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Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis

Developmental Gastroenterology Laboratory, Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

¹Correspondence: Developmental Gastroenterology Laboratory, Massachusetts General Hospital, 149 13th St., Charlestown, MA 02129, USA. E-mail: walker{at}helix.mgh.harvard.edu

	ABSTRACT

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
Neonatal necrotizing enterocolitis (NEC) is a major cause of morbidity in preterm infants. We hypothesize that the intestinal injury in this disease is a consequence of synergy among three of the major risk factors for NEC: prematurity, enteral feeding, and bacterial colonization. Together these factors result in an exaggerated inflammatory response, leading to ischemic bowel necrosis. Human milk may decrease the incidence of NEC by decreasing pathogenic bacterial colonization, promoting growth of nonpathogenic flora, promoting maturation of the intestinal barrier, and ameliorating the proinflammatory response.—Claud, E. C., Walker, W. A. Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis.

Key Words: necrotizing enterocolitis • prematurity • intestinal inflammation

	NEONATAL NECROTIZING ENTEROCOLITIS

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
NECROTIZING ENTEROCOLITIS (NEC) is the most common gastrointestinal emergency in the neonatal intensive care unit (NICU). It is characterized by gastrointestinal dysfunction progressing to pneumatosis intestinalis, pneumoperitoneum, systemic shock, and rapid death in severe cases (1) . Despite its significant effect on preterm morbidity, the exact etiology and pathogenesis of this disease have not been clearly delineated. The most common risk factors cited are prematurity, enteral feeding, and bacterial colonization (2) . Here we intend to provide evidence to support our hypothesis that the intestinal injury in NEC may be the result of synergy of these three risk factors, in which feeding results in colonization of the uniquely susceptible premature intestine with pathogenic bacteria, resulting in an exaggerated inflammatory response.

	COLONIZATION OF THE NEWBORN INTESTINE

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
Environment, variation in pH, intestinal peristalsis, bacterial opposition, and the type of feeding all affect intestinal colonization. Before birth, the infant gut is sterile. Thereafter, it acquires bacteria from the environment. The intestine is initially colonized with a complex flora that reflects maternal vaginal and large intestinal flora (3 , 4) . The preterm infant is next exposed to bacteria in the NICU, with colonization frequently affected by the use of broad-spectrum antibiotics (5 6 7) . Although a range of aerobic and anaerobic flora colonizes normal infants by 10 days of age, infants in the NICU undergo a delayed colonization with a limited number of bacterial species, which tend to be virulent (2 , 8) .

Feeding is another variable in the acquisition of intestinal flora. In breast-fed infants, bifidobacterium is a primary organism, with lactobacillus and streptococcus as minor components. In formula-fed infants, similar amounts of bacteroides and bifidobacterium are found with minor components of the more pathogenic species staphylococcus, Escherichia coli, and clostridia (3) . Since binding of pathogenic organisms can be influenced by the underlying microbial ecology through competition for binding sites or nutrients, production of inhibiting agents, alteration in pH, and synthesis of growth factors, promotion of the growth of competitive nonpathogenic strains of bacteria may protect the infant (8 9 10) .

	RESPONSE OF THE INTESTINE TO BACTERIAL COLONIZATION

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
Microbial pathogens have complex interactions with their host cells, resulting in a variety of responses that can lead to injury. Signal transduction leading to nuclear factor B (NF-B) activation is a key element in the intestinal epithelial cell innate immune response (11) . In its inactive state, NF-B is bound to the inhibitory protein IB. Once IB is phosphorylated, it can be degraded by ubiquitination, freeing NF-B to translocate to the nucleus and stimulate transcription of inflammatory mediators (12) . In cultured intestinal epithelial cells, it has been shown that Salmonella typhimurium activates signal transduction pathways leading to activation of NF-B (11 , 13 , 14) . Other pathogens, including E. coli, Yersinia, Shigella, and Listeria, trigger signal transduction pathways that degrade IB, freeing NF-B to translocate to the nucleus and up-regulate expression of proinflammatory mediators. In contrast, not only can colonization with commensal organisms competitively reduce colonization by these pathological organisms, it may also have anti-inflammatory properties. A recent study by Madara et al. has shown that nonpathogenic Salmonella prevents degradation of IB, limiting further transcription of inflammatory mediators (12) .

