Моделирование протективных факторов грудного молока: нутритивное программирование здоровья ребенка

Обзор посвящен современным возможностям моделирования уникальных свойств грудного молока при производстве детских молочных смесей. Основным направлением такого моделирования является приближение белкового состава смеси к спектру белков грудного молока, прежде всего обеспечение достаточного уровня α-лактальбумина. Этот протеин обладает многонаправленными протективными свойствами; на его основе в организме синтезируется антибактериальный и иммуномодулирующий пептидный комплекс HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells — комплекс α-лактальбумина и олеиновой кислоты). Аминокислотный состав α-лактальбумина обеспечивает мягкое нейропротекторное влияние за счет достаточного уровня триптофана. Небелковые компоненты создаваемых смесей, в т.ч. углеводные и жировые, усиливают их протективные качества и обеспечивают профилактику отсроченных нарушений здоровья. В обзоре приведены сведения об инновационном продукте детского питания, содержащем α-лактальбумин и другие биоактивные компоненты, сходные с таковыми в женском молоке.

1. Martin СR, Ling P-R, Blackburn GL. Review of Infant Feeding: Key Features of Breast Milk and Infant Formula. Nutrients. 2016;8(5):279. doi: 10.3390/nu8050279

2. Mosca F, Giannì ML. Human milk: composition and health benefits. Pediatr Med Chir. 2017;39(2):155. doi: 10.4081/pmc.2017.155

3. Esch BCAM, Porbahaie M, Abbring S, et al. The Impact of Milk and Its Components on Epigenetic Programming of Immune Function in Early Life and Beyond: Implications for Allergy and Asthma. Front Immunol. 2020;11:2141. doi: 10.3389/fimmu.2020.02141

4. Victora СG, Bahl R, Barros AJD, et al. Breastfeeding in the 21st Century: Epidemiology, Mechanisms and Lifelong Effect. Lancet. 2016;387(10017):475–490. doi: 10.1016/S0140-6736(15)01024-7

5. Theurich MA, Davanzo R, Busck-Rasmussen M, et al. Breast-feeding Rates and Programs in Europe: A Survey of 11 National Breastfeeding Committees and Representatives. J Pediatr Gastroenterol Nutr. 2019;68(3):400–407. doi: 10.1097/MPG.0000000000002234

6. Almeida CC, Mendonça Pereira BF, Leandro KC, et al. Bioactive Compounds in Infant Formula and Their Effects on Infant Nutrition and Health: A Systematic Literature Review. Int J Food Sci. 2021; 2021:8850080. doi: 10.1155/2021/8850080

7. Verduci E, D’Elios S, Cerrato L, et al. Cow’s Milk Substitutes for Children: Nutritional Aspects of Milk from Different Mammalian Species, Special Formula and Plant-Based Beverages. Nutrients. 2019;11(8):1739. doi: 10.3390/nu11081739

8. Layman DK, Lönnerdal B, Fernstrom JD. Applications for α-lactalbumin in human nutrition. Nutr Rev. 2018;76(6):444–460. doi: 10.1093/nutrit/nuy004

9. Guo M. Human Milk Biochemistry and Infant Formula. In: Manufacturing Technology. Cambrdige, UK: Elsevier; 2014.

10. Donovan SM. Human Milk Proteins: Composition and Physiological Significance. Nestle Nutr Inst Workshop Ser. 2019; 90:93–101. doi: 10.1159/000490298

11. Heine WE, Klein PD, Reeds PJ. The importance of alpha-lactalbumin in infant nutrition. J Nutr. 1991;121(3):277–283. doi: 10.1093/jn/121.3.277

12. Alamiri F, Riesbeck K, Hakansson AP. HAMLET, a protein complex from human milk, has bactericidal activity and enhances the activity of antibiotics against pathogenic streptococci. Antimicrob Agents Chemother. 2019;63(12):e01193-19. doi: 10.1128/AAC.01193-19

13. Brück WM, Redgrave M, Tuohy KM, et al. Effects of Bovine α-Lactalbumin and Casein Glycomacropeptide — enriched Infant Formulae on Faecal Microbiota in Healthy Term Infants. J Pediatr Gastroenterol Nutr. 2006;43(5):673–679. doi: 10.1097/01.mpg.0000232019.79025.8f

