We previously demonstrated in lactating mice a six- to eightfold increase in the intestinal uptake of the dietary protein, ovalbumin (OVA), administered by gavage. In this study, we tested the possibility that alterations in intestinal morphology, transit time, reduced luminal proteolysis, and enhanced association with the intestinal surface might account for the increased uptake of the protein observed in lactating mice. We found that these animals had a significant increase in length, wet weight, and surface area of the small intestine. No change in the number of Peyer's patches was noted. Intestinal transit was assessed by gavage administration of 125I-OVA and 10 mg OVA and localization of the peak of radioactivity 15, 30, and 60 min after feeding. Although motility (distance traveled per unit time) was not different in lactating and control mice at 15 and 30 min, the fraction of the small intestine traversed by the peak of radioactivity was less in lactating mice. Digestion of 125I-OVA administered by gavage with 10 mg unlabeled OVA was examined by trichloroacetic acid precipitation and gel permeation of the resulting fragments. Lactating and control mice did not show differences in digestion of 125I-OVA by either measurement. The association of 125I-OVA with small intestinal segments, however, was enhanced in lactating mice, especially in the second and third segments of the small intestine. Thus several factors including an increase in length and surface area of the small intestine, prolonged contact of protein with the small intestinal absorptive surface, and enhanced association of the protein with the intestinal surface contribute to increased uptake.(ABSTRACT TRUNCATED AT 250 WORDS)