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Dietary proteins are absorbed primarily as di- and tri- peptides via H⁺/peptide cotransporter (PepT1), a high-capacity, low-affinity apical membrane transporter. AIM: To characterize mechanism(s) of intestinal adaptation of peptide absorption after massive (70%) mid small bowel resection. METHODS: Male Lewis rats (200-250g) were assigned randomly to 4 groups; A) Non-operated control (n=8), B) Sham-operated (transection and primary anastomosis without resection) (n=4), C and D) 70% mid small bowel resection with primary anastomosis of remnant jejunum and ileum studied at 1wk (Group C) (n=5) and 4wk (Group D) (n=5) postoperatively resp. Duodenum, proximal jejunum, distal ileum and colon were harvested at 0, 1, 1, and 4wk in Groups A, B, C, and D resp. Uptake of the ¹⁴C-labeled non-hydrolizable dipeptide glycyl-sarcosine (gly-sar), was measured at a concentration of 1mM in all bowel segments by the everted sleeve technique. Mucosa was harvested to measure gene expression of PepT1 (mRNA by real time RT-PCR; protein by Western blot) and normalized to values for housekeeper genes (GAPDH and β-actin). Results are mean±SEM. RESULTS: Rats that had 70% small bowel resection lost 19±4g weight at 1wk (Group C) compared to 2±4g in sham operated (Group B) (p≤0.02), but gained 59±5g by 4wk (Group D). Gly-sar uptake (nmol/cm/min) did not differ between Groups A and B in any of the 4 regions evaluated (data not shown). Gly-sar uptake tended to be greatest in jejunum for all groups except Group C (Figure). Uptake in duodenum of Group C was greater than control Group A (p<0.003). This augmentation in duodenal uptake did not persist at 4wk in Group D. Gly-sar uptake in ileum was increased in Group D compared to Groups A and C (p<0.06 each). Colonic uptake of gly-sar was negligible in all groups. PepT1 gene expression studies (mRNA and protein) are pending. CONCLUSION: Early adaptation in peptide absorption to massive resection occurs in duodenum. Distal ileum requires longer to adapt. Early adaptive changes in duodenum are transient as distal ileum adapts.