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Purpose: Previously, we demonstrated enhanced adaptation after small bowel resection (SBR) in intestinal-specific retinoblastoma (Rb)-deficient mice along with elevated levels of insulin-like growth factor 2 (IGF2) expression within the villi. The purpose of this study was to verify that the insulin-like growth factor 1 receptor (IGF1R) plays a role in this phenomenon., Methods: Inducible and intestinal specific Rb and IGF1R double knockout mice (iRb/IGF1R-IKO) (n=4) and Rb single knockout mice (iRb-IKO) (n=5) underwent 50% mid SBR. On post-operative day 28, mice were harvested, and structural adaptation was measured as changes in crypt depth and villus height. Rates of enterocyte proliferation were recorded. IGF2 expression within the remnant villi was measured via RT-PCR., Results: Both iRb-IKO and iRb/IGF1R-IKO mice demonstrated enhanced adaptation with at least a 45% increase in both crypt depth and villus height in the proximal and distal remnant bowel. Both groups showed elevation of IGF2 expression in the remnant villi, but there were no differences between the two groups., Conclusion: Epithelial IGF1R is dispensable for IGF2-mediated enhanced intestinal adaptation in retinoblastoma-deficient mice. Our findings suggest that IGF2 signals for enhanced adaptation in cells outside of the epithelium. Further investigation is needed to study the IGF2/IGF1R signaling interaction within the mesenchyme., Level of Evidence: Animal study - not clinical., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Intestinal adaptation structurally represents increases in crypt depth and villus height in response to small bowel resection (SBR). Previously, we found that neither epidermal growth factor receptor (EGFR) nor insulin-like growth factor 1 receptor (IGF1R) function was individually required for normal adaptation. In this study, we sought to determine the effect of disrupting both EGFR and IGF1R expression on resection-induced adaptation., Methods: Intestinal-specific EGFR and IGF1R double knockout mice (EGFR/IGF1R-IKO) (n=6) and wild-type (WT) control mice (n=7) underwent 50% proximal SBR. On postoperative day (POD) 7, structural adaptation was scored by measuring crypt depth and villus height. Rates of crypt cell proliferation, apoptosis, and submucosal capillary density were also compared., Results: After 50% SBR, normal adaptation occurred in both WT and EGFR/IGF1R-IKO. Rates of proliferation and apoptosis were no different between the two groups. The angiogenic response was less in the EGFR/IGF1R-IKO compared to WT mice., Conclusion: Disrupted expression of EGFR and IGF1R in the intestinal epithelial cells does not affect resection-induced structural adaptation but attenuates angiogenesis after SBR. These findings suggest that villus growth is driven by receptors and pathways that occur outside the epithelial cell component, while angiogenic responses may be influenced by epithelial-endothelial crosstalk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Enhanced structural features of resection-induced intestinal adaptation have been demonstrated following the administration of multiple different growth factors and peptides. Among these, the insulin-like growth factor (IGF) system has been considered to be significant. In this study, we employ mutant mouse strains to directly test the contribution of IGF2 and its enterocyte receptor (IGF1R) toward the adaptation response to massive small bowel resection (SBR)., Methods: IGF2-knockout (IGF2-KO) (n=8) and intestine specific IGF1R-knockout mice (IGF1R-IKO) (n=9) and their wild type (WT) littermates (n=5, n=7, respectively) underwent 50% proximal SBR. At post-operative day 7, structural adaptation was measured as crypt depth and villus height. Rates of enterocyte proliferation and apoptosis were also recorded., Results: The successful deletion of IGF2 and IGF1R expression in the enterocytes was confirmed by RT-PCR and Western blot, respectively. Normal adaptation occurred in both IGF2-KO and IGF1R-IKO mice after 50% SBR. Post-operative rates of proliferation and apoptosis in both IGF2-KO and IGF1R-IKO mice were no different than their respective controls., Conclusion: IGF2 and functional IGF1R signaling in enterocytes are both dispensable for resection-induced adaptation responses. The mechanism for IGF-stimulation of intestinal adaptation may involve other ligands or cellular compartments within the intestine., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Previous studies have shown that high-fat diet (HFD) enhances adaptation if provided immediately following small bowel resection (SBR). The purpose of this study was to determine if HFD could further enhance villus growth after resection-induced adaptation had already taken place. C57/Bl6 mice underwent a 50 % proximal SBR or sham operation and were then provided a standard rodent liquid diet (LD) ad lib. After a typical period of adaptation (7 days), SBR and sham-operated mice were randomized to receive either LD or HFD (42 % kcal fat) for an additional 7 days. Mice were then harvested, and small intestine was collected for analysis. Adaptation occurred in both SBR groups; however, the SBR/HFD had significantly increased villus height compared to SBR/LD. Reverse transcription-polymerase chain reaction of villus enterocytes showed a marked increase in CD36 expression in the SBR/HFD group compared with SBR/LD mice. While exposure to increased enteral fat alone did not affect villus morphology in sham-operated mice, HFD significantly increased villus growth in the setting of resection-induced adaptation, supporting the clinical utility of enteral fat in augmenting adaptation. Increased expression of CD36 suggests a possible mechanistic role in dietary fat metabolism and villus growth in the setting of short gut syndrome.