Combined pharmacotherapy that increases proliferation and decreases apoptosis optimally enhances intestinal adaptation.

Background: Adaptation after massive small bowel resection (SBR) is associated with increased rates of enterocyte proliferation (P) and apoptosis (A). In the present study, we sought to determine the effect of dual therapy designed to increase P and simultaneously reduce A.

Methods: C57Bl/6 mice underwent a 50% small bowel resection (SBR) or sham operation, and then received an inhibitor of apoptosis (pan-caspase inhibitor), a stimulus for proliferation (epidermal growth factor; EGF), a combination, or vehicle control. After 3 days, adaptive morphology (villus height, crypt depth) and rates of enterocyte turnover (proliferation and apoptosis) were measured in the remnant ileum.

Results: Adaptation in controls and treated with the inhibitor was similar. EGF-treated mice demonstrated an even greater adaptive response. Combined therapy with the inhibitor and EGF resulted in maximal adaptation as gauged by the greatest increases in villus height and crypt depth and ratio of rates of P to A.

Conclusion: The capacity for adaptation following massive SBR is maintained via tight regulation of cell production and death. Pharmacologic intervention directed at increasing enterocyte proliferation while simultaneously decreasing apoptosis augments adaptation greater than either intervention alone and may provide a useful strategy to clinically amplify adaptation.