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Introduction: Emerging Roles of Bioactive Components in Pediatric Nutrition

2016; Elsevier BV; Volume: 173; Linguagem: Inglês

10.1016/j.jpeds.2016.02.069

1097-6833

Sharon M. Donovan, Bo Lönnerdal,

Neonatal Respiratory Health Research

Human milk is the optimal source of nutrients, but its uniqueness lies in the variety of bioactive proteins, lipids, and carbohydrates it contains.1Ballard O. Morrow A.L. Human milk composition: nutrients and bioactive factors.Pediatr Clin North Am. 2013; 60: 49-74Abstract Full Text Full Text PDF PubMed Scopus (1466) Google Scholar These components provide enzymatic activity2Hernell O. Bläckberg L. Digestion of human milk lipids: physiologic significance of sn-2 monoacylglycerol hydrolysis by bile salt-stimulated lipase.Pediatr Res. 1982; 16: 882-885Crossref PubMed Scopus (74) Google Scholar, 3Johnson K. Ross L. Miller R. Xiao X. Lowe M.E. Pancreatic lipase-related protein 2 digests fats in human milk and formula in concert with gastric lipase and carboxyl ester lipase.Pediatr Res. 2013; 74: 127-132Crossref PubMed Scopus (29) Google Scholar; inhibit proteolytic enzymes4Chowanadisai W. Lönnerdal B. Alpha(1)-antitrypsin and antichymotrypsin in human milk: origin, concentrations, and stability.Am J Clin Nutr. 2002; 76: 828-833PubMed Google Scholar; stimulate neonatal intestinal,5Donovan S. Role of human milk components in gastrointestinal development: current knowledge and future needs.J Pediatr. 2006; 149: S49-S61Abstract Full Text Full Text PDF Scopus (82) Google Scholar immune,6Walker W.A. Iyengar R.S. Breast milk, microbiota, and intestinal immune homeostasis.Pediatr Res. 2015; 77: 220-228PubMed Google Scholar, 7Cummins A.G. Thompson F.M. Postnatal changes in mucosal immune response: a physiological perspective of breast feeding and weaning.Immunol Cell Biol. 1997; 75: 419-429Crossref PubMed Scopus (72) Google Scholar, 8Kaplan J.L. Shi H.N. Walker W.A. The role of microbes in developmental immunologic programming.Pediatr Res. 2011; 69: 465-472Crossref PubMed Scopus (140) Google Scholar and brain development9Herba C.M. Roza S. Govaert P. Hofman A. Jaddoe V. Verhulst F.C. et al.Breastfeeding and early brain development: the Generation R study.Matern Child Nutr. 2013; 9: 332-349Crossref PubMed Scopus (35) Google Scholar, 10McCrory C. Murray A. The effect of breastfeeding on neuro-development in infancy.Matern Child Health J. 2013; 17: 1680-1688Crossref PubMed Scopus (50) Google Scholar; shape the microbiome11Musilova S. Rada V. Vlkova E. Bunesova V. Beneficial effects of human milk oligosaccharides on gut microbiota.Benef Microbes. 2014; 5: 273-283Crossref PubMed Scopus (86) Google Scholar, 12Jost T. Lacroix C. Braegger C. Chassard C. Impact of human milk bacteria and oligosaccharides on neonatal gut microbiota establishment and gut health.Nutr Rev. 2015; 73: 426-437Crossref PubMed Scopus (156) Google Scholar; and protect the infant from infection.13Liu B. Newburg D.S. Human milk glycoproteins protect infants against human pathogens.Breastfeed Med. 2013; 8: 354-362Crossref PubMed Scopus (116) Google Scholar, 14Sankar M.J. Sinha B. Chowdhury R. Bhandari N. Taneja S. Martines J. et al.Optimal breastfeeding practices and infant and child mortality: a systematic review and meta-analysis.Acta Paediatr Suppl. 