	IMMATURE GASTROINTESTINAL IMMUNE SYSTEM OF THE PREMATURE INFANT

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
Ninety percent of infants with NEC are born preterm, and it appears that an immature gastrointestinal immune defense system places a preterm infant at higher risk for NEC. The premature infant has lower gastric acid production and lower levels of protective mucus (5) . These infants have also been noted to have lower proteolytic enzyme activity, leading to incomplete breakdown of toxins (5) . Decreased motility, lower levels of B and T lymphocytes, and lower levels of secretory IgA also increase bacterial adherence to the intestinal mucosa and susceptibility to infection (1 , 5 , 15) . Coupled with increased intestinal mucosal permeability, this potentially leads to the delivery of whole bacteria and endotoxin to the bloodstream (1) .

	FEEDING AND INTESTINAL IMMATURITY

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
Ninety-five percent of affected infants have been enterally fed, and NEC has never been identified in utero (16) . The fetal gut is exposed to amniotic fluid containing hormones and peptides that may have a role in intestinal maturation and preparation for postnatal feeding. The preterm infant may not have completed this maturation process when initially fed. Preterm infants are unable to fully digest carbohydrates and proteins, leading to the production of organic acids, which may be harmful to the developing intestine (17) . Undigested casein, the protein in formula, can function as a chemoattractant for neutrophils (18) .

Several studies have shown that formula-fed infants have a higher incidence of NEC than breast-fed infants (19) . A prospective multicenter study of 926 preterm infants found a 6- to 10-fold increase in the incidence of NEC in formula-fed infants compared with breast milk-fed infants (16) . Breast milk contains factors that enhance intestinal maturation. In addition, human milk provides passive immunity factors such as polymeric IgA (pIgA) and macrophages that may bind antigens, bacteria, or endotoxin and decrease mucosal translocation. It also contains nonspecific antimicrobial factors such as lactoferrin and lysozyme. Together, these features may partially explain this difference in protection of the newborn infant.

	THE ROLE OF BACTERIA AND INFLAMMATION IN NEC

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
Bacteria have long been suspected of having a role in NEC; however, only 30% of NEC patients have positive blood cultures (6) . Epidemics of NEC have occurred, but NEC usually occurs sporadically and has not been associated with a particular pathogen (9) . Rather than a direct infection, this disease process may be a result of secondary inflammatory responses to the organisms (15) .

Histopathologic sections of intestine from infants with NEC reveal a wide variation. Most show evidence of necrosis and inflammation in addition to bacterial overgrowth (1 , 20 , 18) . The cycle of intestinal injury begins with neutrophil migration, which can mechanically disrupt tight junctions between intestinal epithelial cells, increasing transepithelial permeability (21) . Neutrophil activation can lead to inflammatory mediator release resulting in vasoconstriction, ischemia/reperfusion injury, oxygen free radical release, and further disruption of tight junctions and the intestinal barrier (22) .

Ultimately there is exacerbation of an inflammatory cascade with increased tissue and serum levels of inflammatory mediators such as tumor necrosis factor (TNF), interleukin 1 (IL-1), IL-6, IL-8, and platelet-activating factor (PAF) (23 , 24) . It has been shown that PAF levels are elevated in infants with NEC (23) . In rats, exogenous PAF given intravenously results in ischemic bowel necrosis (25) . Furthermore, studies using a rat model of NEC showed that PAF receptor blockade reduced the incidence of NEC (26 27 28 29) . Many stimuli that have been associated with NEC can increase PAF production including hypoxia, enteral feeding (30) , acidosis, TNF, and endotoxin. Once activated, PAF initiates production of other inflammatory mediators (31) . This process is exacerbated in preterm infants by the fact that acetylhydrolase, the enzyme responsible for PAF degradation, is present in decreased amounts in infants. Acetylhydrolase has also specifically been shown to be decreased in infants with NEC (Fig. 1 ; 32 , 33 ).

