Introduction to HMO Academy

HMOs are unique bioactive oligosaccharides, naturally present in human breast milk. HMOs represent the third largest solid component in human breast milk, with levels ranging between 5 and 15 g/L in mature human milk.^1-3

• Jantscher-Krenn E, Bode L. Human milk oligosaccharides and their potential benefits for the breast-fed neonate. Minerva Pediatr. 2012 Feb;64(1):83-99.
• Zivkovic A, German J, Lebrilla C, Mills D. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci. 2011 Mar;108(Suppl 1):4653-8.
• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Apr;22(9):1147-62.

Only 1% to 2% of HMOs are absorbed in the gut and reach the systemic circulation, as infants lack the enzymes necessary to digest HMOs. Therefore, the majority of HMOs reach the lower gut unchanged, where they are fermented to some extent by beneficial gut microbiota, and directly or indirectly support the baby’s immunity.^1-3

• Rudloff S, Kunz C. Milk oligosaccharides and metabolism in infants. Adv Nutr. 2012 May;3:398-405.
• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep;22(9):1147-62.
• Donovan SM, Comstock SS. Human milk oligosaccharides influence neonatal mucosal and systemic immunity. Ann Nutr Metab. 2016 Jan;69(Suppl. 2):41-51.

Breastfeeding has been associated with reduced risk of diarrhoeal diseases and respiratory tract infections in infants.^1,2 HMOs may be partially responsible for this protective effect offered by human breast milk. Evidence suggests that HMOs in human breast milk play an important role in supporting the baby’s immunity.^3-6

• Horta BL, Victora CG. Short-term effects of breastfeeding: a systematic review on the benefits of breastfeeding on diarrhoea and pneumonia mortality [internet]. World health organisation; 2013 [cited 2017; Dec 11]. Available from http://apps.who.int/iris/bitstream/10665/95585/1/9789241506120_eng.pdf.
• Victora C, Bahl R, Barros A, Franca G, Horton S, Krasevec J et al. Breastfeeding in the 21^st century: epidemiology, mechanisms, and lifelong effect. Lancet. 2016 Feb;387:475-90.
• Bode L. The functional biology of human milk oligosaccharides. Early Hum Dev. 2015 Nov; 91(11):619-22.
• Donovan SM, Comstock SS. Human milk oligosaccharides influence neonatal mucosal and systemic immunity. Ann Nutr Metab. 2016 Jan;69(Suppl. 2):41-51.
• Newburg DS, Ruiz-Palacios GM, Morrow AL. Human milk glycans protect infants against enteric pathogens. Annu Rev Nutr. 2005 Jul;25:37-58.
• Morrow AL, Ruiz-Palacios GM, Jiang X, Newburg DS. Human-milk glycans that inhibit pathogen binding protect breast-feeding infants against infectious diarrhea. J Nutr. 2005 May;135(5):1304-7.

Levels of total HMOs seem to decrease over the course of lactation. HMOs range between 20 and 25 g/L in colostrum and 5 and 15 g/L in mature human breast milk.^1,2 The levels of some of the most abundant HMOs, such as 2'fucosyllactose (2’FL) and lacto-N-neotetraose (LNnT), are highest in the colostrum and decrease over the course of lactation.^3,4

References:

• Zivkovic A, German J, Lebrilla C, Mills D. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci. 2010 Mar;108 Suppl 1:4653-8.
• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep;22(9):1147-62.
• Austin S, De Castro C, Bénet T, Hou Y, Sun H, Thakkar S et al. Temporal change of the content of 10 oligosaccharides in the milk of Chinese urban mothers. Nutrients. 2016 Jun;8(6):346.
• Sprenger N, Lee LY, De Castro CA, Steenhout P, Thakkar SK . Longitudinal change of selected human milk oligosaccharides and association to infants’ growth, an observatory, single center, longitudinal cohort study. PloS One. 2017 Feb;12(2):e0171814.

Research has shown that the quantity and type of HMOs in human breast milk mirrors the mother’s blood group characteristics.¹ The relative abundance of fucosylated HMOs is determined by the presence of several fucosyltransferase enzymes, which are encoded by the secretor and Lewis genes.¹ A majority (80%) of the women around the world are secretors, who are able to synthesise an abundance of 2-linked fucosylated HMOs, including 2′-fucosyllactose (2’FL).^1-4

References:

• Blank D, Dotz V, Geyer R, Kunz C. Human milk oligosaccharides and Lewis blood group: individual high-throughput sample profiling to enhance conclusions from functional studies. Adv Nutr. 2012 May;3(3):440S-9S.
• De Leoz M, Gaerlan S, Strum J, Dimapasoc L, Mirmiran M, Tancredi D et al. Lacto-N-tetraose, fucosylation, and secretor status are highly variable in human milk oligosaccharides from women delivering preterm. J Proteome Res. 2012 Aug;11(9):4662-72.
• McGuire MK, Meehan CL, McGuire MA, Williams JE, Foster J, Sellen DW et al. What’s normal? Oligosaccharide concentrations and profiles in milk produced by healthy women vary geographically. Clin Nutr. 2017 May;105:1086-100.
• Sprenger N, Lee LY, De Castro CA, Steenhout P, Thakkar SK. Longitudinal change of selected human milk oligosaccharides and association to infants’ growth, an observatory, single center, longitudinal cohort study. PloS One. 2017 Feb;12(2):e0171814.

