Recent studies have suggested that certain gastrointestinal peptides exert a trophic effect on the small intestine. We chose to evaluate the effect of glucagon and cholecystokinin-octapeptide (CCK-OP) on absorption of substrates in both developing and mature small intestine. Developing small intestine was evaluated in a rat fetal intestine transplant model, and mature rat small intestine was studied in in situ but isolated 10 cm segments of jejunum and ileum. Glucagon, 10 micrograms/kg/day, and CCK-OP, 45 micrograms/kg/day, were delivered continuously for 14 days through a subcutaneous osmotic pump. Intestinal absorption was determined with labeled substrates (14C-galactose and 14C-glycine) by a recirculation perfusion technique. Absorption results were expressed as percentage increase over control. The fetal intestine response to glucagon infusion was a 13% rise in galactose absorption and a 27% rise in glycine absorption. After CCK-OP infusion, fetal galactose absorption was 11% and glycine absorption rose 17%. Mature jejunal galactose absorption rose 53% and glycine absorption rose 55% after glucagon infusion. The ileal response to glucagon was a 271% rise in galactose absorption (p less than 0.05) and a 21% increase in glycine absorption. Infusion of CCK-OP decreased jejunal galactose absorption 3% but increased glycine absorption 41%. The ileal response was a 224% increase in galactose absorption (p less than 0.05) and a 19% increase in glycine absorption. Our data suggest that chronic administration of glucagon and CCK-OP can increase substrate absorption in developing and mature rat small intestine. Perhaps manipulation of the gastrointestinal hormone environment may result in increased absorption in man.