Milk Epidermal Growth Factor and Gut Protection

Abstract

Maternal milk is a complex fluid with multifunctional roles within the developing gastrointestinal tract. Epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF) are members of the family of EGF-related peptides. Biological actions of these growth factors are mediated via interaction with the EGF-receptor (EGF-R). In the early postnatal period, breast milk is the major source of EGF for the developing intestinal mucosa. HB-EGF is also detected in breast milk, but in concentrations 2 to 3 times lower than EGF. Under normal physiological conditions, the intestinal epithelium undergoes a continuing process of cell proliferation, differentiation and maturation. EGF plays an important role in these processes. In pathophysiologic situations, EGF contributes to epithelial protection from injury and post-injury mucosal repair. Necrotizing enterocolitis (NEC) is a devastating disease affecting prematurely born infants. The pathogenesis of NEC is not known and there is no effective treatment for this disease. In an experimental NEC model, oral administration of a physiological dose of EGF significantly reduces the incidence and severity of NEC. HB-EGF provides similar protection against NEC, but only when pharmacological doses are used. Further studies are necessary before EGF can be introduced as an efficient therapeutic approach of intestinal injury. Maternal milk and developing gutMaternal milk is an important and well-balanced source of nutrition for the newborn (1). Milk provides not only major nutrients, vitamins and minerals, but also a plethora of biologically active substances, such as hormones, cytokines, and growth factors (2-6). These biological active factors not only facilitate the development of essential digestive functions, but also regulate the maturation of the intestinal mucosal barrier (7). In addition to their normal physiological functions, many of these factors have the capacity to stimulate the healing and repair processes in injured intestinal epithelium.The gastrointestinal (GI) tract is a complex organ which undergoes substantial changes during the early stages of development. Profound growth, morphological and functional changes are observed during the late gestation and early postnatal period (8). Birth is possibly the most critical period in gastrointestinal development, when placental supply is replaced by enteral nutrition. Enteral nutrition initiates changes in intestinal mucosal structure and function required for utilization of milk feedings. However, intestinal maturation begins long before birth and amniotic fluid plays an important role in this process (7). In addition to its digestive

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“…Gut maturation is significantly affected by EGF and TGF-b, both in utero and then through early lactation. Giving human breast milk to preterm infants greatly reduces the risk of necrotizing enterocolitis, a leading cause of morbidity and mortality in preterm babies (Dvorak, 2010).…”

Are EGF and TLR-4 crucial to understanding the link between milk and NEC?

“…11,12 Interestingly, EGF levels in breast milk of mothers with extremely preterm babies are much higher than in term infants. 11 Numerous experimental studies in rat and mice NEC models confirmed the protective effect of EGF, 13,14 supporting the hypothesis that EGF in breast milk may be, at least in part, responsible for the protection against NEC. However, the exact mechanism for its beneficial effects needed to be clarified.…”

“…22 EGF also alters the balance between regulators of apoptosis thereby reducing intestinal epithelial cell apoptosis and maintaining epithelial homeostasis. 13 Another important role of EGF is its direct effect on neonatal gut development, as was shown by the exogenous infusion of EGF in utero in rabbits, leading to stimulated intestinal growth and increased maturation of intestinal enzyme activity. 23 Using transgenic mice and cultured enteroids, the group of Hackam 24 recently demonstrated that TLR-4 activation induces endoplasmic reticulum-stress mediated apoptotic cell death of intestinal stem cells and subsequent NEC development.…”

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“…Factors that could affect this specific feature of human milk could be both the hormone content and the presence of epidermal growth factor as well as other growth factors that are as yet not completely understood. [18][19][20][21][22][23][24] Anyway, it still remains to be determined whether these adaptations are limited to mucosal hyperplasia or lead to an actual lengthening of the residual intestine. [25][26][27] The radiographic studies we performed sixteen years after intestine resection proved a lengthening of the residual small intestine, 40 cm long, but, unfortunately, the patient refused to undergo a capsule endoscopy, a possibility to obtain a direct evidence of the mucosal morphology.…”