Therapeutic role of enterohormones in short bowel syndrome

Short bowel syndrome-associated chronic intestinal failure is the leading benign cause of long-term dependence on parenteral support in adults. Beyond the loss of absorptive surface area, intestinal resection profoundly modifies entero-hormonal signaling, particularly when the distal ileum and colon are removed or excluded. Enteroendocrine L-cells, mainly located in the terminal ileum and proximal colon, secrete glucagon-like peptide-2, glucagon-like peptide-1 and peptide YY in response to luminal nutrients. These hormones contribute to intestinal adaptation by promoting mucosal growth, enhancing absorptive capacity, modulating gastrointestinal secretion and motility, and activating ileal or colonic brake mechanisms. Among them, glucagon-like peptide-2 represents the main therapeutic pathway currently translated into clinical practice. Teduglutide, a degradation-resistant glucagon-like peptide-2 analogue, has demonstrated efficacy in randomized trials and real-world cohorts by reducing parenteral support requirements and enabling complete weaning in selected patients. However, treatment response is heterogeneous and depends on residual anatomy, baseline parenteral support burden, oral intake, colon-in-continuity, and response kinetics. Therefore, teduglutide should be initiated in carefully selected patients, after optimization of conventional intestinal rehabilitation and exclusion of contraindications, within experienced intestinal failure centers. Structured monitoring is essential to guide safe parenteral support reduction, prevent fluid imbalance, detect adverse events, and ensure appropriate long-term endoscopic and hepatobiliary-pancreatic surveillance. Future perspectives include long-acting glucagon-like peptide-2 analogues and dual glucagon-like peptide-1/glucagon-like peptide-2 agonists, which may further refine treatment strategies. This review summarizes the physiological role of entero-hormones in intestinal adaptation, the current evidence supporting glucagon-like peptide-2 analogue therapy, practical aspects of patient selection and monitoring, and unresolved questions in short bowel syndrome-associated chronic intestinal failure.