues — most notably teduglutide (already approved) and the newer glepaglutide (in trials) — stimulate the intestinal lining to grow, tighten its barrier, and absorb more nutrients. In SBS patients, clinical trials show these drugs can meaningfully cut the amount of intravenous nutrition patients need while also improving liver health and quality of life. The review also synthesizes preclinical and early clinical evidence that GLP-2 analogues dampen gut inflammation, raising the possibility of future applications in inflammatory bowel disease. Safety data compiled so far suggest a low risk of promoting tumors, though the authors emphasize that long-term surveillance is still necessary given GLP-2's pro-growth action on intestinal tissue. The authors frame this shift — from managing malnutrition with IV fluids to actively regenerating gut tissue with hormones — as a paradigm shift in gastrointestinal medicine. Ongoing work on oral or less-frequent-dosing formulations and precision-medicine patient selection could broaden who benefits from these therapies.

• Teduglutide and glepaglutide both significantly raised plasma citrulline levels (a validated biomarker of functional enterocyte mass) and reduced fecal output in SBS clinical trials, with glepaglutide demonstrating efficacy at weekly or bi-weekly dosing intervals compared to teduglutide's daily injection schedule.
• GLP-2 analogues reduced parenteral nutrition (PN) volume requirements and, in some trial populations, enabled complete PN weaning, while concurrently improving markers of intestinal failure-associated liver disease (IFALD) — a major source of morbidity in long-term PN-dependent patients.
• Preclinical models and early clinical data support anti-inflammatory properties of GLP-2 (via cAMP-dependent and IGF-1-mediated pathways) relevant to inflammatory bowel disease, though this indication remains investigational; current safety evidence characterizes neoplastic risk as low but flags the need for prolonged post-marketing surveillance given the peptide's intestinal trophic activity.

This is a narrative minireview (not a primary clinical study or systematic review with formal PRISMA methodology) published in World Journal of Gastrointestinal Pharmacology and Therapeutics in 2026. The authors synthesized published preclinical studies, phase II–III randomized controlled trials, and regulatory-approval data on GLP-2 analogues (principally teduglutide and glepaglutide) across indications including SBS, IBD, and IFALD. No original patient data were collected; evidence was drawn from existing trial reports and mechanistic literature. The review is best characterized as an expert narrative synthesis covering mechanistic, efficacy, and safety dimensions of GLP-2 pharmacology.

As a narrative minireview, the article cannot provide pooled effect-size estimates, assess publication bias, or formally grade the quality of included evidence — limitations that a registered systematic review or meta-analysis would address. Most high-quality efficacy data still derive from SBS populations, leaving the IBD and IFALD applications largely preclinical or hypothesis-generating, so generalizability to those patient groups is speculative. Long-term oncologic safety data beyond trial follow-up windows are absent, which is a critical gap given GLP-2's intestinal pro-proliferative mechanism. The next logical experiments would be adequately powered RCTs of GLP-2 analogues in active IBD and head-to-head trials comparing glepaglutide versus teduglutide on PN-independence endpoints with ≥2-year follow-up.

This review extends the corpus's exploration of intestinal barrier repair and mucosal regeneration by mapping the GLP-2/IGF-1/cAMP axis as a pharmacologically actionable pathway — complementing [§155], which examines how Saccharomyces boulardii modulates intestinal barrier function through microbiota-dependent mechanisms, and collectively suggesting that barrier restoration can be achieved through both probiotic and hormonal routes. The anti-inflammatory dimension of GLP-2 discussed here parallels [§147], which addresses the therapeutic potential of vitamin D in IBD, since both agents modulate immune-epithelial crosstalk in the inflamed gut via distinct upstream signals. The review's treatment of intestinal failure-associated liver disease broadens the mucosal topic beyond luminal pathology, echoing the gut–systemic organ axis theme present in [§146], where lithocholic acid-mediated macrophage reprogramming in ulcerative colitis likewise implicates gut-derived signals in systemic inflammatory outcomes. Taken together, this minireview positions GLP-2 pharmacotherapy as a regenerative complement to the microbiota-modulating and dietary interventions that dominate the current corpus, filling a gap in hormone-based mucosal therapeutics.

• Saccharomyces Boulardii CNCM I-745 on Intestinal Barrier Function
  Both articles target intestinal barrier restoration but through mechanistically distinct routes — GLP-2 receptor agonism vs. probiotic Saccharomyces boulardii — making direct comparison informative for clinicians weighing pharmacologic versus microbiota-based barrier therapies.
• The Role of Vitamin D in Inflammatory Bowel Disease: Clinical Relevance and Therapeutic Potential
  Both reviews address therapeutic agents (GLP-2 analogues and vitamin D) with anti-inflammatory potential in IBD; comparing them reveals complementary immune-modulatory mechanisms and highlights whether combination strategies could be rationale.
• Intermittent fasting alleviates ulcerative colitis via lithocholic acid-mediated macrophage reprogramming
  The lithocholic acid–macrophage axis in ulcerative colitis described here offers a bile-acid-receptor-mediated parallel to GLP-2's enteroendocrine signaling, illustrating two gut-hormone/metabolite pathways that converge on mucosal immune regulation.
• Mechanism of FODMAP Restriction on FGID Patients
  FODMAP restriction in functional gastrointestinal disorders and GLP-2 pharmacotherapy in SBS represent opposite ends of the therapeutic spectrum — dietary subtraction vs. hormonal augmentation — but both ultimately aim to reduce luminal dysfunction, making the contrast conceptually grounding.
• Dietary Intervention with Brown Top Millet Starch Ameliorates Dyslipidaemia and Gut Leakiness in High Fat Diet Fed Models
  This dietary-intervention study examining gut leakiness in a high-fat diet model provides a preclinical comparator for gut-barrier endpoints used in GLP-2 trials, allowing readers to contextualize citrulline and permeability measures across pharmacologic and nutritional intervention paradigms.