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Nitrite in breast milk: roles in neonatal pathophysiology

Abstract

Dietary nitrate has beneficial effects on health maintenance and prevention of lifestyle-related diseases in adulthood by serving as an alternative source of nitric oxide (NO) through the enterosalivary nitrate–nitrite–NO pathway, particularly when endogenous NO generation is lacking due to vascular endothelial dysfunction. However, this pathway is not developed in the early postnatal period due to a lack of oral commensal nitrate-reducing bacteria and less saliva production than in adults. To compensate for the decrease in nitrite during this period, colostrum contains the highest amount of nitrite compared with transitional, mature, and even artificial milk, suggesting that colostrum plays an important role in tentatively replenishing nitrite, in addition to involving a nutritional aspect, until the enterosalivary nitrate–nitrite–NO pathway is established. Increasing evidence demonstrates that breast milk rich in nitrite can be effective in the prevention of neonatal infections and gastrointestinal diseases such as infantile hypertrophic pyloric stenosis and necrotizing enterocolitis, suggesting that breastfeeding is advantageous for newborns at risk, given the physiological role of nitrite in the early postnatal period.

Impact

  • The aim of this review is to discuss the physiological roles of nitrite in breast milk and its implications for neonates.

  • Nitrite in breast milk may compensate for the decrease in nitrite during the early neonatal period until the enterosalivary nitrate–nitrite–nitric oxide pathway is established.

  • Breast milk rich in nitrite may be effective in the prevention of neonatal infections and gastrointestinal diseases by providing nitric oxide bioavailability.

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Fig. 1: Nitrite pool and interactions with the transport of NO activities.
Fig. 2: Plasma nitrite concentrations in fetal sheep at birth.
Fig. 3: Physiological factors that reduce nitrite-mediated NO bioactivity in neonates.
Fig. 4: Intragastric generation of NO in neonates.

References

  1. 1.

    Kobayashi, J., Ohtake, K. & Uchida, H. NO-rich diet for lifestyle-related diseases. Nutrients 7, 4911–4937 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Hord, N. G., Ghannam, J. S., Garg, H. K., Berens, P. D. & Bryan, N. S. Nitrate and nitrite content of human, formula, bovine, and soy milks: implications for dietary nitrite and nitrate recommendations. Breastfeed. Med. 6, 393–399 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Field, C. J. The immunological components of human milk and their effect on immune development in infants. J. Nutr. 135, 1–4 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Comly, H. Cyanosis in infants caused by nitrates in well water. JAMA 129, 112–116 (1945).

    CAS  Article  Google Scholar 

  5. 5.

    Knobeloch, L., Salna, B., Hogan, A., Postle, J. & Anderson, H. Blue babies and nitrate-contaminated well water. Environ. Health Perspect. 108, 675–678 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Blood, A. B. et al. Increased nitrite reductase activity of fetal versus adult ovine hemoglobin. Am. J. Physiol. Heart Circ. Physiol. 296, H237–H246 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Power, G. G. et al. A nobel method of measuring reduction of nitrite-induced methemoglobin applied to fetal and adult blood of humans and sheep. J. Appl. Physiol. 103, 1359–1365 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Berens, P. D., Bryan, N. S. in Nitrite and Nitrate in Human Health and Disease (eds Bryan, N. S. & Loscalzo, J.) 141–152 (Humana Press, Cham, 2017).

  9. 9.

    European Food Safety Authority. Nitrate in vegetables: scientific opinion of the panel on contaminants in the food chain. EFSA J. 689, 1–79 (2008).

    Google Scholar 

  10. 10.

    Phillips, W. E. Naturally occurring nitrate and nitrite in foods in relation to infant methemoglobinaemia. Food Cosmet. Toxicol. 9, 219–228 (1971).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Dusdieker, L. B., Stumbo, P. J., Kross, B. C. & Dungy, C. I. Does increased nitrate ingestion elevate nitrate levels in human milk? Arch. Pediatr. Adolesc. Med. 150, 311–314 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Greer, F. R. & Shannon, M. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics 116, 784–786 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Wargner, D. A., Schultz, D. S., Deen, W. M., Young, V. R. & Tannenbaum, S. R. Metabolic fate of an oral dose of 15N-labeled nitrate in humans: effect of diet supplementation with ascorbic acid. Cancer Res. 43, 1921–1925 (1983).