2015; 104: 3-13Crossref Scopus (402) Google Scholar The diversity of human milk proteins was evidenced by a proteomic analysis that identified over 3 times as many proteins (1606 vs 518 proteins) in human vs rhesus macaque milk, respectively.15Beck K.L. Weber D. Phinney B.S. Smilowitz J.T. Hinde K. Lönnerdal B. et al.Comparative proteomics of human and macaque milk reveals species-specific nutrition during postnatal development.J Proteome Res. 2015; 14: 2143-2157Crossref PubMed Scopus (54) Google Scholar Of the 88 differentially abundant proteins, 93% were present in greater abundance in human milk, including lactoferrin, polymeric immunoglobulin receptor, alpha-1antichymotrypsin, vitamin D-binding protein, and haptocorrin.15Beck K.L. Weber D. Phinney B.S. Smilowitz J.T. Hinde K. Lönnerdal B. et al.Comparative proteomics of human and macaque milk reveals species-specific nutrition during postnatal development.J Proteome Res. 2015; 14: 2143-2157Crossref PubMed Scopus (54) Google Scholar Importantly, the functions of proteins that were more abundant in human vs macaque milk were associated with development of the gastrointestinal tract, the immune system, and the brain.15Beck K.L. Weber D. Phinney B.S. Smilowitz J.T. Hinde K. Lönnerdal B. et al.Comparative proteomics of human and macaque milk reveals species-specific nutrition during postnatal development.J Proteome Res. 2015; 14: 2143-2157Crossref PubMed Scopus (54) Google Scholar Insights into the biological activities of specific bioactive components of human milk can have important implications for the nutritional composition of formulas designed for infants and children.16Lönnerdal B. Infant formula and infant nutrition: bioactive proteins of human milk and implications for composition of infant formulas.Am J Clin Nutr. 2014; 99: 712S-717SCrossref PubMed Scopus (189) Google Scholar Meeting this challenge will be facilitated by methods to isolate biologically active fractions and components from bovine milk, which share structural and functional similarities to human milk proteins.17Lönnerdal B. Biological effects of novel bovine milk fractions.Nestle Nutr Workshop Ser Pediatr Program. 2011; 67: 41-54Crossref PubMed Scopus (39) Google Scholar An Expert Panel, supported by the Mead Johnson Pediatric Nutrition Institute, met in Boston, Massachusetts, April 22-24, 2015, to review basic and clinical research on 2 human milk components, lactoferrin and the milk fat globule membrane (MFGM). The articles in this Supplement provide insights as to why these bioactive components are important for the healthy development of infants and children, as well as propose hypotheses for potential mechanisms of action. The first article in this Supplement provides an overview of the bioactivity of human milk components and their effects on the recipient infant. The following articles focus on the bioactivities of lactoferrin, sphingolipids, sialylated glycoconjugates, and MFGM. Lactoferrin is a 77 kDa, iron-binding multifunctional glycoprotein that is present at high concentration in human milk, relative to cow milk and infant formulas.18Lönnerdal B. Iyer S. Lactoferrin: molecular structure and biological function.Annu Rev Nutr. 1995; 15: 93-110Crossref PubMed Scopus (661) Google Scholar, 19Baker E.N. Baker H.M. A structural framework for understanding the multifunctional character of lactoferrin.Biochimie. 2009; 91: 3-10Crossref PubMed Scopus (205) Google Scholar Lactoferrin concentrations are highest during early lactation (4.91 ± 0.31 g/L) and then rapidly decline to an average concentration of 2.10 ± 0.87 g/L, which remains relatively unchanged from 1 month to 2 years of lactation (Figure).20Rai D. Adelman A.S. Zhuang W. Rai G.P. Boettcher J. Lönnerdal B. Longitudinal changes in lactoferrin concentrations in human milk: a global systematic review.Crit Rev Food Sci Nutr. 2014; 54: 1539-1547Crossref PubMed Scopus (87) Google Scholar Lactoferrin is an immunomodulator21Legrand D. Lactoferrin, a key molecule in immune and inflammatory processes.Biochem Cell Biol. 2012; 90: 252-268Crossref PubMed Scopus (148) Google Scholar and may act through a variety of mechanisms. It has direct bactericidal effects and may interact with the host immune system through interactions with pathogen associated molecules, such as CpG-rich DNA or lipopolysaccharide.22Latorre D. Berlutti F. Valenti P. Gessani S. Puddu P. LF immunomodulatory strategies: mastering bacterial endotoxin.Biochem Cell Biol. 2012; 90: 269-278Crossref PubMed Scopus (33) Google Scholar, 23Haversen L. Ohlsson B.G. Hahn-Zoric M. Hanson L.