Stem cell and niche regulation in human short bowel syndrome.

Vered A Gazit,Miranda U Liang,Adam Surti,David M Alvarado,Deborah C Rubin,John Kirby,Mackenzie Geisman,Nicholas O Davidson,Elzbieta A Swietlicki,Raechel Mcdaniel,William J Symons,Obeid Ilahi,Matthew A Ciorba,Grant Bochicchio,Marc S Levin

doi:10.1172/jci.insight.137905

Abstract

Loss of functional small bowel surface area following surgical resection for disorders such as Crohn’s disease, intestinal ischemic injury, radiation enteritis, and in children, necrotizing enterocolitis, atresia, and gastroschisis, may result in short bowel syndrome, with attendant high morbidity, mortality, and health care costs in the United States. Following resection, the remaining small bowel epithelium mounts an adaptive response, resulting in increased crypt cell proliferation, increased villus height, increased crypt depth, and enhanced nutrient and electrolyte absorption. Although these morphologic and functional changes are well described in animal models, the adaptive response in humans is less well understood. Clinically the response is unpredictable and often inadequate. Here we address the hypotheses that human intestinal stem cell populations are expanded and that the stem cell niche is regulated following massive gut resection in short bowel syndrome (SBS). We use intestinal enteroid cultures from patients with SBS to show that the magnitude and phenotype of the adaptive stem cell response are both regulated by stromal niche cells, including intestinal subepithelial myofibroblasts, which are activated by intestinal resection to enhance epithelial stem and proliferative cell responses. Our data suggest that myofibroblast regulation of bone morphogenetic protein signaling pathways plays a role in the gut adaptive response after resection.

Highlights

Loss of functional small bowel surface area following surgical resection for Crohn’s disease, ischemic injury, radiation enteritis, trauma, or malignancy may result in short bowel syndrome (SBS), an important cause of morbidity, mortality, and health care costs in the United States [1]
There were 9 patients with more than 50% colon remaining in continuity, 1 patient with a sigmoid colostomy who had less than 50% colon remaining, and 7 patients with small bowel ostomies
We found that SBS enteroid size increased when cocultured with SBS intestinal subepithelial myofibroblasts (ISEMFs) compared with cocultures with normal patient ISEMFs (Figure 7, A and C)

Summary

Introduction

Loss of functional small bowel surface area following surgical resection for Crohn’s disease, ischemic injury, radiation enteritis, trauma, or malignancy may result in short bowel syndrome (SBS), an important cause of morbidity, mortality, and health care costs in the United States [1]. The remaining small bowel epithelium mounts an adaptive response, resulting in increased crypt cell proliferation, increased villus height, increased crypt depth, and enhanced nutrient and electrolyte absorption [2]. The functional and morphometric adaptive response is best described in animal models. In humans, this response is influenced by remnant small bowel length, the presence or absence of a colon, and underlying disease activity, yet even accounting for these factors, the response may be unpredictable and inadequate [1, 3]. Even with an accurate assessment of remnant small bowel length, it may require from 2 to 5 years to determine which patients will wean off parenteral (intravenous) nutrition [4]

Methods

Results

Conclusion