View larger version (54K): [in this window] [in a new window]   Figure 1. Plasma PAF levels (open bars), plasma TNF levels (horizontally hatched bars), and plasma acetylhydrolase activity (vertically hatched bars) in NEC patients and control subjects. Plasma PAF and TNF levels were higher in NEC patients than in control patients. Plasma acetylhydrolase activity was lower in NEC patients than in age-matched control subjects. Reproduced with permission from Caplan and Hsueh (33)

	INCREASED SUSCEPTIBILITY OF THE IMMATURE ENTEROCYTE TO BACTERIAL COLONIZATION

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
Our laboratory has studied the interaction between the enterocyte and bacteria and shown that many aspects are developmentally regulated. Cell surface glycoconjugates serve as adhesion sites for a variety of microbes. Creation of specific carbohydrate receptors through glycosylation is a developmentally regulated process that is important in intestinal colonization and defense. Our laboratory has found that newborn intestinal microvillous preparations have increased sialic acid and N-acetylglucosamine residues whereas adult preparations have increased mannose, glucose, and fucose. When glycosyltransferase activity was examined in mice, a correlating increase in 2,6-sialyltransferase activity was noted in the newborn period, declining at the time of weaning. In contrast, 1,2/1,3 fucosyltransferase activity was at low levels in the newborn period and increased at weaning (34 , 35) . These observations have also recently been demonstrated in our laboratory in the human fetus (D. Dai, unpublished data). These differences may be responsible for increased pathogenic colonization in preterm infants. We have shown that pathogenic organisms adhere and translocate across the intestine to a greater extent in immature vs. mature animals.

	EXAGGERATED RESPONSE OF THE IMMATURE ENTEROCYTE TO GRAM-NEGATIVE ORGANISMS

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
As previously discussed, formula-fed infants are more likely to be colonized with gram-negative organisms such as E. coli and Klebsiella than are breast-fed infants (3) . Our laboratory has shown that the enterocyte response to gram-negative organisms is exaggerated in fetal cells. IL-8 secretion and mRNA in response to LPS and IL-1ß were significantly increased in H4 cells (human fetal intestinal cell line) and fetal organ cultures as compared with Caco2 (adult intestinal cell line) or older infant organ culture preparations (Fig. 2 ). Immunohistochemical staining showed that the IL-8 was secreted by the enterocyte, not by lymphoid cells. IL-8 is a chemokine that stimulates migration of neutrophils from intravascular to interstitial sites, which can further exacerbate the inflammatory process. This excessive proinflammatory response may explain why primarily preterm infants develop NEC (36) .

View larger version (26K): [in this window] [in a new window]   Figure 2. Depiction of IL-8 secretion (A) and IL-8 mRNA induction (B) in fetal and infant organ culture preparations in response to LPS (50 µg/ml) or media alone as control. Reproduced with permission from Nanthakumar et al. (36)

	INCOMPLETE METABOLISM OF FOOD SUBSTRATE AND INTESTINAL INJURY

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
The carbohydrate in milk is lactose, which can be fermented to short-chain fatty acids, hydrogen, lactate, and CO₂ when incompletely metabolized (37) . As mentioned, preterm infants often cannot completely metabolize carbohydrates and proteins. Formula-fed infants produce butyrate in the small intestine and breast-fed infants produce lactic acid. High concentrations of short-chain fatty acids may have a toxic effect on the small intestine. They have been shown to lower the pH of the small intestine, causing mucosal breakdown and increasing susceptibility to bacterial translocation (18) . Furthermore, we have shown that priming with the short-chain fatty acid butyrate can increase IL-8 secretion from enterocytes in response to LPS or IL1-ß (38) .

