PUBLICATION
Intestinal adaptation in proximal and distal segments: Two epithelial responses diverge after intestinal separation
- Authors
- Schall, K.A., Holoyda, K.A., Isani, M., Schlieve, C., Salisbury, T., Khuu, T., Debelius, J.W., Moats, R.A., Pollack, H.A., Lien, C.L., Fowler, K., Hou, X., Knight, R., Grikscheit, T.C.
- ID
- ZDB-PUB-161225-2
- Date
- 2017
- Source
- Surgery 161(4): 1016-1027 (Journal)
- Registered Authors
- Knight, Robert, Lien, Ching-Ling (Ellen)
- Keywords
- none
- MeSH Terms
-
- Adaptation, Physiological/drug effects
- Animals
- Biomarkers/metabolism
- Biopsy, Needle
- Cell Proliferation/drug effects
- Disease Models, Animal
- Immunohistochemistry
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/pathology
- Intestine, Small/drug effects*
- Intestine, Small/surgery*
- Male
- Pyrimidines/antagonists & inhibitors*
- Pyrimidines/pharmacology
- Pyrroles/antagonists & inhibitors*
- Pyrroles/pharmacology
- Random Allocation
- Real-Time Polymerase Chain Reaction
- Reference Values
- Sensitivity and Specificity
- Short Bowel Syndrome/drug therapy
- Short Bowel Syndrome/pathology*
- Short Bowel Syndrome/surgery
- Zebrafish
- beta Catenin/metabolism
- PubMed
- 28011012 Full text @ Surgery
Citation
Schall, K.A., Holoyda, K.A., Isani, M., Schlieve, C., Salisbury, T., Khuu, T., Debelius, J.W., Moats, R.A., Pollack, H.A., Lien, C.L., Fowler, K., Hou, X., Knight, R., Grikscheit, T.C. (2017) Intestinal adaptation in proximal and distal segments: Two epithelial responses diverge after intestinal separation. Surgery. 161(4):1016-1027.
Abstract
Background In short bowel syndrome, luminal factors influence adaptation in which the 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 Short bowel syndrome was created in adult male zebrafish by performing a proximal stoma with ligation of the distal intestine. These zebrafish with short bowel syndrome were compared to sham-operated zebrafish. Groups were treated with the Igf1r inhibitor NVP-AEW541, DMSO, a vehicle control, or water for 2 weeks. Proximal and distal intestine were analyzed by hematoxylin and eosin for villus epithelial circumference, inner epithelial perimeter, and circumference. We evaluated BrdU+ cells, including costaining for β-catenin, and the microbiome was evaluated for changes. Reverse transcription quantitative polymerase chain reaction was performed for β-catenin, CyclinD1, Sox9a, Sox9b, and c-Myc.
Results Proximal intestine demonstrated significantly increased adaptation compared to sham-operated proximal intestine, whereas the distal intestine showed no adaptation in the absence of luminal flow. Addition of the Igf1r inhibitor resulted in decreased adaption in the distal intestine but an increase in distal proliferative cells and proximal β-catenin expression. While some proximal proliferative cells in short bowel syndrome colocalized β-catenin and BrdU, the distal proliferative cells did not co-stain for β-catenin. Sox9a increased in the distal limb after division but not after inhibition with the Igf1r inhibitor. There was no difference in alpha diversity or species richness of the microbiome between all groups.
Conclusion Luminal flow in conjunction with short bowel syndrome significantly increases intestinal adaption within the proximal intestine in which proliferative cells contain β-catenin. Addition of an Igf1r inhibitor decreases adaptation in both proximal and distal limbs while increasing distal proliferative cells that do not colocalize β-catenin. Igf1r inhibition abrogates the increase in distal Sox9a expression that otherwise occurs in short bowel syndrome. Mechanoluminal flow is an important stimulus for intestinal adaptation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping