Alterations in pancreatic islet cell function in response to small bowel resection

Metabolic changes occur following intestinal resection; however, the effects on pancreatic function are unknown. Prior studies have demonstrated that glucagon-like protein-1 (GLP-1) signaling is a crucial player in the improved insulin sensitivity after bariatric surgery. In this study, we explore the effect of massive small bowel resection on gut hormone physiology and provide novel insights into the enteropancreatic axis.

Micromanaging the gut: unravelling the regulatory pathways that mediate the intestinal adaptive response

Short bowel syndrome occurs following the loss of a large portion of functional intestine and is associated with high morbidity and mortality. The intestine exhibits pronounced diurnal rhythms in glucose absorption and mounts a profound proliferative response following massive small bowel resection. Understanding the molecular pathways that underpin this could yield novel treatment options. Two in vivo models were employed using the nocturnally active Sprague Dawley® rat, namely daytime feeding and massive small bowel resection. Glucose absorption exhibited a 24-hour periodicity in the gut and peaked during maximal nutrient delivery, mediated by rhythms in the glucose transporter sodium glucose co-transporter 1 (SGLT1). Feeding during the day shifted the peak in the circadian clock gene PER1 and SGLT1. RNA interference and luciferase assays demonstrated that PER1 transcriptionally regulates SGLT1, linking for the first time clock genes and intestinal glucose absorption. Intestinal proliferation also exhibited diurnal rhythmicity, with peak absorptive surface area occurring during maximal nutrient availability. mir-16 is diurnally expressed in intestinal crypts, exhibiting minimal expression during maximal nutritional availability. mir-16 overexpression increased apoptosis and arrested proliferation in vitro. mir-125a was upregulated in intestinal crypts following 80% small bowel resection, and induced apoptosis and growth arrest upon overexpression in vitro. This work provides novel insights into the role of circadian clock genes, intestinal transporters and microRNAs in regulating intestinal absorption and proliferation and is the first demonstration of a role for microRNAs in these adaptive phenomena. Modulation of these pathways may represent a new therapeutic option for the management of short bowel syndrome.

Activated Notch signaling cascade is correlated with stem cell differentiation toward absorptive progenitors after massive small bowel resection in a rat

Notch signaling is thought to act to drive cell versification in the lining of the small intestine. The purpose of the present study was to evaluate the role of the Notch signaling pathway in stem cell differentiation in the late stages of intestinal adaptation after massive small bowel resection in a rat. Male Sprague-Dawley rats were randomly assigned to one of two experimental groups of eight rats each: Sham rats underwent bowel transection and reanastomosis, while SBS rats underwent 75% small bowel resection. Rats were euthanized on day 14. Illumina's Digital Gene Expression (DGE) analysis was used to determine Notch signaling gene expression profiling. Notch-related gene and protein expression was determined using real-time PCR, Western blot analysis, and immunohistochemistry. From seven investigated Notch-related (by DGE analysis) genes, six genes were upregulated in SBS vs. control animals with a relative change in gene expression level of 20% or more. A significant upregulation of Notch signaling-related genes in resected animals was accompanied by a significant increase in Notch-1 protein levels (Western blot analysis) and a significant increase in the number of Notch1 and Hes1 (target gene)-positive cells (immunohistochemistry) compared with sham animals. Evaluation of cell differentiation has shown a strong increase in total number of absorptive cells (unchanged secretory cells) compared with control rats. In conclusion, 2 wk after bowel resection in rats, stimulated Notch signaling directs the crypt cell population toward absorptive progenitors. NEW & NOTEWORTHY This study provides novel insight into the mechanisms of cell proliferation following massive small bowel resection. We show that 2 wk after bowel resection in rats, enhanced stem cell activity was associated with stimulated Notch signaling pathway. We demonstrate that activated Notch signaling cascade directs the crypt cell population toward absorptive progenitors.