Å. Mattsby-Baltzer I. Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-kappa B.Cell Immunol. 2002; 220: 83-95Crossref PubMed Scopus (272) Google Scholar In addition, activated lymphocytes express lactoferrin receptors.24Mincheva-Nilsson L. Hammarström S. Hammarström M.L. Activated human gamma delta T lymphocytes express functional lactoferrin receptors.Scand J Immunol. 1997; 46: 609-618Crossref PubMed Scopus (39) Google Scholar The second article in this Supplement reviews the potential mechanisms whereby lactoferrin exerts its effects on the neonatal immune system. The third article in this Supplement summarizes recent research in the preclinical piglet model demonstrating the efficacy of dietary lactoferrin on promoting gastrointestinal and immune development. The fourth article in this Supplement presents results of lactoferrin, which also is sialylated, on piglet cognitive and brain development. Lastly, preterm infants are at risk for developing sepsis and necrotizing enterocolitis, and human milk feeding has been shown to reduce those risks.25Patel A.L. Johnson T.J. Engstrom J.L. Fogg L.F. Jegier B.J. Bigger H.R. et al.Impact of early human milk on sepsis and health-care costs in very low birth weight infants.J Perinatol. 2013; 33: 514-519Crossref PubMed Scopus (193) Google Scholar, 26Schanler R.J. Lau C. Hurst N.M. Smith E.O. Randomized trial of donor human milk versus preterm formula as substitutes for mothers' own milk in the feeding of extremely premature infants.Pediatrics. 2005; 116: 400-406Crossref PubMed Scopus (479) Google Scholar A recent systematic review reported that bovine lactoferrin reduced the relative risk of necrotizing enterocolitis and sepsis in preterm infants.27Pammi M. Abrams S.A. Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants.Cochrane Database Syst Rev. 2015; 2: CD007137PubMed Google Scholar The fifth and sixth articles in this Supplement summarize the benefits of lactoferrin supplementation in preterm infants. In milk, triglycerides are surrounded by a triple phospholipid membrane known as the MFGM, which is a product of how milk is secreted by the mammary epithelial cells. The MFGM contains an inner coating monolayer and an outer phospholipid/cholesterol bilayer with proteins and glycoproteins derived from the plasma membrane or secretory vesicles. The phospholipids and proteins, including glycoproteins, exert a variety of important nutritional, digestive, and immunologic benefits.28Kanno C. Secretory membranes of the lactating mammary gland.Protoplasma. 1990; 159: 184-208Crossref Scopus (53) Google Scholar, 29Mather I.H. Keenan T.W. Origin and secretion of milk lipids.J Mammary Gland Biol Neoplasia. 1998; 3: 259-273Crossref PubMed Scopus (285) Google Scholar, 30Dewettinck K. Rombaut R. Thienpont N. Trung Le T. Messens K. Van Camp J. Nutritional and technological aspects of milk fat globule membrane material.Int Dairy J. 2008; 18: 436-457Crossref Scopus (404) Google Scholar Currently, MFGM is absent from infant formula because it is removed from the bovine milk starting materials and replaced by vegetable oils. The seventh article in this Supplement reviews how sphingolipids, a component of the MFGM, affect infant gastrointestinal and immune development. The addition of MFGM to infant formula was shown to be safe and well-tolerated in clinical trials.31Billeaud C. Puccio G. Saliba E. Guillois B. Vaysse C. Pecquet S. et al.Safety and tolerance evaluation of milk fat globule membrane-enriched infant formulas: a randomized controlled multicenter non-inferiority trial in healthy term infants.Clin Med Insights Pediatr. 