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Human milk oligosaccharides, infant growth, and adiposity over the first 4 months of lactation

Pediatric Research volume 90, pages 684–693 (2021)Cite this article

Abstract

Background

The relationship between human milk oligosaccharides (HMOs) and infant growth and adiposity is not fully understood and comprehensive studies are missing from the current literature.

Methods

We screened and recruited 370 healthy, pregnant women and their infants from seven European countries. Breastmilk samples were collected using standardized procedures at six time points over 4 months, as were infant parameters. Correlations and associations between HMO area under the curve, anthropometric data, and fat mass at 4 months were tested.

Results

Lacto-N-neotetraose had a negative correlation with the change in length (rs = −0.18, P = 0.02). Sialyllacto-N-tetraose c (LSTc) had a positive correlation with weight for length (rs = 0.19, P = 0.015). Infants at the 25th upper percentile were fed milk higher in 3′-sialyllactose and LSTc (P = 0.017 and P = 0.006, respectively) compared to the lower 25th percentile of the weight-for-length z-score gain over 4 months of lactation. No significant associations between growth and body composition and Lewis or secretor-dependent HMOs like 2′-fucosyllactose were identified.

Conclusions

Changes in the HMO composition of breastmilk during the first 4 months appear to have little influence on infant growth and body composition in this cohort of healthy mothers and infants.

Impact

  • Modest associations exist between individual HMO and infant growth outcomes at least in healthy growing populations.

  • Our study provides a comprehensive investigation of associations between all major HMO and infant growth and adiposity including several time points. Certain groups of HMOs, like the sialylated, may be associated with adiposity during the first months of lactation.

  • HMO may modulate the risk of future metabolic disease. Future population studies need to address the role of specific groups of HMOs in the context of health and disease to understand the long-term impact.

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Fig. 1: Schematic of study design and flow.
Fig. 2: Infant anthropometry from birth to 120 days after birth.
Fig. 3: Weight-for-length from birth until 120 days after birth.
Fig. 4: Fat mass composition from birth until 120 days after birth.
Fig. 5: HMOs area under the curve (AUC) calculated for the entire lactation period and fat mass index at 120 days after birth.
Fig. 6: Growth rate association with HMOs.

References

  1. Ballard, O. & Morrow, A. L. Human milk composition: nutrients and bioactive factors. Pediatr. Clin. N. Am. 60, 49–74 (2013).

    Article  Google Scholar 

  2. Andreas, N. J., Kampmann, B., Mehring & Le-Doare, K. Human breast milk: a review on its composition and bioactivity. Early Hum. Dev. 91, 629–635 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. Kunz, C., Rodriguez-Palmero, M., Koletzko, B. & Jensen, R. Nutritional and biochemical properties of human milk, Part I: general aspects, proteins, and carbohydrates. Clin. Perinatol. 26, 307–333 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. Coppa, G. V. et al. Changes in carbohydrate composition in human milk over 4 months of lactation. Pediatrics 91, 637–641 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bode, L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology 22, 1147–1162 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Kunz, C., Rudloff, S., Baier, W., Klein, N. & Strobel, S. Oligosaccharides in human milk: structural, functional, and metabolic aspects. Annu. Rev. Nutr. 20, 699–722 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. Kunz, C. et al. Influence of gestational age, secretor, and lewis blood group status on the oligosaccharide content of human milk. J. Pediatr. Gastroenterol. Nutr. 64, 789–798 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. Sprenger, N., Binia, A. & Austin, S. Human milk oligosaccharides: factors affecting their composition and their physiological significance. Nestle Nutr. Inst. Workshop Ser. 90, 43–56 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  9. Van Niekerk, E. et al. Human milk oligosaccharides differ between HIV-infected and HIV-uninfected mothers and are related to necrotizing enterocolitis incidence in their preterm very-low-birth-weight infants. J. Nutr. 144, 1227–1233 (2014).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  10. Smilowitz, J. T., Lebrilla, C. B., Mills, D. A., German, J. B. & Freeman, S. L. Breast milk oligosaccharides: structure-function relationships in the neonate. Annu. Rev. Nutr. 34, 143–169 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Thurl, S., Henker, J., Siegel, M., Tovar, K. & Sawatzki, G. Detection of four human milk groups with respect to Lewis blood group dependent oligosaccharides. Glycoconj. J. 14, 795–799 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. Stahl, B. et al. Detection of four human milk groups with respect to Lewis-blood-group-dependent oligosaccharides by serologic and chromatographic analysis. Adv. Exp. Med. Biol. 501, 299–306 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. Kumazaki, T. & Yoshida, A. Biochemical evidence that secretor gene, Se, is a structural gene encoding a specific fucosyltransferase. Proc. Natl Acad. Sci. USA 81, 4193–4197 (1984).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Samuel, T. M. et al. Impact of maternal characteristics on human milk oligosaccharide composition over the first 4 months of lactation in a cohort of healthy European mothers. Sci. Rep. 9, 11767 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. Rudloff, S. & Kunz, C. Milk oligosaccharides and metabolism in infants. Adv. Nutr. 3, 398s–405s (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Goehring, K. C., Kennedy, A. D., Prieto, P. A. & Buck, R. H. Direct evidence for the presence of human milk oligosaccharides in the circulation of breastfed infants. PLoS ONE 9, e101692 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. Vandenplas, Y. et al. Human milk oligosaccharides: 2’-fucosyllactose (2’-FL) and lacto-N-neotetraose (LNnT) in infant formula. Nutrients 10, 1161 (2018).

