Background: Short-bowel syndrome (SBS) is the most common cause of neonatal intestinal failure. Recovery requires intestinal adaptation, dependent on enteral nutrition (EN) and growth factors such as glucagon-like peptide-2 (GLP-2), which is secreted from L cells in the ileum. Neonatal SBS often results in loss of ileum; therefore, we hypothesized that without ileum, endogenous GLP-2 production would be inadequate to promote adaptation. We compared endogenous GLP-2 production and adaptation in neonatal animals with SBS, with and without ileum. Methods: Neonatal piglets (4-6 d) were randomized to 75% mid-intestinal resection, 75% distal-intestinal resection, or sham control without resection. Postoperatively, all piglets commenced parenteral nutrition (PN), tapering as EN was increased to maintain specific growth. results: The resected SBS piglets developed intestinal failure, requiring a longer duration of PN support and experiencing fat malabsorption. The piglets without ileum were not able to wean from PN during the study and did not show adaptation, specifically growth in intestinal length or crypt hyperplasia on histology of the jejunum. Adaptation was observed in the resected SBS piglets with ileum, and these piglets also had an increased plasma GLP-2 level that was not observed in piglets without ileum. conclusion: SBS piglets with ileum undergo adaptation associated with increased endogenous GLP-2 production. SBS piglets without ileum undergo limited adaptation and severe intestinal failure, requiring prolonged PN support. This appears to be related to a deficiency in endogenous GLP-2 production. n eonatal intestinal failure secondary to short-bowel syndrome (SBS) has a particularly poor outcome. It is most common in preterm infants, and necrotizing enterocolitis is the most common cause (1-3). Necrotizing enterocolitis usually results in loss of ileum and right colon and carries a significant mortality (4).After intestinal resection, adaptation of the remnant intestine is essential for survival, compensating for the reduced absorptive surface area, both structurally and functionally (5). This process is regulated by several factors, including the stage of intestinal development, site and length of resection, the underlying disease, nutritional status, and gut-derived hormones and growth factors (6). Among the growth factors, glucagon-like peptide-2 (GLP-2) is considered to have an important role in inducing small-intestinal adaptation after resection. GLP-2 acts specifically at the GLP-2 receptor (GLP-2R), which is expressed throughout the small and large intestines but with greatest concentration in the jejunum (7). GLP-2 is uniquely trophic for the intestine (8). It can stimulate residual small-intestinal adaptation by increasing crypt cell proliferation and inhibiting apoptosis, thereby increasing villus height, crypt depth, mucosal mass, and overall small-intestinal length and weight (9-11). Functionally, GLP-2 increases activities of mucosal enzymes and therefore increases digestion and absorption (...