    Google Scholar 

  14. 14.

    Lundberg, J. O., Weitzberg, E., Lundberg, J. M. & Alving, K. Intragastric nitric oxide production in humans: measurements in expelled air. Gut 35, 1543–1546 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Lundberg, J. O., Weitzberg, E. & Gladwin, M. T. The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug Discov. 7, 156–167 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Kapil, V. et al. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 56, 274–281 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Milsom, A. B., Fernandez, B. O., Garcia-Saura, M. F., Rodriguez, J. & Feelisch, M. Contributions of nitric oxide synthases, dietary nitrite/nitrate, and other sources to the formation of NO signaling products. Antioxid. Redox Signal. 17, 422–432 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Kleinbongard, P. et al. Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic. Biol. Med. 35, 790–796 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Waltz, P., Escobar, D., Botero, A. M. & Zuckerbraun, B. S. Nitrate/nitrite as critical mediators to limit oxidative injury and inflammation. Antioxid. Redox Signal. 23, 328–239 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Kim-Shapiro, D. B. & Gladwin, M. T. Mechanisms of nitrite bioactivation. Nitric Oxide 38, 58–68 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Srihirun, S. et al. Platelet inhibition by nitrite is dependent on erythrocytes and deoxygenation. PLoS ONE 7, e30380 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Tsuchiya, K. et al. Malfunction of vascular control in lifestyle-related diseases: formation of systemic hemoglobin-nitric oxide complex (HbNO) from dietary nitrite. J. Pharmacol. Sci. 96, 395–400 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Jia, L., Bonaventura, C., Bonaventura, J. & Stamler, J. S. S-nitrosohemoglobin: a dynamic activity of blood involved in vascular control. Nature 380, 221–226 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Stamler, J. S. et al. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 276, 2034–2037 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Roche, C. J., Cassera, M. B., Dantsker, D., Hirsch, R. E. & Friedman, J. M. Generating S-nitrosothiols from hemoglobin mechanisms, conformational dependence, and physiological relevance. J. Biol. Chem. 288, 22408–22425 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Pawloski, J. R., Hess, D. T. & Stamler, J. S. Export by red blood cells of nitric oxide bioactivity. Nature 409, 622–626 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Helms, C. C., Gladwin, M. T. & Kin-Shapiro, D. B. Erythrocytes and vascular function: oxygen and nitric oxide. Front. Physiol. 9, 1–9 (2018).

    Google Scholar 

  28. 28.

    Pernow, J., Mahdi, A., Yang, J. & Zhou, Z. Red blood cell dysfunction: a new player in cardiovascular disease. Cardiovasc. Res. 115, 1596–1605 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Sun, C. W. et al. Hemoglobin β93 cysteine is not required for export of nitric oxide bioactivity from the red blood cell. Circulation 139, 2654–2663 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Schmidt, H. H. H. W. & Feelisch, M. Red blood cell-derived nitric oxide bioactivity and hypoxic vasodilation. To β93 or not to β93? Circulation 139, 2664–2667 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    DeMartino, A. W., Kim-Shapiro, D. B., Patel, R. P. & Gladwin, M. T. Nitrite and nitrate chemical biology and signaling. Br. J. Pharmacol. 176, 228–245 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Walthall, K., Cappon, G. D., Hurt, tM. E. & Zoetis, T. Postnatal development of the gastrointestinal system: a species comparison. Birth Defects Res. B 74, 132–156 (2005).

    CAS  Article  Google Scholar 

  33. 33.

