Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in the gastrointestinal tract. GLP-1 actions regulate blood glucose, whereas GLP-2 exerts trophic effects on intestinal mucosal epithelium. Although GLP-1 actions are preserved in diseases such as diabetes, GLP-2 action has not been extensively studied in the setting of intestinal disease. We have now evaluated the biological effects of a human GLP-2 analog in the setting of experimental murine nonsteroidal antiinflammatory drug-induced enteritis. Human (h)[Gly(2)]GLP-2 significantly improved survival whether administered before, concomitant with, or after indomethacin. h[Gly(2)]GLP-2-treated mice exhibited reduced histological evidence of disease activity, fewer intestinal ulcerations, and decreased myeloperoxidase activity in the small bowel (P < 0.05, h[Gly(2)]GLP-2- vs. saline-treated controls). h[Gly(2)]GLP-2 significantly reduced cytokine induction, bacteremia, and the percentage of positive splenic and hepatic bacterial cultures (P < 0.05). h[Gly(2)]GLP-2 enhanced epithelial proliferation (P < 0.05 for increased crypt cell proliferation in h[Gly(2)]GLP-2- vs. saline-treated mice after indomethacin) and reduced apoptosis in the crypt compartment (P < 0.02). These observations demonstrate that a human GLP-2 analog exerts multiple complementary actions that serve to preserve the integrity of the mucosal epithelium in experimental gastrointestinal injury in vivo.