Establishing a Short Bowel Model in Mice as a Tool for Studying Genetic Risk Factors of Intestinal Failure

Abstract

Introduction: Short bowel syndrome (SBS) is a severe condition in which the patient is unable to acquire enough energy due to insufficient bowel length. Failed surgery is the main reason for SBS. Therapy consists in total parenteral nutrition or bowel transplantation. Since the patient population with SBS is heterogenous and it is therefore difficult to perform studies, we established an experimental model to study adaptation in surgery induced short bowel in mice. Herein we report the results after the first 104 animals. Methods: Male C57B6/J mice (Jackson Laboratories) weighing approximately 30 g were switched to liquid diet ad libitum 48h before surgery. They were anaesthetized using ketamine/xylazine intraperitoneally. Mice were intubated and ventilated throughout surgery. Using the operation microscope, a median laparotomy was performed, the cecum exteriorized and 11 cm of small bowel proximal to the cecum exposed. The mesentery of this small bowel including the very proximal part of the ascending colon was clipped using micro clips, the bowel then resected. The bowel was anastomosed using 10–0 nylon suture performing 11–13 full thickness stitches. The bowel was then replaced into the abdominal cavity, irrigated with saline and the abdomen closed. The animals were kept on liquid diet for at least 1 week. Animal condition was measured daily using the wellness score. Sham operation with transection 11 cm proximal to the cecum was used as control. The study was approved by the local animal welfare committee. Results: Animals that died on the day of surgery or day one postoperatively were excluded from analysis because anesthesiologic reasons were observed. The mean length of resected bowel was 11.3 cm. Median body weight loss was 16% in the resected group compared to 8% in the sham group. Unlike Sham controls, resected mice developed diarrhea and prolonged weight loss. Overall survival was 69% in the resected group and 95% in the sham group. Causes of death or surgical complications of all 104 resected mice were ileus (12%), anastomotic insufficiency (6%), anastomotic stenosis (3%), others such as GI bleeding, lung edema etc.) and unknown (21%). The surgical procedure was adapted in course of training including using thinner suture material and different feeding postoperatively. Conclusion: We established a clinical relevant mouse model to study mechanisms of intestinal adaptation and the influence of genetic risk factors (NOD2 mutation or others) on the course of SBS.