    PubMed Central  Article  CAS  Google Scholar 

  18. Alderete, T. L. et al. Associations between human milk oligosaccharides and infant body composition in the first 6 mo of life. Am. J. Clin. Nutr. 102, 1381–1388 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Larsson, M. W. et al. Human milk oligosaccharide composition is associated with excessive weight gain during exclusive breastfeeding-an explorative study. Front. Pediatr. 7, 297 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  20. Davis, J. C. et al. Growth and morbidity of Gambian infants are influenced by maternal milk oligosaccharides and infant gut microbiota. Sci. Rep. 7, 40466 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Charbonneau, M. R. et al. Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition. Cell 164, 859–871 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Cowardin, C. A. et al. Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition. Proc. Natl Acad. Sci. USA 116, 11988–11996 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sprenger, N., Lee, L. Y., De Castro, C. A., Steenhout, P. & Thakkar, S. K. Longitudinal change of selected human milk oligosaccharides and association to infants’ growth, an observatory, single center, longitudinal cohort study. PLoS ONE 12, e0171814 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. Phipps, K. R. et al. Safety evaluation of a mixture of the human-identical milk oligosaccharides 2’-fucosyllactose and difucosyllactose. Food Chem. Toxicol. 120, 552–565 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. Lee, S. et al. 2’-Fucosyllactose supplementation improves gut-brain signaling and diet-induced obese phenotype and changes the gut microbiota in high fat-fed mice. Nutrients 12, 1003 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  26. Fields, D. A., Higgins, P. B. & Radley, D. Air-displacement plethysmography: here to stay. Curr. Opin. Clin. Nutr. Metab. Care 8, 624–629 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  27. Ellis, K. J. et al. Body-composition assessment in infancy: air-displacement plethysmography compared with a reference 4-compartment model. Am. J. Clin. Nutr. 85, 90–95 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. Urlando, A., Dempster, P. & Aitkens, S. A new air displacement plethysmograph for the measurement of body composition in infants. Pediatr. Res. 53, 486–492 (2003).

    PubMed  Article  PubMed Central  Google Scholar 

  29. Austin, S. & Benet, T. Quantitative determination of non-lactose milk oligosaccharides. Anal. Chim. Acta 1010, 86–96 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. van Leeuwen, S. S. et al. Rapid milk group classification by 1H NMR analysis of Le and H epitopes in human milk oligosaccharide donor samples. Glycobiology 24, 728–739 (2014).

    PubMed  Article  CAS  Google Scholar 

  31. WHO MGRS Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr Suppl. 450, 76–85 (2006).

  32. Victora, C. G. et al. Maternal and child undernutrition: consequences for adult health and human capital. Lancet 371, 340–357 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Martorell, R. & Zongrone, A. Intergenerational influences on child growth and undernutrition. Paediatr. Perinat. Epidemiol. 26(Suppl. 1), 302–314 (2012).

    PubMed  Article  Google Scholar 

  34. Subramanian, S. et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 510, 417–421 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Smith, M. I. et al. Gut microbiomes of Malawian twin pairs discordant for Kwashiorkor. Science 339, 548–554 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Mosca, F. & Gianni, M. L. Human milk: composition and health benefits. Pediatr. Med. Chir. 39, 155 (2017).