	ROLE OF BREAST MILK IN PREVENTION OF NEC

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
Lucas and Cole showed in their prospective study a decline in the incidence of NEC with advancing gestational age in breast milk-fed but not in formula-fed infants. This suggests that maturity of the intestinal mucosal barrier improved by advancing gestational age and breast milk is important (16) . Furthermore, data support the notion that by modulating intestinal colonization and supporting inherent host gastrointestinal defense, breast milk may decrease the incidence of NEC.

Breast milk interferes with adherence of pathogenic bacteria by providing pIgA and oligosaccharides. Polymeric IgA is produced by the immune system of the mother specifically against enteric pathogens to which she has been exposed. Oligosaccharides function as receptor analog decoys, binding bacteria before they can adhere to glycoconjugates on the microvillous membrane (39) . To promote colonization with nonpathogenic bacteria, breast milk contains growth factors for bifidobacterium (40) .

Breast milk also provides hormones, growth factors, and nucleotides that facilitate the maturation of the intestinal mucosal barrier. This may decrease bacterial translocation across the intestine. Cortisol, growth hormone, insulin-like growth factor, erythropoietin, and thyroid hormone have all been identified in breast milk. Epidermal growth factor (EGF) is found in highest quantity in colostrum from mothers of preterm infants and is a growth stimulator of epithelial cells. Transforming growth factor (TGF) is found in breast milk and has an immunomodulatory role in addition to inducing differentiation of intestinal epithelial cells (41) . Breast milk also provides glutamine and nucleotides that affect cell growth (42) .

To ameliorate the proinflammatory response, breast milk contains an IL-1 receptor antagonist, TGF-ß, and IL-10. Breast milk also contains acetylhydrolase, which metabolizes PAF to inactive lyso-PAF. It has been shown that acetylhydrolase activity is higher in preterm than term human milk (43) . Furthermore, breast milk may be beneficial by providing antioxidant factors such as vitamin E, beta carotene, and ascorbic acid (2 , 44) .

	OTHER APPROACHES

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
For infants for whom breast milk is not available, we speculate that it may be prudent to mimic properties of breast milk. Several studies have shown that prenatal steroids reduce morbidity from NEC (45 , 46) . In animal studies, pups from pregnant rats injected with dexamethasone had more mature and ordered microvillous membranes, increased jejunal sucrase, increased salivary amylase, increased gastric acid secretion, increased activity of gastric pepsinogen, increased pancreatic amylase, and decreased bacterial translocation (47 , 48) . Animal studies have also shown that prenatal steroids alter bacterial colonization, resulting in decreased bacterial counts and fewer gram-negative organisms, possibly by maturation of glycosyltransferase activity (49 , 50) . A study by Furakawa et al. showed that in a rat model, pretreatment of the animal with dexamethasone before PAF injection to induce ischemic bowel necrosis increased acetylhydrolase levels and prevented intestinal injury (51) . Other clinical and animal studies have indicated that postnatal cortisone may also induce maturation; however, recent analyses raising questions about adverse neurological outcome in the face of postnatal steroids give one pause (46 , 52) . Supplementation with growth factors such as EGF or TGF may also aid in gut maturation.

Probiotics are another area of intense research. A probiotic is a live anaerobic bacterial food supplement that benefits the recipient by improving the intestinal flora balance. Probiotics have been shown to be beneficial in other conditions, such as C. difficile pseudomembranous colitis and rotavirus diarrhea, and have been shown to restore normal flora after antibiotic administration (53) . Other studies have shown that orally administered nonenteropathogenic bacteria can colonize the newborn gut and reduce colonization with pathogenic strains (54 , 55) . Animal studies have suggested that the administration of bifidobacterium decreases the incidence of NEC through modulation of the inflammatory cascade (56) . One clinical study has shown a decreased incidence of NEC with oral administration of lactobacillus and bifidobacterium to human infants (57) . Although probiotics appear safe in infants, their efficacy in preventing NEC in infants still requires further investigation.