14. Fontana A, Spolaore B, Polverino de Laureto P. The biological activities of protein/oleic acid complexes reside in the fatty acid. Biochim Biophys Acta. 2013;1834(6):1125–1143. doi: 10.1016/j.bbapap.2013.02.041

15. Ushida Y, Shimokawa Y, Matsumoto H, et al. Effects of bovine alpha-lactalbumin on gastric defense mechanisms in naive rats. Biosci Biotechnol Biochem. 2003;67(3):577–583. doi: 10.1271/bbb.67.577

16. Kelleher SL, Chatterton D, Nielsen K, et al. Glycomacropeptide and alpha-lactalbumin supplementation of infant formula affects growth and nutritional status in infant rhesus monkeys. Am J Clin Nutr. 2003;77(5):1261–1268. doi: 10.1093/ajcn/77.5.1261

17. Kyvsgaard JN, Ellervik C, Lindkvist EB, et al. Perinatal Whole Blood Zinc Status and Cytokines, Adipokines, and Other Immune Response Proteins. Nutrients. 2019;11(9):1980. doi: 10.3390/nu11091980

18. Abdollahi M, Ajami M, Abdollahi Z, et al. Zinc supplementation is an effective and feasible strategy to prevent growth retardation in 6 to 24 month children: A pragmatic double blind, randomized trial. Heliyon. 2019;5(11):e02581. doi: 10.1016/j.heliyon.2019.e02581

19. Szymlek-Gay EA, Lonnerdal B, Abrams SA, et al. α-Lactalbumin and caseinglycomacropeptide do not affect iron absorption from formula in healthy term infants. J Nutr. 2012;142(7):1226–1231. doi: 10.3945/jn.111.153890

20. Lönnerdal B. Excess iron intake as a factor in growth, infections, and development of infants and young children. Am J Clin Nutr. 2017;106(Suppl 6):1681S–1687S. doi: 10.3945/ajcn.117.156042

21. Raffaeli G, Manzoni F, Cortesi V, et al. Iron Homeostasis Disruption and Oxidative Stress in Preterm Newborns. Nutrients. 2020;12(6):1554. doi: 10.3390/nu12061554

22. Аллергия к белкам коровьего молока у детей: клинические рекомендации. — М.: Союз педиатров России; 2018. — 52 с.

23. Намазова-Баранова Л.С., Вишнёва Е.А., Чемакина Д.С. и др. Современные методы диетотерапии аллергии к белкам коровьего молока у детей раннего возраста // Педиатрическая фармакология. — 2021. — Т. 18. — № 3. — С. 233–238. doi: 10.15690/pf.v18i3.2283

24. Järvinen КМ, Martin Н, Oyoshi МК. Immunomodulatory Effects of Breast Milk on Food Allergy. Ann Allergy Asthma Immunol. 2019;123(2):133–143. doi: 10.1016/j.anai.2019.04.022

25. Ho JCS, Nadeem A, Svanborg C. HAMLET — a protein-lipid complex with broad tumoricidal activity. Biochem Biophys Res Comm. 2017;482(3):454–458. doi: 10.1016/j.bbrc.2016.10.092

26. Nakamura T, Aizawa T, Kariya R, et al. Molecular mechanisms of the cytotoxicity of human α-lactalbumin made lethal to tumor cells (HAMLET) and other protein-oleic acid complexes. J Biol Chem. 2013;288(20):14408–14416. doi: 10.1074/jbc.M112.437889

27. Sullivan LM, Kehoe JJ, Barry L, et al. Gastric digestion of α-lactalbumin in adult human subjects using capsule endoscopy and nasogastric tube sampling. Br J Nutr. 2014;112(4):638–646. doi: 10.1017/S0007114514001196

28. Fischer W, Gustafsson L, Mossberg AK, et al. Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival. Cancer Res. 2004;64(6): 2105–2112. doi: 10.1158/0008-5472.can-03-2661

29. Puthia M, Storm P, Nadeem A, et al. Prevention and treatment of colon cancer by peroral administratioin of HAMLET (human α-lactalbumin made lethal to tumour cells). Gut. 2013;63(1): 131–142. doi: 10.1136/gutjnl-2012-303715

30. Gustafsson L, Leijonhufvud I, Aronsson A, et al. Treatment of skin papillomas with topical alpha-lactalbumin-oleic acid. N Engl J Med. 2004;350(26):2663–2672. doi: 10.1056/NEJMoa032454

31. Bosi A, Banfi D, Bistoletti M, et al. Tryptophan Metabolites Along the Microbiota-Gut-Brain Axis: An Interkingdom Communication System Influencing the Gut in Health and Disease. Int J Tryptophan Res. 2020;13:1178646920928984. doi: 10.1177/1178646920928984.

