Human milk contains an abundance of biologically active components that are highly likely to contribute to the short- and long-term benefits of breastfeeding. Many of these components are proteins; this article describes some of these proteins, such as α-lactalbumin, lactoferrin, osteopontin, and milk fat globule membrane proteins. An important consideration when adding bioactive proteins to infant formula is that the total protein content of formula needs to be reduced, because formula-fed infants have significantly higher concentrations of serum amino acids, insulin, and blood urea nitrogen than do breastfed infants. When reducing the protein content of formula, the amino acid composition of the formula protein becomes important because serum concentrations of the essential amino acids should not be lower than those in breastfed infants. Both the supply of essential amino acids and the bioactivities of milk proteins are dependent on their digestibility: some proteins act only in intact form, others act in the form of larger or small peptides formed during digestion, and some are completely digested and serve as a source of amino acids.
The protein content of infant formula has traditionally been considerably higher than that of human milk. Although it has been lowered during the past decades, this still holds true. There were several reasons for this higher amount of protein, but the primary reason was the lower digestibility of cow-milk protein, limiting the supply of essential amino acids. With less intense heat treatment of the formula protein sources (skim milk protein, whey protein), this difference is no longer as pronounced. The higher protein intake of formula-fed infants is manifested by significantly higher concentrations of most plasma amino acids and of blood urea nitrogen than those in breastfed infants. This has been considered as a potential source of “metabolic stress” on tissues such as the liver and kidneys in the still-developing infant (17). Perhaps more concerning is the significantly higher concentrations of serum insulin in formula-fed infants than in breastfed infants (18), most likely caused by the elevated concentrations of the branched-chain, insulinogenic amino acids (valine, leucine, isoleucine). The long-term consequences of this early hyperinsulinemia have not been studied in detail, but it is quite possible that they are linked to the higher risk of diabetes and obesity in formula-fed infants. Large ongoing studies such as the European Union Early Nutrition Programming Project (19) are likely to provide more information on these risks and the underlying mechanisms.
The extent of protein digestibility becomes a critical issue for both essential amino acid supply and the potential bioactivities of bovine-milk proteins. When lowering the protein concentration in infant formula, the first limiting amino acid becomes tryptophan (13). One approach that has been used to avoid this is to add free tryptophan (and possibly other amino acids that subsequently become limiting) to the formula (20). It is highly likely, however, that these added amino acids will be absorbed much faster than protein-bound amino acids, which need proteolysis to occur before uptake, and thus reach target tissues (liver, brain) more rapidly. The metabolic consequences of this have not yet been studied adequately. Another approach is to increase the proportion of α-lactalbumin in formula (21). α-Lactalbumin has a relatively high proportion of tryptophan and is commercially available as an enriched whey fraction. Clinical studies have shown that lowering the protein amount in infant formula coupled with an increased proportion of α-lactalbumin results in plasma tryptophan concentrations similar to those in breastfed infants.
13. Lo¨nnerdal B, Lien EL. Nutritional and physiologic significance of alpha- lactalbumin in infants. Nutr Rev 2003;61:295–305
17. Ra¨iha¨ NC, Axelsson IE. Protein nutrition during infancy: an update. Pediatr Clin North Am 1995;42:745–64.
18. Zetterstro¨m R, Ginsburg BE, Lindblad BS, Persson B. Relation between protein intake, plasma valine, and insulin secretion during early infancy. Klin Padiatr 1985;197:371–4.
19. Socha P, Grote V, Gruszfeld D, Janas R, Demmelmair H, Closa- Monasterolo R, Subı´as JE, Scaglioni S, Verduci E, Dain E, et al; European Childhood Obesity Trial Study Group. Milk protein intake, the metabolic-endocrine response, and growth in infancy: data from a randomized clinical trial. Am J Clin Nutr 2011;94(suppl):1776S–84S.
20. Fazzolari-Nesci A, Domianello D, Sotera V, Raiha NC. Tryptophan fortification of adapted formula increases plasma tryptophan concentrations to levels not different from those found in breast-fed infants. J Pediatr Gastroenterol Nutr 1992;14:456–9.
21. Davis AM, Harris BJ, Lien EL, Pramuk K, Trabulsi J. Alpha-lactalbuminrich infant formula fed to healthy term infants in a multicenter study: plasma essential amino acids and gastrointestinal tolerance. Eur J Clin Nutr 2008;62:1294–301.
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