Exogenous nucleotides as a formula supplement have been suggested. Nucleotides are important metabolites that serve as a ‘conditional essential nutrient’ in times of stress. They have a role in controlling cell turnover and a role in immunity (58) . There is an increased requirement for nucleotides in rapidly proliferating cells such as intestinal epithelial cells and they are present in higher concentrations in breast milk than in infant formulas (42) . They are taken up by intestinal cell lines and organ culture preparations and have a role in intestinal epithelial cell proliferation and differentiation (59 , 60) .

	SUMMARY

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 
Necrotizing enterocolitis is a devastating condition with high morbidity and mortality. It specifically affects preterm infants and appears to be the result of an inflammatory response to pathogenic organisms. The balance of pro- and anti-inflammatory influences appears to be the fundamental issue. We have provided evidence to support our hypothesis that intestinal injury in NEC may be the consequence of synergy of prematurity, enteral feeding, and bacterial colonization. Feeding may result in colonization of the premature intestine with pathogenic bacteria, resulting in an exacerbated inflammatory response. Preterm infants are uniquely susceptible because of an immature immune system unable to sufficiently protect against pathogenic organisms. In addition, immature glycosylation patterns may actually promote colonization by pathogenic bacteria, and the immune response of the immature enterocyte may itself increase injury by excessive cytokine production in response to gram-negative organisms. We suggest that breast milk feeding can reduce colonization by pathogenic organisms and induce colonization by commensal organisms. This may modulate inflammatory reactions, decreasing intestinal injury.

	ACKNOWLEDGMENTS

 
Supported by grants from the National Institutes of Health (RO1-HD31852, R37-HD12437, and PO1-DK33506).

Received for publication January 19, 2001. Accepted for publication February 15, 2001.

	REFERENCES

TOP ABSTRACT NEONATAL NECROTIZING... COLONIZATION OF THE NEWBORN... RESPONSE OF THE INTESTINE... IMMATURE GASTROINTESTINAL IMMUNE... FEEDING AND INTESTINAL... THE ROLE OF BACTERIA... INCREASED SUSCEPTIBILITY OF THE... EXAGGERATED RESPONSE OF THE... INCOMPLETE METABOLISM OF FOOD... ROLE OF BREAST MILK... OTHER APPROACHES SUMMARY REFERENCES

 