32. Waclawiková B, El Aidy S. Role of microbiota and tryptophan metabolites in the remote effect of intestinal inflammation on brain and depression. Pharmaceuticals (Basel). 2018;11(3):E63. doi: 10.3390/ph11030063

33. Strandwitz P. Neurotransmitter modulation by the gut microbiota. Brain Res. 2018;1693(Pt B):128–133. doi: 10.1016/j.brainres.2018.03.015

34. Gao K, Mu Ch-L, Farzi A, et al. Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. Adv Nutr. 2020;11(3): 709–723. doi: 10.1093/advances/nmz127

35. Cubero J, Valero V, Sánchez J, et al. The circadian rhythm of tryptophan in breast milk affects the rhythms of 6-sulfatoxymelatonin and sleep in newborn. Neuro Endocrinol Lett. 2005;26(6):657–661.

36. Arslanoglu S, Bertino E, Nicocia M, Moro GE. WAPM Working Group on Nutrition: potential chronobiotic role of human milk in sleep regulation. J Perinat Med. 2012;40(1):1–8. doi: 10.1515/jpm.2011.134

37. Kałużna-Czaplińska J, Gątarek P, Chirumbolo S, et al. How important is tryptophan in human health? Crit Rev Food Sci Nutr. 2019;59(1):72–88. doi: 10.1080/10408398.2017.1357534

38. Binks H, Vincent GE, Gupta Ch, et al. Effects of Diet on Sleep: A Narrative Review. Nutrients. 2020;12(4):936. doi: 10.3390/nu12040936

39. Jiang F. Sleep and Early Brain Development. Ann Nutr Metab. 2019;75(Suppl 1):44–54. doi: 10.1159/000508055

40. Smith RP, Easson C, Lyle SM, et al. Gut microbiome diversity is associated with sleep physiology in human. PLoS One. 2019; 14(10):e0222394. doi: 10.1371/journal.pone.0222394

41. Italianer MF, Naninck EFG, Roelants JA, et al. Circadian Variation in Human Milk Composition, a Systematic Review. Nutrients. 2020;12(8):2328. doi: 10.3390/nu12082328

42. De Caro C, Leo A, Nesci V, et al. A. Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy. Sci Rep. 2019;9(1):1–10. doi: 10.1038/s41598-019-50542-0

43. Russo E, Scicchitano F, Citraro R, et al. Protective activity of α-lactoalbumin (ALAC), a whey protein rich in tryptophan, in rodent models of epileptogenesis. Neuroscience. 2012;226:282–288. doi: 10.1016/j.neuroscience.2012.09.021

44. Errichiello L, Pezzella M, Santulli L, et al. A proof-of-concept trial of the whey protein alfa-lactalbumin in chronic cortical myoclonus. Mov Disord. 2011;26(14):2573–2575. doi: 10.1002/mds.23908

45. Ingvordsen Lindahl IE, Artegoitia VM, Downey E, et al. Quantification of Human Milk Phospholipids: the Effect of Gestational and Lactational Age on Phospholipid Composition. Nutrients. 2019;11(2):222. doi: 10.3390/nu11020222

46. de la Garza Puentes A, Alemany AM, Chisaguano AM, et al. The Effect of Maternal Obesity on Breast Milk Fatty Acids and Its Association with Infant Growth and Cognition — The PREOBE Follow-Up. Nutrients. 2019;11(9):2154. doi: 10.3390/nu11092154

47. Kim H, Kim H, Lee E, et al. Association between maternal intake of n-6 to n-3 fatty acid ratio during pregnancy and infant neurodevelopment at 6 months of age: results of the MOCEH cohort study. Nutr J. 2017;16(1):23. doi: 10.1186/s12937-017-0242-9

48. Huërou-Luron IL, Lemaire M, Blat S. Health benefits of dairy lipids and MFGM in infant formula. OCL. 2018;25(3):D306. doi: 10.1051/ocl/2018019

