title: Intestinal Epithelial-Specific mTORC1 Activation Enhances Intestinal Adaptation After Small Bowel Resection.
abstract: OBJECTIVE
  Intestinal adaptation is a compensatory response to the massive loss of small intestine after surgical resection. We investigated the role of intestinal epithelial cell-specific mammalian target of rapamycin complex 1 (i-mTORC1) in intestinal adaptation after massive small bowel resection (SBR).
  
  
  METHODS
  We performed 50% proximal SBR on mice to study adaptation. To manipulate i-mTORC1 activity,Villin-CreERtransgenic mice were crossed with tuberous sclerosis complex (TSC)1flox/floxorRaptorflox/floxmice to inducibly activate or inactivate i-mTORC1 activity with tamoxifen. Western blot was used to confirm the activity of mTORC1. Crypt depth and villus height were measured to score adaptation. Immunohistochemistry was used to investigate differentiation and rates of crypt proliferation.
  
  
  RESULTS
  After SBR, mice treated with systemic rapamycin showed diminished structural adaptation, blunted crypt cell proliferation, and significant body weight loss. Activating i-mTORC1 via TSC1 deletion induced larger hyperproliferative crypts and disorganized Paneth cells without a significant change in villus height. After SBR, ablating TSC1 in intestinal epithelium induced a robust villus growth with much stronger crypt cell proliferation, but similar body weight recovery. Acute inactivation of i-mTORC1 through deletion of Raptor did not change crypt cell proliferation or mucosa structure, but significantly reduced lysozyme/matrix metalloproteinase-7-positive Paneth cell and goblet cell numbers, with increased enteroendocrine cells. Surprisingly, ablation of intestinal epithelial cell-specific Raptor after SBR did not affect adaptation or crypt proliferation, but dramatically reduced body weight recovery after surgery.
  
  
  CONCLUSIONS
  Systemic, but not intestinal-specific, mTORC1 is important for normal adaptation responses to SBR. Although not required, forced enterocyte mTORC1 signaling after resection causes an enhanced adaptive response.
authors.affiliation: Division of Pediatric Surgery, St. Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Lauren
authors.initials: L
authors.lastname: Barron
authors.affiliation: Division of Pediatric Surgery, St. Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Raphael C
authors.initials: RC
authors.lastname: Sun
authors.affiliation: Division of Pediatric Surgery, St. Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Bola
authors.initials: B
authors.lastname: Aladegbami
authors.affiliation: Division of Pediatric Surgery, St. Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Erwin
authors.affiliation: Division of Pediatric Surgery, St. Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Brad W
authors.initials: BW
authors.lastname: Warner
authors.affiliation: Division of Pediatric Surgery, St. Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
keywords: Differentiation; EGF, epidermal growth factor; IHC, immunohistochemistry; MMP, matrix metalloproteinase; PCR, polymerase chain reaction; Raptor; S6K, S6 kinase; SBR, small bowel resection; TAM, tamoxifen; TSC, tuberous sclerosis complex; TSC1; WT, wild type; i-TSC-/-, intestinal epithelial cell–specific tuberous sclerosis complex 1 null mice; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; p-HH3, phosphorylated histone H3