1. Faix, R. G., Adams, J. T. (1994) Neonatal necrotizing enterocolitis: current concepts and controversies. Adv. Pediatr. Infect. Dis. 9,1-36[Medline]
2. Kosloske, A. M. (1994) Epidemiology of necrotizing enterocolitis. Acta Paediatr. Suppl. 396,2-7[Medline]
3. Harmsen, H. J., Wildeboer-Veloo, A. C., Raangs, G. C., Wagendorp, A. A., Klijn, N., Bindels, J. G., Welling, G. W. (2000) Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J. Pediatr. Gastroenterol. Nutr. 30,61-67[Medline]
4. Gronlund, M. M., Lehtonen, O. P., Eerola, E., Kero, P. (1999) Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery. J. Pediatr. Gastroenterol. Nutr. 28,19-25[Medline]
5. Udall, J. N., Jr (1990) Gastrointestinal host defense and necrotizing enterocolitis. J. Pediatr. 117,S33-S43[Medline]
6. Hoy, C., Millar, M. R., MacKay, P., Godwin, P. G., Langdale, V., Levene, M. I. (1990) Quantitative changes in faecal microflora preceding necrotising enterocolitis in premature neonates. Arch. Dis. Child. 65,1057-1059[Abstract]
7. Murray, R. D. (1990) Effects of bacterial fermentation end products on intestinal function: implications for intestinal dysfunction. J. Pediatr. 117,S59-S63[Medline]
8. Orrhage, K., Nord, C. E. (1999) Factors controlling the bacterial colonization of the intestine in breast-fed infants. Acta Paediatr. Suppl. 88,47-57
9. Panigrahi, P., Gupta, S., Gewolb, I. H., Morris, J. G., Jr (1994) Occurrence of necrotizing enterocolitis may be dependent on patterns of bacterial adherence and intestinal colonization: studies in Caco-2 tissue culture and weanling rabbit models. Pediatr. Res. 36,115-121[Medline]
10. Lodinova-Zadnikova, R., Slavikova, M., Tlaskalova-Hogenova, H., Adlerberth, I., Hanson, W. A., Wold, A., Carlsson, B., Svanborg, C., Mellander, L. (1991) The antibody response in breast-fed and non-breast-fed infants after artificial colonization of the intestine with Escherichia coli O83. Pediatr. Res. 29,396-399[Medline]
11. Elewaut, D., DiDonato, J. A., Kim, J. M., Truong, F., Eckmann, L., Kagnoff, M. F. (1999) NF-kappa B is a central regulator of the intestinal epithelial cell innate immune response induced by infection with enteroinvasive bacteria. J. Immunol. 163,1457-1466[Abstract/Free Full Text]
12. Neish, A. S., Gewirtz, A. T., Zeng, H., Young, A. N., Hobert, M. E., Karmali, V., Rao, A. S., Madara, J. L. (2000) Prokaryotic regulation of epithelial responses by inhibition of IkappaB-alpha. Science 289,1560-1563[Abstract/Free Full Text]
13. Hobbie, S., Chen, L. M., Davis, R. J., Galan, J. E. (1997) Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. J. Immunol. 159,5550-5559[Abstract]
14. Gewirtz, A. T., Rao, A. S., Simon, P. O., Jr, Merlin, D., Carnes, D., Madara, J. L., Neish, A. S. (2000) Salmonella typhimurium induces epithelial IL-8 expression via Ca²⁺-mediated activation of the NF-kappaB pathway. J. Clin. Invest. 105,79-92[Medline]
15. Caplan, M. S., MacKendrick, W. (1993) Necrotizing enterocolitis: a review of pathogenetic mechanisms and implications for prevention. Pediatr. Pathol. 13,357-369[Medline]
16. Lucas, A., Cole, T. J. (1990) Breast milk and neonatal necrotising enterocolitis. Lancet 336,1519-1523[Medline]
17. Clark, D. A., Miller, M. J. (1990) Intraluminal pathogenesis of necrotizing enterocolitis. J. Pediatr. 117,S64-S67[Medline]
18. Carbonaro, C. A., Clark, D. A., Elseviers, D. (1988) A bacterial pathogenicity determinant associated with necrotizing enterocolitis. Microb. Pathog. 5,427-436[Medline]
19. Beeby, P. J., Jeffery, H. (1992) Risk factors for necrotising enterocolitis: the influence of gestational age. Arch. Dis. Child. 67,432-435[Abstract]
20. Ballance, W. A., Dahms, B. B., Shenker, N., Kliegman, R. M. (1990) Pathology of neonatal necrotizing enterocolitis: a ten-year experience. J. Pediatr. 117,S6-S13[Medline]
