Vasoactive intestinal polypeptide promotes intestinal barrier homeostasis and protection against colitis in mice.
Inflammatory bowel disease is a chronic gastrointestinal inflammatory disorder associated with changes in neuropeptide expression and function, including vasoactive intestinal peptide (VIP). VIP regulates intestinal vasomotor and secretomotor function and motility; however, VIP's role in development and maintenance of colonic epithelial barrier homeostasis is unclear. Using VIP deficient (VIPKO) mice, we investigated VIP's role in epithelial barrier homeostasis, and susceptibility to colitis. Colonic crypt morphology and epithelial barrier homeostasis were assessed in wildtype (WT) and VIPKO mice, at baseline. Colitic responses were evaluated following dinitrobenzene sulfonic acid (DNBS) or dextran-sodium sulfate (DSS) exposure. Mice were also treated with exogenous VIP. At baseline, VIPKO mice exhibited distorted colonic crypts, defects in epithelial cell proliferation and migration, increased apoptosis, and altered permeability. VIPKO mice also displayed reduced goblet cell numbers, and reduced expression of secreted goblet cell factors mucin 2 and trefoil factor 3. These changes were associated with reduced expression of caudal type homeobox 2 (Cdx2), a master regulator of intestinal function and homeostasis. DNBS and DSS-induced colitis were more severe in VIPKO than WT mice. VIP treatment rescued the phenotype, protecting VIPKO mice against DSS colitis, with results comparable to WT mice. In conclusion, VIP plays a crucial role in the development and maintenance of colonic epithelial barrier integrity under physiological conditions and promotes epithelial repair and homeostasis during colitis.
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Xiujuan
X
Wu
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Victoria S
VS
Conlin
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Vijay
V
Morampudi
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Natasha R
NR
Ryz
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Yasmin
Y
Nasser
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Ganive
G
Bhinder
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, United States of America.
Kirk S
KS
Bergstrom
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Hong B
HB
Yu
Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.
Chris C M
CC
Waterhouse
Faculty of Medicine, University of Toronto, Ontario, Canada.
Allison M J
AM
Buchan
Department of Pathology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Oana E
OE
Popescu
Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
William T
WT
Gibson
Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, United States of America.
James A
JA
Waschek
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Bruce A
BA
Vallance
Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
Kevan
K
Jacobson
D000818:Animals; D000071616:CDX2 Transcription Factor; D002452:Cell Count; D003092:Colitis / Q000473:pathology / Q000517:prevention & control*; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D020397:Goblet Cells / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020011:Protective Agents / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000172:deficiency / Q000378:metabolism*
D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D020011:Protective Agents; D014157:Transcription Factors; C045305:2,4-dinitrofluorobenzene sulfonic acid; D014660:Vasoactive Intestinal Peptide; D004139:Dinitrofluorobenzene