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Title: DIET- AND COLONIZATION-DEPENDENT INTESTINAL DYSFUNCTION PREDISPOSES TO NECROTIZING ENTEROCOLITIS IN PRETERM PIGS

Author
item SANGILD, P - ROYAL VET AG UNIV, DK
item SIGGERS, R - ROYAL VET AG UNIV, DK
item SCHMIDT, M - ROYAL VET AG UNIV, DK
item ELNIF, J - ROYAL VET AG UNIV, DK
item BJORNVAD, C - ROYAL VET AG UNIV, DK
item THYMANN, T - ROYAL VET AG UNIV, DK
item GRONDAHL, M - ROYAL VET AG UNIV, DK
item HANSEN, A - ROYAL VET AG UNIV, DK
item JENSEN, S - DANISH INST AG SCI, DK
item BOYE, M - DANISH INST FOOD&VET, DK
item MOELBAK, L - DANISH INST FOOD&VET, DK
item BUDDINGTON, R - MISSISSIPPI ST UNIV
item WESTROM, BJORN - UNIV LUND, SWEDEN
item HOLST, JENS - UNIV LUND, SWEDEN
item Burrin, Douglas - Doug

Submitted to: Gastroenterology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/1/2006
Publication Date: 5/1/2006
Citation: Sangild, P.T., Siggers, R.H., Schmidt, M., Elnif, J., Bjornvad, C.R., Thymann, T., Grondahl, M.L., Hansen, A.K., Jensen, S.K., Boye, M., Moelbak, L., Buddington, R.K., Westrom, B.R., Holst, J.J., Burrin, D.G. 2006. Diet- and colonization-dependent intestinal dysfunction predisposes to necrotizing enterocolitis in preterm pigs. Gastroenterology. 130(6):1776-1792.

Interpretive Summary: A significant component of the health care costs in the United States is associated with the care of infants born either preterm or with a low birth weight (LBW). The immaturity of the gastrointestinal tract contributes to the relatively high rate of morbidity and mortality in these infants. A major gastrointestinal disease in these infants is necrotizing enterocolitis (NEC). In the U.S., approximately 500,000 preterm infants are born annually with an increased risk of developing NEC, and medical care for NEC alone costs over $5 billion annually, accounting for approximately 19% of the total costs all newborns. The goal of this study was to develop a clinical relevant, animal model of NEC that can be used to determine the root causes of the disease. The study examined the presence of NEC in groups of piglets that were born premature and fed either breast milk, also called colostrum, or formula. In addition, pigs were reared in an incubator without any germs present to test whether bacteria are necessary for NEC to occur. The key findings were that the incidence of NEC was much higher in pigs fed formula compared to breast milk, similar to what is found in human infants. In addition, the results showed that bacteria are necessary for NEC to occur, and Clostridium species may be a key bacteria involved in the cause of disease. The findings also show that premature piglets are a novel animal model to test the causes of spontaneous development of NEC and will be useful to develop preventative treatments for this devastating infant disease.

Technical Abstract: BACKGROUND & AIMS: Preterm birth and formula feeding are key risk factors associated with necrotizing enterocolitis (NEC) in infants, but little is known about intestinal conditions that predispose to disease. Thus, structural, functional, and microbiologic indices were used to investigate the etiology of spontaneous NEC development in preterm pigs. METHODS: Piglets were delivered by cesarean section at 92% gestation, reared in infant incubators, and fed infant formula or colostrum every 3 hours (n = 120) until tissue collection at 1-2 days of age. RESULTS: Clinical and histopathologic signs of NEC were observed in 57% of pigs fed FORMULA (26/46) and in 5% of pigs fed COLOSTRUM (2/38) (P < .05). Relative to COLOSTRUM, both healthy and sick FORMULA pigs had reduced intestinal villous heights, enzyme activities, nutrient absorption, and antioxidant levels and higher inducible nitric oxide synthetase activity (P < .05). In healthy pigs, mucosal microbial diversity remained low and diet independent. NEC pigs showed bacterial overgrowth, and a high mucosal density of Clostridium perfringens was detected in some but not all pigs. Germ-free conditions and antiserum against Clostridium perfringens toxin prevented intestinal dysfunction and NEC in formula-fed pigs, whereas the gut trophic factors, epidermal growth factor, and glucagon-like peptide 2 had limited effects. CONCLUSIONS: A subclinical, formula-induced mucosal atrophy and dysfunction predispose to NEC and bacterial overgrowth. The adverse feeding effects are colonization dependent and may be reduced by factors in colostrum that include antibodies against aggressive toxins such as those of Clostridium perfringens.