Intestinal Epithelial-Specific mTORC1 Activation Enhances Intestinal Adaptation After Small Bowel Resection

Abstract

Background & AimsIntestinal 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).MethodsWe performed 50% proximal SBR on mice to study adaptation. To manipulate i-mTORC1 activity, Villin-CreER transgenic mice were crossed with tuberous sclerosis complex (TSC)1flox/flox or Raptorflox/flox mice 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.ResultsAfter 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.ConclusionsSystemic, 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.

Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer

“…Along with apoptosis, necroptosis has emerged as a critical player in the regulation of intestinal homeostasis (13). Although mTOR has been previously linked to intestinal epithelium growth and proliferation (42)(43)(44)64), here we discovered an unexpected role for mTOR in epithelium necroptosis. Overall, studies from others (41,44) and us strongly suggest that precision control of mTOR activity in the gut epithelium is crucial for intestinal homeostasis.…”

“…Moreover, under nutrient-sufficient conditions, mTOR can contribute to autophagy inhibition through phosphorylating and inactivating the autophagy initiator ULK1 (40). Further, the emerging evidence has also begun to link mTOR to intestinal homeostasis and tumorigenesis (41)(42)(43)(44)(45). Genetic ablation of mTOR in IECs revealed a critical role for mTOR in the regulation of caloric restriction (41), Paneth/goblet cell development (42,44), and proliferation of transformed epithelium (43).…”

“…Further, the emerging evidence has also begun to link mTOR to intestinal homeostasis and tumorigenesis (41)(42)(43)(44)(45). Genetic ablation of mTOR in IECs revealed a critical role for mTOR in the regulation of caloric restriction (41), Paneth/goblet cell development (42,44), and proliferation of transformed epithelium (43). Given the widespread association between mTOR dysregulation, chronic inflammation, and colon cancer, it becomes imperative to understand whether and how environmental factors might influence mTOR activation in the pathogenesis of IBD and colon cancer.…”

First Degree Relatives of Patients with Celiac Disease Harbour an Intestinal Transcriptomic Signature that Might Protect them from Enterocyte Damage

“…At the molecular level the mTOR (mechanistic target of rapamycin) pathway, which has been shown to be central to the maintenance of the crypt-villous axis, is regulated in FDR in a way that promotes the formation of villi. The mTOR C1 and c myc - APC pathways have been shown to be essential in regulation of the crypt-villous architecture 18 , 19 . These studies also show that the mTOR C1 pathway is progressively downregulated from the crypt to the villous and that this may be involved in regulating epithelial cell renewal along the crypt-villous axis.…”

“…These studies also show that the mTOR C1 pathway is progressively downregulated from the crypt to the villous and that this may be involved in regulating epithelial cell renewal along the crypt-villous axis. The disruption of genes involved in the mTOR pathway has been shown to improve cellular proliferation in crypts and to enhance villous growth 19 . Therefore, the regulation of the mTOR C1 pathway may be central to the maintenance of the crypt-villous architecture in the intestinal mucosa of FDR.…”