    Pun, P. et al. Changes in plasma and urinary nitrite after birth in premature infants at risk for necrotizing enterocolitis. Pediatr. Res. 79, 432–437 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Jones, J. A., Hopper, A. O., Power, G. G. & Blood, A. B. Dietary intake and bio-activation of nitrite and nitrate in newborn infants. Pediatr. Res. 77, 173–181 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Thomas, D. D. Breathing new life into nitric oxide signaling: a brief overview of the interplay between oxygen and nitric oxide. Redox Biol. 5, 225–233 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Torres-Cuevas, I. et al. Oxygen and oxidative stress in the perinatal period. Redox Biol. 12, 674–681 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Chobanyan-Jürgens, K. et al. Renal carbonic anhydrases are involved in the reabsorption of endogenous nitrite. Nitric Oxide 26, 126–131 (2012).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  38. 38.

    Kanady, J. A. et al. Nitrate reductase activity of bacteria in saliva of term and preterm infants. Nitric Oxide 27, 193–200 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Castellote, C. et al. Premature delivery influences the immunological composition of colostrum and transitional and mature human milk. J. Nutr. 141, 1181–1187 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Sohn, K., Kalanetra, K. M., Mills, D. A. & Underwood, M. A. Buccal administration of human colostrum: impact on the oral microbiota of premature infants. Pediatr. Neonatol. 58, 534–540 (2017).

    Article  Google Scholar 

  41. 41.

    Subcommittee on Nutrition During Lactation, Committee on Nutritional Status During Pregnancy and Lactation, Food and Nutrition Board, Institute of Medicine & National Academy of Science. Nutrition During Lactation (National Academy Press, Washington, DC, 1991).

  42. 42.

    Iizuka, T. et al. Non-enzymatic nitric oxide generation in the stomach of breastfed neonates. Acta Pediatr. 88, 1053–1055 (1999).

    CAS  Article  Google Scholar 

  43. 43.

    Kanematsu, Y. et al. Dietary doses of nitrite restore circulating nitric oxide level and improve renal injury in L-NAME-induced hypertensive rats. Am. J. Physiol. Ren. Physiol. 295, F1457–F1462 (2008).

    CAS  Article  Google Scholar 

  44. 44.

    Hancock, J. T. et al. Antimicrobial properties of milk: dependence on presence of xanthine oxidase and nitrite. Antimicrob. Agents Chemother. 46, 3308–3310 (2002). 42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Cieslak, M., Ferreira, C. H. F., Shifrin, Y., Pan, J. & Belik, J. Human milk H2O2 content: does it benefit preterm infants? Pediatr. Res. 83, 687–692 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Li, H., Samouilov, A., Liu, X. & Zweier, J. L. Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrate reduction: evaluation of its role in nitrite and nitric oxide generation in anoxic tissues. Biochemistry 42, 1150–1159 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Stevens, C. R. et al. Antibacterial properties of xanthine oxidase in human milk. Lancet 356, 829–830 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Harrison, R. Milk xanthine oxidase: properties and physiological roles. Int. Dairy J. 16, 546–554 (2006).

    CAS  Article  Google Scholar 

  49. 49.

    Latchaw, L. A., Jacir, N. N. & Harris, B. H. The development of pyloric stenosis during transpyloric feedings. J. Pediatr. Surg. 24, 823–824 (1989).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Panteli, C. New insight into the pathogenesis of infantile pyloric stenosis. Pediatr. Surg. Int. 25, 1043–1052 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Krogh, C. et al. Familial aggregation and heritability of pyloric stenosis. JAMA 303, 2393–2399 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Huang, L. T., Tiao, M. M., Lee, S. Y., Hsieh, C. S. & Lin, J. W. Low plasma nitrite in infantile hypertrophic pyloric stenosis patients. Dig. Dis. Sci. 51, 869–872 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Huang, P. L., Dawson, T. M., Bredt, D. S., Snyder, S. H. & Fishman, M. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75, 1273–1286 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Chung, E. et al. Genetic evidence for the neuronal nitric oxide synthase gene (NOS19 as a susceptibility locus for infantile pyloric stenosis. Am. J. Hum. Genet. 58, 363–370 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Barbosa, I. M., Ferrante, S. M. & Mandarim-De-Lacerda, C. A. Role of nitric oxide synthase in the etiopathogenesis of hypertrophic pyloric stenosis in infants. J. Pediatr. 77, 307–312 (2001).

    CAS  Google Scholar 

  56. 56.