21. Madara, J. L. (1990) Warner-Lambert/Parke-Davis Award lecture. Pathobiology of the intestinal epithelial barrier. Am. J. Pathol. 137,1273-1281[Abstract]
22. Kinugasa, T., Sakaguchi, T., Gu, S., Reinecker, H. C. (2000) Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118,1001-1011[Medline]
23. Caplan, M. S., Sun, X. M., Hseuh, W., Hageman, J. R. (1990) Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J. Pediatr. 116,960-964[Medline]
24. Harris, M. C., Costarino, A. T., Jr, Sullivan, J. S., Dulkerian, S., McCawley, L., Corcoran, L., Butler, S., Kilpatrick, L. (1994) Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. J. Pediatr. 124,105-111[Medline]
25. Gonzalez-Crussi, F., Hsueh, W. (1983) Experimental model of ischemic bowel necrosis. The role of platelet-activating factor and endotoxin. Am. J. Pathol. 112,127-135[Abstract]
26. Caplan, M. S., Kelly, A., Hsueh, W. (1992) Endotoxin and hypoxia-induced intestinal necrosis in rats: the role of platelet activating factor. Pediatr. Res. 31,428-434[Medline]
27. Caplan, M. S., Hedlund, E., Adler, L., Lickerman, M., Hsueh, W. (1997) The platelet-activating factor receptor antagonist WEB 2170 prevents neonatal necrotizing enterocolitis in rats. J. Pediatr. Gastroenterol. Nutr. 24,296-301[Medline]
28. Hsueh, W., Gonzalez-Crussi, F., Arroyave, J. L. (1987) Platelet-activating factor: an endogenous mediator for bowel necrosis in endotoxemia. FASEB J 1,403-405[Abstract]
29. Wallace, J. L., Steel, G., Whittle, B. J., Lagente, V., Vargaftig, B. (1987) Evidence for platelet-activating factor as a mediator of endotoxin-induced gastrointestinal damage in the rat. Effects of three platelet-activating factor antagonists. Gastroenterology 93,765-773[Medline]
30. MacKendrick, W., Hill, N., Hsueh, W., Caplan, M. (1993) Increase in plasma platelet-activating factor levels in enterally fed preterm infants. Biol. Neonate 64,89-95[Medline]
31. Caplan, M. S., MacKendrick, W. (1994) Inflammatory mediators and intestinal injury. Clin. Perinatol. 21,235-246[Medline]
32. Caplan, M., Hsueh, W., Kelly, A., Donovan, M. (1990) Serum PAF acetylhydrolase increases during neonatal maturation. Prostaglandins 39,705-714[Medline]
33. Caplan, M. S., Hsueh, W. (1990) Necrotizing enterocolitis: role of platelet activating factor, endotoxin, and tumor necrosis factor. J. Pediatr. 117,S47-S51[Medline]
34. Chu, S. H., Walker, W. A. (1986) Developmental changes in the activities of sialyl- and fucosyltransferases in rat small intestine. Biochim. Biophys. Acta 883,496-500[Medline]
35. Dai, D., Nanthkumar, N. N., Newburg, D. S., Walker, W. A. (2000) Role of oligosaccharides and glycoconjugates in intestinal host defense. J. Pediatr. Gastroenterol. Nutr. 30,S23-S33
36. Nanthakumar, N. N., Fusunyan, R. D., Sanderson, I., Walker, W. A. (2000) Inflammation in the developing human intestine: a possible pathophysiologic contribution to necrotizing enterocolitis. Proc. Natl. Acad. Sci. USA 97,6043-6048[Abstract/Free Full Text]
37. Kien, C. L. (1990) Colonic fermentation of carbohydrate in the premature infant: possible relevance to necrotizing enterocolitis. J. Pediatr. 117,S52-S58[Medline]
38. Fusunyan, R. D., Quinn, J. J., Ohno, Y., MacDermott, R. P., Sanderson, I. R. (1998) Butyrate enhances interleukin (IL)-8 secretion by intestinal epithelial cells in response to IL-1beta and lipopolysaccharide. Pediatr. Res. 43,84-90[Medline]
39. Newburg, D. S. (2000) Oligosaccharides in human milk and bacterial colonization. J. Pediatr. Gastroenterol. Nutr. 30,S8-S17
40. Petschow, B. W., Talbott, R. D., Batema, R. P. (1999) Ability of lactoferrin to promote the growth of Bifidobacterium spp. in vitro is independent of receptor binding capacity and iron saturation level. J. Med. Microbiol. 48,541-549[Abstract]
