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      Animal models of necrotizing enterocolitis: review of the literature and state of the art

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          Abstract

          Necrotizing enterocolitis (NEC) remains the leading cause of gastrointestinal surgical emergency in preterm neonates. Over the last five decades, a variety of experimental models have been developed to study the pathophysiology of this disease and to test the effectiveness of novel therapeutic strategies. Experimental NEC is mainly modeled in neonatal rats, mice and piglets. In this review, we focus on these experimental models and discuss the major advantages and disadvantages of each. We also briefly discuss other models that are not as widely used but have contributed to our current knowledge of NEC.

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          Most cited references35

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          Mortality of necrotizing enterocolitis expressed by birth weight categories.

          Low birth weight is the most important risk factor for developing necrotizing enterocolitis (NEC). We aimed to establish birth weight-based benchmarks for in-hospital mortality in neonates with NEC. Five hundred eleven centers belonging to the Vermont Oxford Network prospectively evaluated 71,808 neonates with birth weight of 501 to 1500 g between January 2005 and December 2006. The primary outcome variable was in-hospital mortality. Birth weight was divided into 4 categories by 250-g increments. The NEC risk (P < .001) and mortality (P < .001) decreased with higher birth weight category. Necrotizing enterocolitis was associated with a significant odds ratio for death for each category (P < .001). Across groups, the odds ratio for NEC mortality increased with higher birth weight category (category 1 = 1.6 vs category 4 = 9.9; P < .001). The in-hospital mortality rate of neonates with NEC remains high and is significantly related to birth weight category. Although the risk and absolute mortality of NEC decrease with higher birth weight, the odds ratios indicate that NEC has a relatively greater impact upon mortality at higher birth weight. These data afford birth weight-based mortality benchmarks that may be useful in assessing single center NEC outcomes and facilitating comparisons between centers.
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            Diet- and colonization-dependent intestinal dysfunction predisposes to necrotizing enterocolitis in preterm pigs.

            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. 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. 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. 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.
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              Paneth cell ablation in the presence of Klebsiella pneumoniae induces necrotizing enterocolitis (NEC)-like injury in the small intestine of immature mice

              SUMMARY Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. During NEC pathogenesis, bacteria are able to penetrate innate immune defenses and invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Normally, Paneth cells appear in the intestinal crypts during the first trimester of human pregnancy. Paneth cells constitute a major component of the innate immune system by producing multiple antimicrobial peptides and proinflammatory mediators. To better understand the possible role of Paneth cell disruption in NEC, we quantified the number of Paneth cells present in infants with NEC and found that they were significantly decreased compared with age-matched controls. We were able to model this loss in the intestine of postnatal day (P)14-P16 (immature) mice by treating them with the zinc chelator dithizone. Intestines from dithizone-treated animals retained approximately half the number of Paneth cells compared with controls. Furthermore, by combining dithizone treatment with exposure to Klebsiella pneumoniae, we were able to induce intestinal injury and inflammatory induction that resembles human NEC. Additionally, this novel Paneth cell ablation model produces NEC-like pathology that is consistent with other currently used animal models, but this technique is simpler to use, can be used in older animals that have been dam fed, and represents a novel line of investigation to study NEC pathogenesis and treatment.
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                Author and article information

                Contributors
                Journal
                Innov Surg Sci
                Innov Surg Sci
                iss
                iss
                iss
                Innovative Surgical Sciences
                De Gruyter
                2364-7485
                10 March 2018
                June 2018
                : 3
                : 2
                : 87-92
                Affiliations
                deptDivision of General and Thoracic Surgery, Developmental and Stem Cell Biology Program, Peter Gilgan Center for Research and Learning , universityThe Hospital for Sick Children, University of Toronto, 1524C-555 University Avenue , Toronto, ON M5G 1X8, Canada
                deptDivision of General and Thoracic Surgery, Developmental and Stem Cell Biology Program, Peter Gilgan Center for Research and Learning , universityThe Hospital for Sick Children, University of Toronto , 1524C-555 University Avenue, Toronto, ON M5G 1X8, Canada, Phone: +1-416-813-7564 ext. 202413
                Author notes
                Corresponding author: Augusto Zani, MD, PhD, Division of General and Thoracic Surgery, Developmental and Stem Cell Biology Program, Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, University of Toronto, 1524C-555 University Avenue, Toronto, ON M5G 1X8, Canada, Phone: +1-416-813-7564 ext. 202413
                Article
                iss-2017-0050
                10.1515/iss-2017-0050
                6604570
                22930834
                fa51f9db-1e93-4f0e-8bf1-42a8e791d52c
                ©2018 Sulistyo A., et al., published by De Gruyter, Berlin/Boston

                This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

                History
                : 20 December 2017
                : 19 February 2018
                Page count
                Pages: 9
                Categories
                Reviews

                mice,mutant,nec,pig,rat,transgenic
                mice, mutant, nec, pig, rat, transgenic

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