Intestinal Adaptation in Proximal and Distal Segments: Two Epithelial Responses Diverge After Intestinal Separation

Introduction: In short bowel syndrome (SBS), luminal factors influence adaptation in which truncated intestine increases villus lengths and crypt depths to increase nutrient absorption. No study has evaluated the effect of adaptation within the distal intestine after intestinal separation. We evaluated multiple conditions including Igf1r inhibition in proximal and distal segments after intestinal resection to evaluate the epithelial effects of the absence of mechanoluminal stimulation. Methods: SBS was created in adult male zebrafish by performing proximal stoma/distal intestinal ligation. These were compared to sham zebrafish. Groups were treated with NVP-AEW541; DMSO, a vehicle control; or water for 2 weeks. Proximal and distal intestine were analyzed by H&E for villus epithelial circumference (VEP), inner epithelial perimeter (IEP), and circumference. BrdU+ cells and the microbiome were evaluated. An alternate microCT approach was employed to assess surface area Results: Proximal intestine demonstrated significantly increased adaptation compared to sham proximal intestine, whereas distal intestine showed no adaptation in the absence of luminal flow. Addition of Igf1r inhibitor resulted in decreased adaption in the distal intestine but an increase in distal proliferative cells. There was no difference in alpha diversity of the microbiome between all groups. Micro CT evaluation of surface area conferred no benefit in data analysis. Conclusion: Luminal flow in conjunction with SBS significantly increases intestinal adaption within the proximal intestine while addition of an Igf1r inhibitor diminishes adaptation in both proximal and distal limbs, while increasing distal proliferative cells. Mechanoluminal flow is an important stimulus for adaptation.