41. Bernt, K. M., Walker, W. A. (1999) Human milk as a carrier of biochemical messages. Acta Paediatr. Suppl. 88,27-41[Medline]
42. Barness, L. A. (1994) Dietary sources of nucleotides—from breast milk to weaning. J. Nutr. 124,128S-130S
43. Moya, F. R., Eguchi, H., Zhao, B., Furukawa, M., Sfeir, J., Osorio, M., Ogawa, Y., Johnston, J. M. (1994) Platelet-activating factor acetylhydrolase in term and preterm human milk: a preliminary report. J. Pediatr. Gastroenterol. Nutr. 19,236-239[Medline]
44. Aynsley-Green, A., Lucas, A., Lawson, G. R., Bloom, S. R. (1990) Gut hormones and regulatory peptides in relation to enteral feeding, gastroenteritis, and necrotizing enterocolitis in infancy. J. Pediatr. 117,S24-S32[Medline]
45. Crowley, P., Chalmers, I., Keirse, M. J. (1990) The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br. J. Obstet. Gynaecol. 97,11-25[Medline]
46. Halac, E., Halac, J., Begue, E. F., Casanas, J. M., Indiveri, D. R., Petit, J. F., Figueroa, M. J., Olmas, J. M., Rodriguez, L. A., Obregon, R. J., et al (1990) Prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: a controlled trial. J. Pediatr. 117,132-138[Medline]
47. Israel, E. J., Schiffrin, E. J., Carter, E. A., Freiberg, E., Walker, W. A. (1990) Prevention of necrotizing enterocolitis in the rat with prenatal cortisone. Gastroenterogy 99,1333-1338[Medline]
48. Neu, J., Ozaki, C. K., Angelides, K. J. (1986) Glucocorticoid-mediated alteration of fluidity of brush border membrane in rat small intestine. Pediatr. Res. 20,79-82[Medline]
49. Schiffrin, E. J., Carter, E. A., Walker, W. A., Frieberg, E., Benjamin, J., Israel, E. J. (1993) Influence of prenatal corticosteroids on bacterial colonization in the newborn rat. J. Pediatr. Gastroenterol. Nutr. 17,271-275[Medline]
50. Ozaki, C. K., Chu, S. H., Walker, W. A. (1989) Developmental changes in galactosyltransferase activity in the rat small intestine. Biochim. Biophys. Acta 991,243-247[Medline]
51. Furukawa, M., Lee, E. L., Johnston, J. M. (1993) Platelet-activating factor-induced ischemic bowel necrosis: the effect of platelet-activating factor acetylhydrolase. Pediatr. Res. 34,237-241[Medline]
52. Yeh, T. F., Lin, Y. J., Huang, C. C., Chen, Y. J., Lin, C. H., Lin, H. C., Hsieh, W. S., Lien, Y. J. (1998) Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics 101,E7
53. Bennet, R., Nord, C. E., Zetterstrom, R. (1992) Transient colonization of the gut of newborn infants by orally administered bifidobacteria and lactobacilli. Acta Paediatr 81,784-787[Medline]
54. Lodinova-Zadnikova, R., Sonnenborn, U. (1997) Effect of preventive administration of a nonpathogenic Escherichia coli strain on the colonization of the intestine with microbial pathogens in newborn infants. Biol. Neonate 71,224-232[Medline]
55. Rastegar Lari, A., Gold, F., Borderon, J. C., Laugier, J., Lafont, J. P. (1990) Implantation and in vivo antagonistic effects of antibiotic-susceptible Escherichia coli strains administered to premature newborns. Biol. Neonate 58,73-78[Medline]
56. Caplan, M. S., Jilling, T. (2000) Neonatal necrotizing enterocolitis: possible role of probiotic supplementation. J. Pediatr. Gastroenterol. Nutr. 30,S18-S22
57. Hoyos, A. B. (1999) Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit. Int. J. Infect. Dis. 3,197-202[Medline]
58. Walker, W. A. (1996) Exogenous nucleotides and gastrointestinal immunity. Transplant Proc 28,2438-2441[Medline]
59. Sanderson, I. R., He, Y. (1994) Nucleotide uptake and metabolism by intestinal epithelial cells. J. Nutr. 124,131S-137S
60. Tanaka, M., Lee, K., Martinez-Augustin, O., He, Y., Sanderson, I. R., Walker, W. A. (1996) Exogenous nucleotides alter the proliferation, differentiation and apoptosis of human small intestinal epithelium. J. Nutr. 126,424-433

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