    Kusafuka, T. & Puri, P. Altered messenger RNA expression of the neuronal nitric oxide synthase gene in infantile hypertrophic pyloric stenosis. Pediatr. Surg. Int. 12, 576–579 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Wayne, C. et al. Formula-feeding and hypertrophic pyloric stenosis: is there an association? A case–control study. J. Pediatr. Surg. 51, 779–782 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Krogh, C., Biggar, R. J., Fischer, T. K., Lindholm, M. & Wohlfahrt, J. Bottle-feeding and the risk of pyloric stenosis. Pediatrics 130, e943–e949 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Neu, J. & Walker, W. A. Necrotizing enterocolitis. N. Eng. J. Med. 364, 255–264 (2011).

    CAS  Article  Google Scholar 

  60. 60.

    Gephart, M. S. M., McGrath, J. M., Effken, J. A. & Halpern, M. D. Necrotizing enterocolitis risk: state of the science. Adv. Neonatal Care 12, 77 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Patel, R. M. & Denning, P. W. Intestinal microbiota and its relationship with necrotizing enterocolitis. Pediatr. Res. 78, 232–238 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Bazacliu, C. & Neu, J. Pathophysiology of necrotizing enterocolitis: an update. Curr. Pediatr. Rev. 15, 68–87 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Yazji, I. et al. Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling. Proc. Natl Acad. Sci. USA 110, 9451–9456 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Mally, P. et al. Association of necrotizing enterocolitis with elective packed red cell transfusions in stable, growing, premature neonates. Am. J. Perinatol. 23, 451–458 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Reynolds, J. D. et al. S-nitrosohemoglobin deficiency: A mechanism for loss of physiological activity in banked blood. Proc. Natl Acad. Sci. USA 104, 17058–17062 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Azarov, I. et al. Nitric oxide scavenging by red blood cells as a function of hematocrit and oxygenation. J. Biol. Chem. 280, 39024–39032 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Cortese-Krott, M. M. et al. Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease. Blood 120, 4229–4237 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Sanchez, C. M. et al. Relationship between packed red blood cell storage time and arginase concentration. Eur. J. Anaesthesiol. 28, 92 (2011).

    Article  Google Scholar 

  69. 69.

    Yang, J., Gonon, A. T., Sjöquist, P. O., Lundberg, J. O. & Pernow, J. Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity. Proc. Natl Acad. Sci. USA 110, 15049–15054 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Patel, R. M. et al. Association of red blood cell transfusion, anemia, and necrotizing enterocolitis in very low-birth-weight infants. JAMA 315, 889–897 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Dezfulian, C., Raat, N., Shiva, S. & Gladwin, M. T. Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics. Cardiovasc. Res. 75, 327–338 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Rassaf, T., Ferdinandy, P. & Schulz, R. Nitrite in organ protection. Br. J. Pharmacol. 171, 1–11 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Blood, A. B. The medicinal chemistry of nitrite as a source of nitric oxide signaling. Curr. Top. Med. Chem. 17, 1758–1768 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Totzeck, M., Hendgen-Cotta, U. B. & Rassaf, T. Nitrite-nitric oxide signaling and cardioprotection. Adv. Exp. Med. Biol. 982, 335–346 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Ibrahim, Y. I. et al. Inhaled nitric oxide therapy increases blood nitrite, nitrate, and S-nitrosohemoglobin concentrations in infants with pulmonary hypertension. J. Pediatr. 160, 245–251 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Bloch, K. D., Ichinose, F., Roberts, J. D. Jr. & Zapol, W. M. Inhaled NO as a therapeutic agent. Cardiovasc. Res. 75, 339–348 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Jones, J. A. et al. Nitrite and nitrate concentrations and metabolism in breast milk, infant formula, and parenteral nutrition. JPEN J. Parenter. Enter. Nutr. 38, 856–866 (2014).

    CAS  Article  Google Scholar 

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I would like to thank Editage (www.editage.com) for English language editing.

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Kobayashi, J. Nitrite in breast milk: roles in neonatal pathophysiology. Pediatr Res 90, 30–36 (2021). https://doi.org/10.1038/s41390-020-01247-y

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