Stimulation of intestinal growth and function with DPP-IV inhibition in a mouse short bowel syndrome model

Glucagon-like peptide-2 (GLP-2) has been shown to be effective in patients with short bowel syndrome (SBS), but is rapidly inactivated by dipeptidyl peptidase-IV (DPP4). We used an orally-active DPP4 inhibitor (DPP4-I), MK-0626, to determine the efficacy of this approach to promote adaptation after SBS, determined optimal dosing, and identified further functional actions in a SBS mouse model. Ten week old mice underwent a 50% proximal small bowel resection (SBR). Dose optimization was determined over a 3-day post-SBS period. The established optimal dose was given for 7 days, 30 days, 90 days, and 7 days followed by 23 days washout period. Adaptive response was assessed by morphology, intestinal epithelial cell (IEC) proliferation (PCNA), epithelial barrier function (transepithelial resistance), RT-PCR for intestinal transport proteins, GLP-2R, and IGF-1R, and GLP-2 plasma levels. Glucose-stimulated sodium transport was assessed for intestinal absorptive function. Seven days of DPP4-I treatment facilitated an increase in GLP-2R levels, intestinal growth, and IEC proliferation. Treatment led to differential effects over time with greater absorptive function early, and enhanced proliferation at later time points. Interestingly, 7 day treatment followed by 23 days of non-treatment showed continued adaptation. DPP-IV-I enhanced IEC proliferative action up to 90-days post-resection, but this action seemed to peak by 30 days, as did GLP-2 plasma levels. Thus, use of DPP4-I treatment may prove to be a viable treatment for accelerating intestinal adaptation with SBS.