Inducible nitric oxide synthase knockout mice are resistant to diet-induced loss of gut barrier function and intestinal injury.
Loss of gut barrier function has been documented to occur in animals receiving total parenteral nutrition (TPN) and certain liquid diets. However, the mechanisms responsible for diet-induced gut barrier dysfunction remain to be fully determined. Thus we tested the hypothesis that increased intestinal nitric oxide production contributes to this phenomenon. To test this hypothesis, iNOS-deficient (iNOS -/-) mice and their wild-type littermates (iNOS +/+) were fed either chow or TPN solution for 14 days. Subsequently they were killed and gut barrier function was assessed by measuring bacterial translocation to the mesenteric lymph node (MLN) complex. Additionally, intestinal bacterial population levels, gut morphology, plasma and intestinal nitric oxide levels, as well as intestinal levels of the nitric oxide synthase (NOS) enzymes cNOS and iNOS, were measured. Bacterial translocation occurred in the iNOS +/+ but not the iNOS -/- mice receiving oral TPN solution. Oral TPN-induced bacterial translocation was associated with increased intestinal bacterial population levels as well as morphologic evidence of intestinal injury. Plasma and intestinal levels of the nitric oxide products, nitrite/nitrate, were increased in the iNOS +/+ mice fed the TPN solution but not in the chow-fed groups or the iNOS -/- mice receiving TPN solution. Last, intestinal iNOS, but not cNOS, activity was increased in the iNOS +/+ oral TPN-fed mice. These results implicate a role for increased intestinal nitric oxide production, through iNOS, in the pathogenesis of oral TPN-induced gut barrier dysfunction and injury.
Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103-2714, USA. edeitch@undnj.edu
Edwin A
EA
Deitch
Alexander
A
Shorshtein
Jesse
J
Houghton
Qi
Q
Lu
Dazhong
D
Xu
D000818:Animals; D004032:Diet; D007422:Intestines / Q000201:enzymology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism*
D019001:Nitric Oxide Synthase