Combined stimulation of enterocyte proliferation and inhibition of apoptosis maximally enhances intestinal adaptation

Abstract

Introduction. Following massive small bowel resection (SBR), there is an important adaptive response in the remnant ileum characterized by augmented enterocyte proliferation and apoptosis. This study tests the hypothesis that combined stimulation of enterocyte proliferation and inhibition of apoptosis would enhance adaptation to a greater extent than either perturbation alone. Methods. Bax-null mice in which postresection apoptosis is not induced and wild-type (WT) littermates underwent 50% proximal SBR or Sham operation (bowel transection with reanastomosis). Mice from both groups were then randomized to receive administration of epidermal growth factor (EGF) a stimulator of enterocyte proliferation or saline, which served as a control. Roughly 3–5 mice per group were studied. After 3 days alterations in morphology (villus height, crypt depth) and enterocyte turnover (proliferation − % uptake BrdU; apoptosis − # apoptotic bodies identified by TUNEL immunostaining) were measured. Results. Adaptation after SBR occurred normally in WT and bax-null mice. Treatment with EGF resulted in an expected greater adaptation response in the WT mice. In bax-null mice EGF amplified the adaptation response even further (Figure). Conclusion. The magnitude of resection-induced adaptation is dependent upon a tight balance between rates of enterocyte proliferation and apoptosis. This study suggests that a dual therapeutic strategy directed at increasing enterocyte proliferation coupled with preventing apoptosis is better than either approach alone. These findings offer a new treatment paradigm as a means to encourage a maximal adaptation response following the acute loss of significant intestinal length.