Is Dietary Epidermal Growth Factor Absorbed by Premature Human Infants?

Sm, Gale; Read, Leanna C.; George-Nascimento, Carlos; Jc, Wallace; Ballard, F. J.

doi:10.1159/000242903

Cited by 35 publications

(12 citation statements)

References 18 publications

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“…There is evidence from animal models that certain agents not only may interact with the gastrointestinal tract but also may be absorbed into the systemic circulation of the recipient (51). In human neonates, whereas some ingested peptides such as epidermal growth factor are absorbed systemically, other molecules, including erythropoietin and granulocyte-colony stimulating factor, are not (52)(53)(54). Further work is needed in this area, as improved understanding of the fate of various luminal peptides and other bioactive factors is likely to be of immense importance in neonatal nutrition.…”

Section: Discussionmentioning

confidence: 99%

IL-8/CXC Ligand 8 Survives Neonatal Gastric Digestion as a Result of Intrinsic Aspartyl Proteinase Resistance

Maheshwari

Guida

et al. 2005

Pediatr Res

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The human fetus and neonate swallow biologically significant quantities of IL-8/CXC ligand 8 (CXCL8) in amniotic fluid and breast milk, and this remains measurable through simulated neonatal gastric and proximal intestinal digestions. We sought to confirm the structural and functional integrity of IL-8/CXCL8 in digestates and determine the mechanisms underlying this protease resistance. We observed that in comparison with BSA, IL-8/CXCL8 is highly resistant to pepsin and can be detected intact in assays for structural, immunologic, and functional integrity. In a computational molecular docking simulation, IL-8/ CXCL8 was observed to fit poorly in the pepsin active site. On the basis of simulated mutation analyses, we hypothesized that this protease resistance is due to disulfide bond-related tertiary folding in IL-8/CXCL8. This was confirmed on chemical reduction of these groups. IL-8/CXC ligand 8 (CXCL8), the prototypal neutrophilspecific CXC chemokine in humans, is a key mediator of acute inflammation (1). In the developing intestine, elevated serum and tissue IL-8/CXCL8 concentrations are associated with inflammatory conditions such as necrotizing enterocolitis (2,3). It seems anomalous that the human fetal/neonatal gastrointestinal lumen is normally exposed to biologically significant IL-8/CXCL8 concentrations in swallowed amniotic fluid (4,5) and breast milk (6 -9).In an in vitro model of neonatal gastric and proximal intestinal conditions, IL-8/CXCL8 remains undigested, as tested by enzyme immunoassay (8). Recombinant human IL-8/CXCL8 promotes cellular migration, proliferation, and differentiation in intestinal epithelial cell (IEC) lines, besides protecting these cells from chemical injury (8). For assessing the physiologic relevance of these effects, the intact survival of IL-8/CXCL8 through gastric digestion needs confirmation in assays for structural and functional integrity. We hypothesized that IL-8/ CXCL8 survives neonatal gastric digestion as a result of an intrinsic resistance to aspartyl proteinase activity. We treated recombinant human IL-8/CXCL8 (rhIL-8/CXCL8) with an established gastric fluid model (Simulated Gastric Fluid; USP, 10) (10) and measured IL-8/CXCL8 concentration and bioactivity in a variety of assays. IL-8/CXCL8 -pepsin interaction was studied further in computational simulations involving molecular docking. The protease resistance of IL-8/CXCL8 was identified to be due to its disulfide bond-related tertiary folding and confirmed in actual chemical reduction experiments. METHODSSimulated gastric fluid (SGF) was prepared with 3.2 mg/mL of porcine pepsin (3200 -4500 units/mg protein; Sigma Chemical Co., St. Louis, MO) in 0.2% NaCl/0.7% HCl (pH 1.2; US Pharmacopoeia) (10). Carrier-free rhIL-8/ CXCL8 (R&D Systems, Minneapolis, MN) and BSA (control; Sigma Chemical Co.) were freshly reconstituted in PBS as 0.25-mg/mL solutions, which provided a pepsin:protein ratio of 50:1.