    PubMed  Article  Google Scholar 

  37. Eriksen, K. G., Christensen, S. H., Lind, M. V. & Michaelsen, K. F. Human milk composition and infant growth. Curr. Opin. Clin. Nutr. Metab. Care 21, 200–206 (2018).

    CAS  PubMed  Article  Google Scholar 

  38. Coppa, G. V. et al. Oligosaccharides in 4 different milk groups, Bifidobacteria, and Ruminococcus obeum. J. Pediatr. Gastroenterol. Nutr. 53, 80 (2011).

    CAS  PubMed  Article  Google Scholar 

  39. Austin, S. et al. Temporal change of the content of 10 oligosaccharides in the milk of Chinese urban mothers. Nutrients 8, 346 (2016).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  40. Lefebvre, G. et al. Time of lactation and maternal fucosyltransferase genetic polymorphisms determine the variability in human milk oligosaccharides. Front. Nutr. 29, 574459 (2020).

  41. De Leoz, M. L. et al. Lacto-N-tetraose, fucosylation, and secretor status are highly variable in human milk oligosaccharides from women delivering preterm. J. Proteome Res. 11, 4662–4672 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. Austin, S. et al. Human milk oligosaccharides in the milk of mothers delivering term versus preterm infants. Nutrients 11, 1282 (2019).

    CAS  PubMed Central  Article  Google Scholar 

  43. Spevacek, A. R. et al. Infant maturity at birth reveals minor differences in the maternal milk metabolome in the first month of lactation. J. Nutr. 145, 1698–1708 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Nakhla, T., Fu, D., Zopf, D., Brodsky, N. L. & Hurt, H. Neutral oligosaccharide content of preterm human milk. Br. J. Nutr. 82, 361–367 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. Cheng, L. et al. More than sugar in the milk: human milk oligosaccharides as essential bioactive molecules in breast milk and current insight in beneficial effects. Crit. Rev. Food Sci. Nutr. 24, 1–17 (2020).

    Google Scholar 

  46. Berger, B. et al. Linking human milk oligosaccharides, infant fecal community types, and later risk to require antibiotics. mBio 11, 03196–19 (2020).

    Article  Google Scholar 

  47. Backhed, F. et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 17, 690–703 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  48. Korpela, K. et al. Fucosylated oligosaccharides in mother’s milk alleviate the effects of caesarean birth on infant gut microbiota. Sci. Rep. 8, 13757 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. Matsuki, T. et al. A key genetic factor for fucosyllactose utilization affects infant gut microbiota development. Nat. Commun. 24, 11939 (2016).

    Article  CAS  Google Scholar 

  50. Macfarlane, G. T. & Macfarlane, S. Fermentation in the human large intestine: its physiologic consequences and the potential contribution of prebiotics. J. Clin. Gastroenterol. 45(Suppl.), 120–127 (2011).

    Article  Google Scholar 

  51. Rasmussen, S. H. et al. Antibiotic exposure in early life and childhood overweight and obesity: a systematic review and meta-analysis. Diabetes Obes. Metab. 20, 1508–1514 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  52. Victora, C. G. et al. Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet 30, 475–490 (2016).

    Article  Google Scholar 

  53. Larsson, M. W. et al. Excessive weight gain followed by catch-down in exclusively breastfed infants: an exploratory study. Nutrients 10, 1290 (2018).

    PubMed Central  Article  CAS  Google Scholar 

  54. Larsson, M. W., Larnkjaer, A., Christensen, S. H., Molgaard, C. & Michaelsen, K. F. Very high weight gain during exclusive breastfeeding followed by slowdown during complementary feeding: two case reports. J. Hum. Lact. 35, 44–48 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  55. Alexander, D. D. et al. Growth of infants consuming whey-predominant term infant formulas with a protein content of 1.8 g/100 kcal: a multicenter pooled analysis of individual participant data. Am. J. Clin. Nutr. 104, 1083–1092 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. Lagström, H. et al. Associations between human milk oligosaccharides and growth in infancy and early childhood Am. J. Clin. Nutr. 769–778 (2020).