2014; 8: 51-60Crossref PubMed Google Scholar The eighth article in this Supplement summarizes the outcomes of recent randomized control trials of MFGM in term infants, demonstrating wide-spread benefits in terms of cognitive, metabolic, and health outcomes.32Gurnida D.A. Rowan A.M. Idjradinata P. Muchtadi D. Sekarwana N. Association of complex lipids containing gangliosides with cognitive development of 6-month-old infants.Early Hum Dev. 2012; 88: 595-601Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 33Timby N. Lönnerdal B. Hernell O. Domellöf M. Cardiovascular risk markers until 12 mo of age in infants fed a formula supplemented with bovine milk fat globule membranes.Pediatr Res. 2014; 76: 394-400Crossref PubMed Scopus (46) Google Scholar, 34Timby N. Domellöf E. Hernell O. Lönnerdal B. Domellöf M. Neurodevelopment, nutrition, and growth until 12 mo of age in infants fed a low-energy, low-protein formula supplemented with bovine milk fat globule membranes: a randomized controlled trial.Am J Clin Nutr. 2014; 99: 860-868Crossref PubMed Scopus (231) Google Scholar, 35Timby N. Hernell O. Vaarala O. Melin M. Lönnerdal B. Domellöf M. Infections in infants fed formula supplemented with bovine milk fat globule membranes.J Pediatr Gastroenterol Nutr. 2015; 60: 384-389Crossref PubMed Scopus (127) Google Scholar In summary, clinical and epidemiologic data provide evidence of short- and long-term benefits of human milk.36Section on BreastfeedingBreastfeeding and the use of human milk.Pediatrics. 2012; 129: e827-e841Crossref PubMed Scopus (3446) Google Scholar, 37Kramer M.S. Kakuma R. Optimal duration of exclusive breastfeeding.Cochrane Database Syst Rev. 2012; 8: CD003517PubMed Google Scholar, 38Robinson S.M. Infant nutrition and lifelong health: current perspectives and future challenges.J Dev Orig Health Dis. 2015; 6: 384-389Crossref PubMed Scopus (33) Google Scholar The complexity of human milk bioactivities and the potential for synergistic activities between lipid, carbohydrate, and protein components present a challenge for formula manufacturers seeking to recapitulate the functional benefits of human milk. Basic and preclinical research has identified multifunctional proteins that are candidates for supplementation to infant formula, including lactoferrin, MFGM, and osteopontin.39Lönnerdal B. Kvistgaard A.S. Peerson J.M. Donovan S.M. Peng Y.M. Growth, nutrition, and cytokine response of breast-fed Infants and infants fed formula with added bovine osteopontin.J Pediatr Gastroenterol Nutr. 2016; 62: 650-657Crossref PubMed Scopus (31) Google Scholar The findings summarized herein demonstrate that lactoferrin and MFGM isolated from bovine milk retain bioactivity and are safe and efficacious additions to infant formula. The authors received an honorarium to serve as a co-chairs of the Mead Johnson Pediatric Institute Bioactive Expert Panel to write a manuscript and serve as co-guest editors for this supplement. The sponsor had no involvement in preparing the manuscript, and the authors are entirely and exclusively responsible for its content. S.D. has received honoraria from Arla Foods, Kerry Foods Ingredients, Mead Johnson Nutrition, and Nestle. B.L. has received honoraria from Mead Johnson Nutrition, Arla Foods, Hero, Albion, Valio, Humana, Biostime, Nestle, and Nestle Nutrition Institute.