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An Interactomics Overview of the Human and Bovine Milk Proteome Over Lactation Lina Zhang1, Aalt D

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Zhang et al. Proteome Science (2017) 15:1 DOI 10.1186/s12953-016-0110-0 RESEARCH Open Access An interactomics overview of the human and bovine milk proteome over lactation Lina Zhang1, Aalt D. J. van Dijk2,3,4 and Kasper Hettinga1* Abstract Background: Milk is the most important food for growth and development of the neonate, because of its nutrient composition and presence of many bioactive proteins. Differences between human and bovine milk in low abundant proteins have not been extensively studied. To better understand the differences between human and bovine milk, the qualitative and quantitative differences in the milk proteome as well as their changes over lactation were compared using both label-free and labelled proteomics techniques. These datasets were analysed and compared, to better understand the role of milk proteins in development of the newborn. Methods: Human and bovine milk samples were prepared by using filter-aided sample preparation (FASP) combined with dimethyl labelling and analysed by nano LC LTQ-Orbitrap XL mass spectrometry. Results: The human and bovine milk proteome show similarities with regard to the distribution over biological functions, especially the dominant presence of enzymes, transport and immune-related proteins. At a quantitative level, the human and bovine milk proteome differed not only between species but also over lactation within species. Dominant enzymes that differed between species were those assisting in nutrient digestion, with bile salt- activated lipase being abundant in human milk and pancreatic ribonuclease being abundant in bovine milk. As lactation advances, immune-related proteins decreased slower in human milk compared to bovine milk. Notwithstanding these quantitative differences, analysis of human and bovine co-expression networks and protein- protein interaction networks indicated that a subset of milk proteins displayed highly similar interactions in each of the different networks, which may be related to the general importance of milk in nutrition and healthy development of the newborn. Conclusions: Our findings promote a better understanding of the differences and similarities in dynamics of human and bovine milk proteins, thereby also providing guidance for further improvement of infant formula. Keywords: Proteomics, Protein interaction networks, Lactation, Human milk, Bovine milk Background proteins, including both high and low abundant pro- Milk is one of the richest foods, as it provides complete teins, were characterized in the last few decades [3–5]. nutrition and bioactive components for healthy develop- However, milk proteins are variable in presence and ment of the newborn. These nutritional and bioactive concentration due to many factors. One of the most ob- components are essential for the neonate, for example vious factors causing differences in protein concentra- for cognitive development, pathogen prevention, intes- tion is species differences [6]. Caseins accounts for 80% tinal microflora modulation, and development of the im- (w/w) of the bovine milk proteins, and for 50% of hu- mune system [1, 2]. Of these bioactive components, man milk proteins [4]. In addition, β-lactoglobulin exists proteins have attracted great attention because of their in bovine milk but cannot be found in human milk [6, importance in the protection of the neonate. With the 7]. Human and bovine milk diverge not only in their development of proteomics techniques, more and more high abundant protein composition, but also in their low abundant protein composition. A total of 268 and 269 * Correspondence: [email protected] proteins were previously identified in human and bovine 1Dairy Science and Technology, Food Quality and Design Group, Wageningen University, Postbox 8129, 6700EV Wageningen, The Netherlands milk, respectively, in our previous study [8]. Of these Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. Proteome Science (2017) 15:1 Page 2 of 14 proteins, 44 from human milk and 51 from bovine milk Result were related to the host defense system. Specifically, the A total of 379 proteins were quantified through reana- concentration of proteins involved in the mucosal im- lyzing the human and bovine milk of data set 1 prepared mune system, immunoglobulin A, CD14, lactoferrin, and by filter-aided sample preparation (FASP) and LC-MS/ lysozyme, were present in much higher concentration in MS. The specific number of identified proteins in milk human milk than bovine milk [8]. fat globule membrane (MFGM) and milk serum proteins Furthermore, milk proteins also differ in concentration for both human and bovine species are shown in Fig. 1. over lactation. Immunoglobulins have been reported to Of these quantified proteins, 93 proteins present in both change rapidly in concentration from colostrum to ma- species. Figure 2 shows that both human milk and bo- ture milk in both human [9, 10] and bovine milk [11– vine milk have similar distribution over biological func- 13]. Moreover, the low abundant proteins, such as com- tions in quantified MFGM and milk serum proteins. plement proteins, lipid synthesis and transport proteins, Transport proteins, enzymes, and immune-related pro- and enzymes were also reported to change as lactation teins were the three dominant biological function groups advances [14, 15]. However, the differences in changes of in both human and bovine milk (Fig. 2). The biological proteins over lactation has not been reported between enrichment of these three protein groups were shown in human milk and bovine milk directly, although we re- Additional file 1: Table S1. However, the number of pro- ported the changes in the species separately [13, 16–18]. teins in these three dominant groups was different be- As human milk is used as reference and bovine milk is tween human and bovine milk. Bovine milk contained a used as protein source for producing infant formula higher number of transport proteins than human milk [19], the differences in the health outcomes between (Fig. 2), which was dominated by lipid and protein trans- breastfed and formula-fed infants could be related to the porters. Although the number of enzymes were similar, differences in the nutrient intake [6]. Breastfed infants they were quite different in the type between human and were reported to have fewer infections (gastrointestinal bovine milk. The enzymes assisting nutrient digestion infections, acute otitis media), reduced risk for celiac were bile salt-activated lipase (CEL), and lipoprotein lip- disease, obesity, and diabetes compared to formula-fed ase (LPL) alpha-trypsin chain 1 (PRSS1) in human milk infants [19]. Therefore, the aim of this study is to better (Table 1) [16, 18], whereas pancreatic ribonuclease 1 understand the role of different proteins, especially those (RNASE1), LPL, and ribonuclease 4 (RNASE4) were involved in immune activity, in both human milk and bo- dominant in bovine milk [13, 17]. vine milk through elaborating the existing data in qualita- Tables 1 and 2 show the quantitative differences of tive and quantitative proteome [8] and their changes over common MFGM and milk serum proteins between lactation [13, 16–18]. Separate interactomics studies of human and bovine milk. Lipid synthesis and transport human and bovine milk proteins have previously been proteins, including fatty acid-binding protein, heart performed, using published data collected from many dif- (FABP3), perilipin-2 (PLIN2), butyrophilin subfamily 1 ferent sources [20, 21]. In this study, the analysis is a com- member A1 (BTN1A1), lactadherin (MFGE8), and platelet parative data analysis on both species simultaneously, glycoprotein 4 (CD36), were present at approximately 10– where data has been collected on a single instrument [8, 100 times higher abundance in bovine MFGM (p < 0.05). 13, 16–18], throughout lactation, allowing a better com- Serum albumin (ALB), monocyte differentiation antigen parison between species. CD14 (CD14), alpha-lactalbumin (LALBA), lactoferrin In the current study, the human and bovine milk data in (LTF), toll-like receptor 2 (TLR2), alpha-1-antitrypsin (SER- Data set 1 [8] was reanalysed by Maxquant to give a more PINA1), alpha-1-antichymotrypsin (SERPINA3), clusterin precise comparison in the quantitative differences be- (CLU), and polymeric immunoglobulin receptor (PIGR) tween human and bovine milk proteins. The changes of showed higher concentrations in human milk, especially for both human and bovine milk proteome over lactation in ALB, LTF, SERPINA3, and CD14, which were around 20– Data set 2 [13, 16–18] were reanalysed using a co- 100 times higher in human milk serum (p < 0.05). expression (expression meaning the relative abundance) Since milk serum protein content is far higher than network approach and integrated with protein-protein MFGM protein content [20], the quantitative changes interaction network data. The additional analysis
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