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Section: Discussionmentioning

confidence: 99%

IL-8/CXC Ligand 8 Survives Neonatal Gastric Digestion as a Result of Intrinsic Aspartyl Proteinase Resistance

Maheshwari

Guida

et al. 2005

Pediatr Res

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“…EGF is available to the fetus in amniotic fluid and to the newborn infant in breast milk, in large amounts. It is not denatured by gastric acid,31 allowing it to bind to receptors in the stomach, and it is absorbed intact from the immature gut 32. We have already documented that the developing human stomach has the functional capacity to produce gastric acid from the end of the first trimester29 and that even the most immature infant can produce and maintain a gastric pH of below 4 33.…”

Section: Discussionmentioning

confidence: 99%

Role of epidermal growth factor and transforming growth factor alpha in the developing stomach

Kelly

Newell²,

Brownlee³

et al. 1997

Archives of Disease in Childhood - Fetal and Neonatal Edition

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Aims-To determine whether epidermal growth factor (EGF) or the related transforming growth factor (TGF ) may have a role in the developing human stomach; to substantiate the presence of EGF in human liquor in the non-stressed infant and whether EGF in amniotic fluid is maternally or fetally derived. Methods-The temporal expression and localisation of EGF, TGF , and their receptors during fetal and neonatal life were examined in 20 fetal and five infant stomachs. Simultaneously, samples of amniotic fluid and fetal urine from 10 newborn infants were collected and assayed for EGF by radioimmunoassay. Results-EGF immunoreactivity was not noted in any of the specimens examined. In contrast, TGF immunoreactivity was shown in mucous cells from 18 weeks of gestation onwards. EGF receptor immunoreactivity was seen on superficial mucous cells in gastric mucosa from 18 weeks of gestation onwards. The median concentration of EGF was 30 and 8.5 pg/ml in amniotic fluid and fetal urine, respectively, suggesting that EGF is not produced by the fetus. Conclusions-This study adds weight to the hypothesis that swallowed EGF, probably produced by the amniotic membranes, and locally produced TGF , may have a role in the growth and maturation of the human stomach. (Arch Dis Child 1997;76:F158-F162)

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“…Colostrum contains high concentrations of epidermal growth factor, 29 which has been shown to enter the systemic circulation in the infant 30 and therefore may play a role in inducing maturation in the infant intestine and other tissues. Interestingly, the concentration of epidermal growth factor is particularly high in breastmilk from mothers whose infants have been born prematurely.…”

Section: Factors Modulating Intestinal Immunitymentioning

confidence: 99%

Academy of Breastfeeding Medicine Founder's Lecture 2008: Breastfeeding—An Extrauterine Link Between Mother and Child

Rautava

Walker

2009

Breastfeeding Medicine

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In addition to a near-optimal combination of nutrients for the growing infant, breastmilk contains a wide array of bioactive molecules that are known to protect the infant against infectious disease and modulate the composition of the indigenous intestinal microbiota. A growing number of factors that modulate the infant's immunophysiology have also been identified in breastmilk. We suggest that this early immunomodulation via breastmilk is vital for infant health and may explain the epidemiological data indicating that breastmilk reduces the risk of immunoinflammatory conditions in infancy and also later in life. The body of scientific data regarding the role of transforming growth factor-␤ in breastmilk in enhancing healthy immune maturation and reducing the risk of disease is reviewed in this article.3

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Is Dietary Epidermal Growth Factor Absorbed by Premature Human Infants?

Cited by 35 publications

References 18 publications

IL-8/CXC Ligand 8 Survives Neonatal Gastric Digestion as a Result of Intrinsic Aspartyl Proteinase Resistance

IL-8/CXC Ligand 8 Survives Neonatal Gastric Digestion as a Result of Intrinsic Aspartyl Proteinase Resistance

Role of epidermal growth factor and transforming growth factor alpha in the developing stomach

Academy of Breastfeeding Medicine Founder's Lecture 2008: Breastfeeding—An Extrauterine Link Between Mother and Child

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