The structural and functional changes during intestinal adaptation are necessary to compensate for the sudden loss of digestive and absorptive capacity after massive intestinal resection. When the adaptive response is inadequate, short bowel syndrome (SBS) ensues and patients are left with the requirement for parenteral nutrition and its associated morbidities. Several hormones have been studied as potential enhancers of the adaptation process. The effects of growth hormone (GH), insulin-like growth factor-1, epidermal growth factor and glucagon-like peptide-2 (GLP-2) on adaptation have been studied extensively in animal models. In addition, GH and GLP-2 have shown promise for the treatment of short bowel syndrome in clinical trials in humans. Several lesser studied hormones, including leptin, corticosteroids, thyroxine, testosterone and estradiol, are also discussed.

Increased apoptosis in crypt enterocytes is a key feature of intestinal adaptation following massive small bowel resection (SBR). Expression of the proapoptotic factor Bax has been shown to be required for resection-induced apoptosis. It has also been demonstrated that p38-α MAPK (p38) is necessary for Bax activation and apoptosis in vitro. The present studies were designed to test the hypothesis that p38 is a key regulator of Bax activation during adaptation after SBR in vivo. Enterocyte expression of p38 was deleted by tamoxifen administration to activate villin-Cre in adult mice with a floxed Mapk14 (p38-α) gene. Proximal 50% SBR or sham operations were performed on wild-type (WT) and p38 intestinal knockout (p38-IKO) mice under isoflurane anesthesia. Mice were killed 3 or 7 days after operation, and adaptation was analyzed by measuring intestinal morphology, proliferation, and apoptosis. Bax activity was quantified by immunoprecipitation, followed by Western blotting. After SBR, p38-IKO mice had deeper crypts, longer villi, and accelerated proliferation compared with WT controls. Rates of crypt apoptosis were significantly lower in p38-IKO mice, both at baseline and after SBR. Levels of activated Bax were twofold higher in WT mice after SBR relative to sham. In contrast, activated Bax levels were reduced by 67% in mice after p38 MAPK deletion. Deleted p38 expression within the intestinal epithelium leads to enhanced adaptation and reduced levels of enterocyte apoptosis after massive intestinal resection. p38-regulated Bax activation appears to be an important mechanism underlying resection-induced apoptosis.

Purpose Intestinal adaptation following massive small bowel resection (SBR) permits improved absorption of enteral nutrition despite significant loss of bowel length. Epidermal growth factor (EGF) and its receptor (EGFR) have previously been established to play major roles in the pathogenesis of adaptation. This study tested the hypothesis that EGFR signaling within the epithelial cell compartment (enterocytes) is required for intestinal adaptation. Methods We developed a tamoxifen-inducible Villin-Cre/LoxP recombinant system for enterocyte-directed EGFR deletion using EGFR-floxed mice. EGFR-null mice and wild type (WT) littermates underwent either 50% proximal SBR or sham operation. Ileal tissue was harvested on post-operative day 7. To assess for adaptation, villus height and crypt depth as well as rates of crypt cell proliferation and apoptosis were measured. Results Adaptation after SBR occurred normally, as demonstrated by significant increases in villus height, crypt depth, crypt proliferative and apoptotic index in both the WT and EGFR-null mice. Conclusion Enterocyte EGFR expression is not required for the adaptation response to massive SBR. This novel finding suggests that enterocyte proliferation during adaptation is regulated by EGFR signaling in cells other than enterocytes, perhaps within the mesenchymal cell compartment of the bowel wall via factor(s) that are presently unknown.

Background-Adaptive villus growth following massive small bowel resection (SBR) is an important response to the loss of intestinal surface area and is regulated via epidermal growth factor receptor (EGFR) signaling. Increased levels of the pro-angiogenic chemokine (CXC) ligand 5 (CXCL5) have been found within the adapting bowel in which angiogenesis is increased. We sought to determine if CXCL5 was expressed specifically in the villus mesenchymal zone (area of increased blood vessel growth) and if this expression was affected by EGF.

Purpose The magnitude of intestinal adaptation is considered to correlate with the extent of small bowel resection (SBR). However, this association has never been tested in mice. We sought to test the hypothesis that a greater SBR will induce a greater adaptation response. Methods C57/B6 mice underwent 50% SBR, 75% SBR, or sham operation and were sacrificed on postoperative day 7. The magnitude of adaptation was compared between 50% SBR and 75% SBR as changes in villus height, crypt depth, as well as rates of apoptosis and proliferation. Results 75% SBR led to decreased survival and increased weight loss compared to 50% SBR. The remnant ileum of both 50% SBR and 75% SBR displayed similar crypt expansion, enhanced villi, and increased apoptotic indices. Proliferation rates increased after 50% and 75% SBR equally. Conclusion Models of resection greater than 50% in mice result in greater morbidity and mortality and do not magnify the adaptation response to massive SBR. The use of more extreme resection models does not appear to provide added benefit for investigating mechanisms of intestinal adaptation.