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

Abstract

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.