49. Baack ML, Puumala SE, Messier S, et al. What is the relationship between gestational age and docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels? Prostaglandins Leukot Essent Fatty Acids. 2015;100:5–11. doi: 10.1016/j.plefa.2015.05.003

50. Joardar A, Sen AK, Das S. Docosahexaeoic acid facilitates cell maturation and beta-adrenergic transmission in astrocytes. J Lipid Res. 2006;47(3):571–581. doi: 10.1194/jlr.M500415-JLR200

51. Innis SM. Impact of maternal diet on human milk composition and neurological development of infants. Am J Clin Nutr. 2014; 99(3):734S–741S. doi: 10.3945/ajcn.113.072595

52. Auestad N, Scott DT, Janowsky JS. Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age. Pediatrics. 2003;112(3 Pt 1):e177–e183. doi: 10.1542/peds.112.3.e177

53. Deoni SC, Dean DC 3rd, Piryatinsky I, et al. Breastfeeding and early white matter development: A cross-sectional study. Neuroimage. 2013;82:77–86. doi: 10.1016/j.neuroimage.2013.05.090

54. Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012;22(9):1147–1162. doi: 10.1093/glycob/cws074

55. Kunz C. Historical Aspects of Human Milk Oligosaccharides. Adv Nutr. 2012;3(3):430S–439S. doi: 10.3945/an.111.001776

56. Walsh C, Lane JA, van Sinderen D, et al. Human milk oligosaccharides: Shaping the infant gut microbiota and supporting health. J Funct Foods. 2020;72:104074. doi: 10.1016/j.jff.2020.104074

57. Barile D, Rastall RA. Human milk and related oligosaccharides as prebiotics. Curr Opin Biotechnol. 2013;24(2):214–219. doi: 10.1016/j.copbio.2013.01.008

58. Bode L. Human Milk Oligosaccharides: Next-Generation Functions and Questions. Nestle Nutr Inst Workshop Ser. 2020; 94:115–123. doi: 10.1159/000505339

59. Osborn DA, Sinn JK. Prebiotics in infants for prevention of allergy. Cochrane Database Syst Rev. 2013;(3):CD006474. doi: 10.1002/14651858.CD006474

60. Schlimme E, Martin D, Meisel H. Nucleosides and nucleotides: natural bioactive substances in milk and colostrums. Brit J Nutr. 2000;84(1):59–68. doi: 10.1017/s0007114500002269

61. Garwolińska D, Namieśnik J, Kot-Wasik A, et al. Chemistry of Human Breast Milk-A Comprehensive Review of the Composition and Role of Milk Metabolites in Child Development. J Agric Food Chem. 2018;66(45):11881–11896. doi: 10.1021/acs.jafc.8b04031

62. Woltil HA, van Beusekom CM, Siemensma AD, et al. Erythrocyte and plasma cholesterol ester long-chain polyunsaturated fatty acids of low-birth-weight babies fed preterm formula with and without ribonucleotides: comparison with human milk. Am J Clin Nutr. 1995; 62(5):943–949. doi: 10.1093/ajcn/62.5.943

63. Le Huërou-Luron I, Blat S, Boudry G. Breast-v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects. Nutr Res Rev. 2010;23(1):23–36. doi: 10.1017/S0954422410000065

64. Cansev M. Uridine and cytidine in the brain: their transport and utilization. Brain Res Rev. 2006;52(2):389–397. doi: 10.1016/j.brainresrev.2006.05.001

65. Lönnerdal В. Infant formula and infant nutrition: bioactive proteins of human milk and implications for composition of infant formulas. Am J Clin Nutr. 2014;99(3):712S–717S. doi: 10.3945/ajcn.113.071993

66. Lien EL, Davis AM, Euler AR, et al. Growth and safety in term infants fed reducedprotein formula with added bovine alpha-lactalbumin. J Pediatr Gastroenterol Nutr. 2004;38(2):170–176. doi: 10.1097/00005176-200402000-00013

67. Lönnerdal B, Erdmann P, Thakkar SK, et al. Longitudinal evolution of true protein, amino acids and bioactive proteins in breast milk: a developmental perspective. J Nutr Biochem. 2017;41:1–11. doi: 10.1016/j.jnutbio.2016.06.001