Peptide YY (PYY), a proabsorptive hormone, is released into the circulation and lumen of the small intestine after a meal. We have recently found that intraluminal PYY is proabsorptive in the ileum. The purpose of this study was to examine the effects of intraluminal administration of a new substituted PYY (22-36) analog on intestinal absorption of electrolytes and water. Twelve conditioned 20-kg dogs had 25-cm jejunal, 25-cm ileal, or 20-cm colonic Thiry-Vella fistulas (TVF) surgically constructed under general anesthesia (jejunal and ileal TVF, N = 6, and colonic TVF, N = 6). After a 2-week recovery period, the animals received the intraluminal PYY analog, BIM-43004, in the ileum (200 pmole/kg) or colon (300 pmole/kg) for 60 min after a 90-min steady-state basal period was confirmed. The TVF were perfused with an isotonic buffer solution containing [14C]polyethylene glycol as a volume marker. Ion and water transport were measured every 15 min. Net water absorptions were significant in the ileum and colon but not in the jejunum upon intraluminal administration of the PYY analog, BIM-43004. Colonic water absorptions were increased more than twofold above basal absorption rates and ileal absorptions were increased more than 1.5-fold upon addition of intraluminal BIM-43004. Sodium and chloride ion absorption in the colon and ileum paralleled water fluxes. We are describing for the first time a synthetic peptide analog of PYY that produces significant water and electrolyte absorption in the ileum and colon when administered luminally. This synthetic analog may have therapeutic potential in patients with malabsorptive disorders.