Effects of Milk Osteopontin on Intestine, Neurodevelopment, and Immunity

Summary

Osteopontin (OPN) is an acidic phosphorylated glycoprotein. It is a multifunctional protein which is involved in cell proliferation and differ- entiation, biomineralization, immunomodulatory activities, and myelina- tion. OPN contains integrin and CD44 receptor binding sites, and it exerts its pleiotropic functions by binding to its receptors on the cell membrane and triggering cellular signaling pathways. OPN is expressed in various cell types, such as epithelial cells and immune cells, and it is found in most
body fluids, including milk and blood. It is present at increased concentration in human milk, but not in cow milk and infant formula. Milk OPN is relatively resistant to gastrointestinal digestion, and it may, therefore, contribute to intestinal development. Additionally, orally ingested OPN appears in the circulatory system, which suggests that milk OPN exerts its multiple functions also systemically (Fig. 1).

Milk OPN is commercially available since methods to isolate OPN from cow milk have been established. Bioactivities of milk OPN were investigated using cell lines, animal models, and randomized clinical trials, and the results from these studies demonstrated that there are three major functions of milk OPN in early life. First, milk OPN contributes to intestinal proliferation and maturation. It stimulates proliferation, differentiation, and immunity of human intestinal epithelial cells [1]. In a study in rhesus monkeys, monkey infants fed formula supplemented with bovine milk OPN for 3 months exhibited a transcriptome more similar to the breastfed group, and OPN upregulated genes involved in cell proliferation, migration, survival, and signaling pathways from integrin and CD44 receptors [2]. Second, milk OPN promotes neurodevelopment in early infancy. It was shown that OPN is abundantly present in
the brain and regulated brain myelination. In an established OPN mouse model, wild-type mouse pups nursed by wild-type or OPN knockout dams received milk with abundant OPN or no OPN. The orally ingested milk OPN upregulated endogenous OPN in the brain and thus promoted proliferation and differentiation of NG-2 glia into oligodendrocytes.

As a consequence, brain myelination and cognitive development were enhanced [3]. Finally, milk OPN stimulates immune development. In mice with colitis induced by dextran sulfate sodium, oral administration of bovine milk OPN showed reduced inflammatory symptoms. Further, OPN may alter the gut microbiota to fight enterotoxigenic Escherichia coli infection in piglets. Additionally, in a randomized clinical trial in infants 1–6 months of age, infants were either breastfed, fed regular formula, or fed OPN-supplemented formula. Infants fed OPN-supplemented formula had significantly lower serum TNF-α levels and fewer days of illness com- pared with infants fed regular formula, and their immune cell profile was more similar to that of breastfed infants [4, 5].

In conclusion, milk OPN plays important roles in the development
of the intestine, brain, and immunity.

References
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