title: Intestinal adaptation in proximal and distal segments: Two epithelial responses diverge after intestinal separation.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Pediatric Surgery and Developmental Biology and Regenerative Medicine, Saban Research Institute, Children's Hospital Los Angeles and USC Keck School of Medicine, Los Angeles, CA.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Schall
authors.affiliation: Division of Pediatric Surgery and Developmental Biology and Regenerative Medicine, Saban Research Institute, Children's Hospital Los Angeles and USC Keck School of Medicine, Los Angeles, CA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Holoyda
authors.affiliation: Division of Pediatric Surgery and Developmental Biology and Regenerative Medicine, Saban Research Institute, Children's Hospital Los Angeles and USC Keck School of Medicine, Los Angeles, CA.
authors.forename: Mubina
authors.initials: M
authors.lastname: Isani
authors.affiliation: Division of Pediatric Surgery and Developmental Biology and Regenerative Medicine, Saban Research Institute, Children's Hospital Los Angeles and USC Keck School of Medicine, Los Angeles, CA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Schlieve
authors.affiliation: Department of Radiology, USC Keck School of Medicine, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Tasha
authors.initials: T
authors.lastname: Salisbury
authors.affiliation: Department of Radiology, USC Keck School of Medicine, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Thien
authors.initials: T
authors.lastname: Khuu
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA.
authors.forename: Justine W
authors.initials: JW
authors.lastname: Debelius
authors.affiliation: Department of Radiology, USC Keck School of Medicine, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Rex A
authors.initials: RA
authors.lastname: Moats
authors.affiliation: Department of Radiology, USC Keck School of Medicine, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Pollack
authors.affiliation: Division of Cardiothoracic Surgery, Saban Research Institute, Children's Hospital Los Angeles and USC Keck School of Medicine, Los Angeles, CA.
authors.forename: Ching-Ling
authors.initials: CL
authors.lastname: Lien
authors.affiliation: Division of Pediatric Surgery and Developmental Biology and Regenerative Medicine, Saban Research Institute, Children's Hospital Los Angeles and USC Keck School of Medicine, Los Angeles, CA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Fowler
authors.affiliation: Division of Pediatric Surgery and Developmental Biology and Regenerative Medicine, Saban Research Institute, Children's Hospital Los Angeles and USC Keck School of Medicine, Los Angeles, CA.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA.
authors.forename: Rob
authors.initials: R
authors.lastname: Knight
authors.affiliation: Division of Pediatric Surgery and Developmental Biology and Regenerative Medicine, Saban Research Institute, Children's Hospital Los Angeles and USC Keck School of Medicine, Los Angeles, CA. Electronic address: tgrikscheit@chla.usc.edu.
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Grikscheit
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001707:Biopsy, Needle; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000601:surgery*; D008297:Male; D011743:Pyrimidines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011758:Pyrroles / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D012680:Sensitivity and Specificity; D012778:Short Bowel Syndrome / Q000188:drug therapy / Q000473:pathology* / Q000601:surgery; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015415:Biomarkers; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D051176:beta Catenin