The role of milk-borne epidermal growth factor on hepatic development in artificially reared suckling rats

Abstract

Breast milk contains many biologically active substances, including epidermal growth factor (EGF), that are absent from artificial milk formulas. Previous studies have shown dramatic growth and maturation effects of milk-borne EGF on the intestine. This raises the question as to whether artificial milk formulas should be supplemented with biologically active substances, such as EGF. As a result, this dissertation examined whether feeding suckling rats artificial milk formula supplemented with EGF modulates liver development. The normal development of hepatic cells in suckling and weanling rats also was characterized. Additionally, this dissertation examined whether gut-derived endotoxin and tumor necrosis factor alpha (TNFα) play a role in liver development. Dam-fed suckling and weanlings showed increases in the reorganization of hepatocellular plates, numbers of binucleated hepatocytes, and a tendency for sinusoidal endothelial cell fenestrae density and porosity to increase with age. Monocytic derived cells increased at days 8-12 and decreased at day 16. Hepatic stellate cells decreased with age. Colon microbial flora and portal venous endotoxin were present from day 8 onward. Compared to artificial milk formula feeding alone, EGF in the artificial formula elicited increased numbers of binucleated hepatocytes, changes in colon microbial flora, and a tendency for increased numbers of Kupffer cells and portal venous endotoxin. Compared to breast milk, the artificial diet caused decreases in binucleated hepatocytes, increases in monocytic derived cells, Kupffer cells, hepatic stellate cells, portal venous endotoxin and changes in the composition of the colon microbial flora. These increases in cells may be due to colonization of the colon with microbial flora which increased portal venous endotoxin. Increased endotoxin may provide a stimulus for the recruitment of monocytic derived cells to the liver and differentiation into Kupffer cells, which then stimulates hepatic stellate cell proliferation. However, the increases in portal venous endotoxin were not sufficient to elicit hepatic TNFα, mRNA production. In conclusion, milk-borne EGF is involved in differentiation of hepatocytes and changes colon microbial flora that occur in suckling rats. Whether accelerating maturation of hepatocyte is beneficial or detrimental to the suckling rats remains to be determined. Therefore, the supplementation of artificial milk formula with EGF warrants further consideration and research.