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The Milk Peptidome: A Gold Mine of Bioactivities

    A jug of milk with a string of protein fragments around the jug, strung like lights.

    Written by: David Dallas, Ph.D., Junai Gan | Issue # 26 | 2014

    • Both human and bovine milk contain naturally occurring protein fragments (peptides) with the ability to exert biological functions, including antibacterial and immunomodulatory effects.
    • Additional breakdown of human milk proteins occurs in the infant stomach despite its high pH, releasing a large number of additional peptides.
    • Further research into proteolysis during infant digestion will give a better understanding of the specific functions of these peptides inside humans.

    If you drank a glass of milk with your breakfast this morning, you may have given your body far more than a dose of bone-strengthening calcium. Recent research suggests that milk also contains protein fragments with the ability to lower blood pressure, inhibit harmful bacterial growth, boost immune system function and enhance calcium absorption. All of these functions have been ascribed to fragments of milk proteins (peptides) that occur naturally in bovine milk.

    Although milk is well known as a good source of protein, the discovery of these naturally occurring functional protein fragments is recent. In the past, proteins were thought to be broken down into amino acids, and then absorbed in the body. However, recent evidence shows that many protein fragments survive digestion for extended periods. Therefore, dietary proteins can no longer be considered simply as an amino acid source for protein synthesis. In a paper published in January 2014, our team identified hundreds of endogenous peptides in Holstein cow milk, many of which have beneficial functions [1]. These peptides are inactive within milk proteins, but take on their respective functions when these proteins are cleaved by milk enzymes. Thus, in addition to providing building blocks for protein synthesis, the naturally occurring milk peptides likely provide consumers with many additional health benefits.

    The study examined milk samples collected from six Holstein cows during their peak lactation period. Both the number and amounts of milk peptides present among the six cows were remarkably consistent, indicating a highly controlled enzymatic degradation system. Our team determined that the majority of the identified protein cleavages came from the action of a naturally occurring enzyme called plasmin, which is selectively pulled from the mother’s blood into her milk.

    Thanks to the efforts of other researchers [2], some of the peptides identified in these bovine milk samples have already been tested for biological functionality and been proven active. For example, an αs1-casein-derived peptide called isracidin prevents the growth of Staphylococcus aureus, a species of bacteria responsible for infections and some foodborne illnesses [3]. Another peptide, casoparan, can have immunomodulatory effects [4]. Each of the six samples also had between 35 and 37 phosphorylated peptides (the post-translational addition of a phosphate group). Phosphate groups are negatively charged, allowing them to bind calcium ions, which enhances calcium absorption in the consumer.

    The presence of functional peptides is not limited to bovine milk. Recent research has shown that human milk contains hundreds of endogenous peptides, many of which are highly similar to known functional peptides [5]. In another recent study, our team examined what happens to milk proteins and peptides in the infant stomach [6]. Previously, it was thought that little digestion happened in newborn babies’ stomachs because of the high post-feeding pH, which normally would inhibit the action of the main gastric protease, pepsin. We analyzed gastric extracts from infants who had been fed human milk. Hundreds of novel peptides are released in the infant stomach, and bioinformatic enzyme analysis (not yet published) has revealed that pepsin is active, despite the high pH. Perhaps more interestingly, this analysis revealed that the mother’s milk proteases are active in the infant stomach and are responsible for a majority of digestion there!

    The next step in this research will be to follow the digestion process even further—to see what happens in the bloodstream, stool and urine. The goal is to gain a complete picture of protein digestion in babies. Annotating the specific location of these milk protein fragments will help to reveal how they might function in the infant.


    1.  Dallas DC, Guerrero A, Parker EA, Garay LA, Bhandari A, Lebrilla CB, Barile D, German JB (2013). Peptidomic profile of milk of Holstein cows at peak lactation. J Agric Food Chem 62: 58–65.

    2.  Clare DA, Swaisgood HE (2000). Bioactive milk peptides: a prospectus. J Dairy Sci 83: 1187-1195.

    3.  Lahov E, Regelson W (1996). Antibacterial and immunostimulating casein-derived substances from milk: casecidin, isracidin peptides. Food Chem Toxicol 34: 131-145.

    4.  Lebrun I, Cavallaro V, Juliano L, Juliano MA, de Sousa e Silva MC (2004). Effects of ‘casoparan’, a peptide isolated from casein hydrolysates with mastoparan-like properties. Mediators Inflamm 13: 263-268.

    5.  Dallas DC, Guerrero A, Khaldi N, Castillo PA, Martin WF, Smilowitz JT, Bevins CL, Barile D, German JB, Lebrilla CB (2013). Extensive in vivo human milk peptidomics reveals specific proteolysis yielding protective antimicrobial peptides. J Proteome Res 2013. 12: 2295-2304.

    6.  Dallas DC, Guerrero A, Khaldi N, Borghese R, Bhandari A, Underwood MA, Lebrilla CB, German JB, Barile D (2014). A peptidomic analysis of human milk digestion in the Infant stomach reveals protein-specific degradation patterns. J Nutr Apr 3. [Epub ahead of print].