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Title: Prematurity reduces citrulline-arginine-nitric oxide production and precedes the onset of necrotizing enterocolitis in piglets

Author
item ROBINSON, JASON - Children'S Nutrition Research Center (CNRC)
item SMITH, VICTORIA - California Polytechnic State University
item STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)
item AGARWAL, UMANG - Children'S Nutrition Research Center (CNRC)
item PREMKUMAR, MURALIDHAR - Baylor College Of Medicine
item LAU, PATRICIO - Baylor College Of Medicine
item CRUZ, STEPHANIE - Baylor College Of Medicine
item MANJARIN, RODRIGO - California Polytechnic State University
item OLUTOYE, OLUYINKA - Baylor College Of Medicine
item Burrin, Douglas - Doug
item MARINI, JUAN - Children'S Nutrition Research Center (CNRC)

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/24/2018
Publication Date: 7/26/2018
Citation: Robinson, J.L., Smith, V.A., Stoll, B., Agarwal, U., Premkumar, M.H., Lau, P., Cruz, S.M., Manjarin, R., Olutoye, O., Burrin, D.G., Marini, J.C. 2018. Prematurity reduces citrulline-arginine-nitric oxide production and precedes the onset of necrotizing enterocolitis in piglets. American Journal of Physiology - Gastrointestinal and Liver Physiology. 5:9. https://doi.org/10.1152/ajpgi.00198.2018.
DOI: https://doi.org/10.1152/ajpgi.00198.2018

Interpretive Summary: Necrotizing enterocolitis (NEC) is a disease that affects neonates and results in the inflammation and necrosis of the intestine. The cause of NEC is poorly understood, but prematurity, the initiation of feeding and the establishment of the bacterial flora seem to play a main role in the development of this disease. The small intestine is the main site for the production of the amino acid citrulline which then is used somewhere else in the body to make the amino acid arginine. Arginine is utilized not only to make protein, but it has other functional roles in immunity and in the maintenance of appropriate blood flow to the different organs. As consequence of NEC and the destruction of intestinal cells, citrulline production decreases. However, it is not clear if citrulline production is also reduced by prematurity, preceding the development of the disease. In this study, we have shown that citrulline production is reduced in premature pigs and that it occurs before the establishment of the disease. This indicates that citrulline (and arginine) may be involved in the development of the disease and supplementation with these amino acids may reduce the susceptibility to NEC.

Technical Abstract: Necrotizing enterocolitis (NEC) is associated with low plasma arginine and vascular dysfunction. It is not clear whether low intestinal citrulline production, the precursor for arginine synthesis, occurs before and thus predisposes to NEC or if it results from tissue damage. This study was designed to test the hypothesis that whole-body rates of citrulline, arginine and nitric oxide synthesis are low in premature pigs and that they precede NEC. Piglets delivered by cesarean-section at 103-d (Preterm, PT), 110-d (Near-Term, NT), or 114-d of gestation (Full-Term, FT) were given total parenteral nutrition and after 2 days, orogastrically fed infant formula for 42h to induce NEC. Citrulline and arginine fluxes were determined before and during the feeding protocol. Gross macroscopic and histological NEC scores, and plasma Fatty Acid Binding Protein (iFABP) concentration were determined as indicators of NEC. Intestinal gene expression for enzymes of the arginine pathway were quantitated. A lower (P < 0.05) survival rate was observed for PT (8/27) than for NT (9/9) and FT pigs (11/11). PT pigs had higher macroscopic gross (P < 0.05) and histological NEC (P < 0.05) scores, and iFABP concentration (P < 0.05) than pigs of more advanced gestational age. PT pigs had lower citrulline production and arginine fluxes (P < 0.05) throughout, and a reduced gene expression in genes of the citrulline-arginine pathway. In summary, intestinal enzyme expression and whole body citrulline and arginine fluxes were reduced in PT pigs compared to animals of more advance gestational age and preceded the development of NEC.