  57. Storm, H. M. et al. 2’-Fucosyllactose is well tolerated in a 100% whey, partially hydrolyzed infant formula with bifidobacterium lactis: a randomized controlled trial. Glob. Pediatr. Health 6, https://doi.org/10.1177/2333794X19833995 (2019).

  58. Puccio, G. et al. Effects of infant formula with human milk oligosaccharides on growth and morbidity: a randomized multicenter trial. J. Pediatr. Gastroenterol. Nutr. 64, 624–631 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Marriage, B. J., Buck, R. H., Goehring, K. C., Oliver, J. S. & Williams, J. A. Infants fed a lower calorie formula with 2’FL show growth and 2’FL uptake like breast-fed infants. J. Pediatr. Gastroenterol. Nutr. 61, 649–658 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Kajzer, J., Oliver, J. & Marriage, B. Gastrointestinal tolerance of formula supplemented with oligosaccharides. FASEB J. 30(Suppl.), 671.4-.4 (2016).

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Acknowledgements

This study was funded by Nestlé Research, Société des Produits Nestlé, Switzerland.

Author information

Author notes

  1. These authors contributed equally: Aristea Binia, Luca Lavalle

Affiliations

  1. Nestlé Research, Société des Produits Nestlé SA, Lausanne, Switzerland

    Aristea Binia, Luca Lavalle, Cheng Chen, Sean Austin, Euridice Castaneda-Gutierrez & Norbert Sprenger

  2. Ospedale del Ponte, Varese, Italy

    Massimo Agosti

  3. Al Jashi Isam Private Med. Practice, Bucharest, Romania

    Isam Al-Jashi

  4. Hospital de São Marcos, Braga, Portugal

    Almerinda Barroso Pereira

  5. Instituto de Investigação em Ciências da Vida e Saúde, Braga, Portugal

    Maria Jose Costeira

  6. Hospital de S. João, Porto, Portugal

    Maria Gorett Silva

  7. Karolinska University Hospital, Stockholm, Sweden

    Giovanna Marchini & Mireille Vanpée

  8. Hospital Clínico Universitario de Valencia, Valencia, Spain

    Cecilia Martínez -Costa

  9. Oslo University Hospital, Oslo, Norway

    Tom Stiris

  10. Polizu Hospital, Bucharest, Romania

    Sylvia-Maria Stoicescu

  11. Centre d’Investigation Clinique de Lille, Hôpital Jeanne de Flandre, Lille, France

    Thameur Rakza

  12. Hôpital des enfants, CHU Pellegrin, Bordeaux, France

    Claude Billeaud

  13. Hôpital de la Croix Rousse, Lyon, France

    Jean-Charles Picaud

  14. Umeå University, Umeå, Sweden

    Magnus Domellöf

  15. Cultivate: Nutrition Content + Strategy, Decatur, GA, USA

    Rachel Adams

Authors
  1. Aristea Binia
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  2. Luca Lavalle
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Contributions

A.B., L.L., C.C., S.A., E.C.-G., M.A., I.A.-J., A.B.P., M.J.C., M.G.S., G.M., C.M.-C., T.S., S.-M.S., M.V., T.R., C.B., J.-C.P., and M.D., had substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. A.B., N.S., R.A., M.V., M.A., M.J.C., C.M.C., and M.D. drafted the article and/or revised it critically for important intellectual content; and all authors had a final approval of the version to be published.

Corresponding author

Correspondence to Aristea Binia.

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Competing interests

A.B., L.L., C.C., S.A., E.C.-G., and N.S. are or were (ECG) employees of Société des Produits Nestlé during the study. R.A.’s work on this manuscript was funded by Société des Produits Nestlé. All other authors M.A., I.A.-J., A.B.P., M.J.C., M.G.S., G.M., C.M.-C., T.S., S.-M.S., M.V., T.R., C.B., J.-C.P., and M.D. received funding from Société des Produits Nestlé S.A. to conduct the study.

Statement of consent

The participants provided a written informed consent form to participate in the study after receiving explanations and having read and understood the purpose and the objectives of the study in their respective local languages. The study was registered at www.clinicaltrials.gov with the identifier NCT01894893.

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Binia, A., Lavalle, L., Chen, C. et al. Human milk oligosaccharides, infant growth, and adiposity over the first 4 months of lactation. Pediatr Res 90, 684–693 (2021). https://doi.org/10.1038/s41390-020-01328-y

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