Currently, there is not much evidence to suggest whether the duration of pregnancy has a significant effect on the HMOs present in human breast milk. However, one recent study revealed that total HMOs in preterm breast milk does not differ from that of term breast milk, over the course of lactation.¹

• Kunz C, Meyer C, Collado MC, Geiger L, Garcia-Mantrana I, Berua-Rios B et al. Influence of gestational age, secretor, and Lewis blood group status on the oligosaccharide content of human milk. J Pediatr Gastroenterol Nutr. 2017 May;64(5):789-798.

HMOs are a unique bioactive component of human breast milk, which are synthesised by the mammary gland. They have a complex structure consisting of 5 building blocks, namely glucose, galactose, N-acetylglucosamine, fucose and sialic acid. All HMOs contain lactose as the core element at one end and mainly fucose or sialic acids at the other terminal position, between which the oligosaccharides can be elongated and branched with up to 15 structures of galactose and N-acetylglucosamine to create small or large HMOs.^1,2

References:

• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Apr;22(9):1147-62.
• Bode L. Human milk oligosaccharides: prebiotics and beyond. Nutr Rev. 2009 Nov;67(suppl_2):S183-91.

HMOs, the complex structures unique to human breast milk, are structurally different from the less complex oligosaccharides like galacto-oligosaccharides (GOS)/ fructooligosaccharides (FOS)  which are currently being added to infant formulae. HMOs have several structure-specific benefits and provide more immune benefits than GOS/FOS.^1-4

References:

• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Apr;22(9):1147-62.
• Comstock SS, Li M, Wang M, Monaco MH, Kuhlenschmidt TB, Kuhlenschmidt MS et al. Dietary human milk oligosaccharides but not prebiotic oligosaccharides increase circulating natural killer cell and mesenteric lymph node memory T cell populations in noninfected and rotavirus-infected neonatal piglets. J Nutr. 2017 Jun;147(6):1041-7.
• Goehring KC, Marriage BJ, Oliver JS, Wilder JA, Barrett EG, Buck RH. Similar to those who are breastfed, infants fed a formula containing 2′-fucosyllactose have lower  inflammatory cytokines in a randomized controlled trial. J Nutr. 2016 Dec;146(12):2559-66.
• Hoeflinger JL, Davis SR, Chow J, Miller MJ. In vitro impact of human milk oligosaccharides on Enterobacteriaceae growth. J Agric Food Chem. 2015 Mar;63(12):3295-302.

The amount and variety of oligosaccharides in human breast milk are unique and not found in bovine milk or milk from other farm animals. Levels of oligosaccharides are more than 100-fold higher in human breast milk than in cow’s milk; also the number and types of oligosaccharides in human breast milk are more varied when compared to cow’s milk.^1,2

References:

• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep;22(9):1147-62.
• Urashima T, Taufik E, Fukuda K, Asakuma S. Recent advances in studies on milk oligosaccharides of cows and other domestic farm animals. Biosci Biotechnol Biochem. 2013 Mar;77(3):455-66.

More than 150 unique types of HMOs have been identified so far.¹ They are classified into 3 different categories depending on their terminal position: namely, fucosylated HMOs, such as 2’FL; non-fucosylated HMOs, such as LNnT; and sialylated HMOs, such as 3’SL.²

References:

• Bode L, Contractor N, Barile D, Pohl N, Prudden AR, Boons GJ, Jin Y, Jennewein S. Overcoming the limited availability of human milk oligosaccharides: challenges and opportunities for research and application. Nutr Rev. 2016 Sep;74(10):635-44.
• Smilowitz J, Lebrilla C, Mills D, German J, Freeman S. Breast milk oligosaccharides: structure-function relationships in the neonate. Ann Rev Nutr. 2014 Jul;34(1):143-69.

HMOs, the third largest component of human breast milk, are synthesised by the mammary gland, thereby forming a natural part of human breast milk.¹

Reference:

• Jantscher-Krenn E, Bode L. Human milk oligosaccharides and their potential benefits for the breast-fed neonate. Minerva Pediatr. 2012 Feb;64(1):83-99.

2’fucosyllactose (2ʹFL) and lacto-N-neotetraose (LNnT) are among the 10 most abundant oligosaccharides in human breast milk, which collectively constitute more than 75% of total HMOs. Interestingly, 2’FL, a fucosylated HMO, and LNnT, a non-fucosylated HMO, are among the most researched HMOs.^1-3

References:

• Bode L, Jantscher-Krenn E. Structure-function relationships of human milk oligosaccharides. Adv Nutr Int Rev J. 2012 May;3(3):383S-91S.
• Austin S, De Castro CA, Bénet T, Hou Y, Sun H, Thakkar SK et al. Temporal change of the content of 10 oligosaccharides in the milk of Chinese urban mothers. Nutrients. 2016 Jun;8(6):346.
• Smilowitz J, Lebrilla C, Mills D, German J, Freeman S. Breast milk oligosaccharides: structure-function relationships in the neonate. Ann Rev Nutr. 2014 Jul;34(1):143-69.

Research suggests that HMOs support immunity in 4 main ways, as follows:

• Promoting the growth of beneficial gut bacteria^1,2
• Preventing pathogens from binding to the intestinal wall, which reduces their ability to infect the infant^1,3
• Assisting gut barrier function, which can help prevent pathogen binding to the intestinal cells^1,3
• Directly modulating the immune system, which helps in educating the developing immune system^1,4

References

• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep;22(9):1147-62.
• Sela DA, Mills DA. Nursing our microbiota: molecular linkages between bifidobacteria and milk oligosaccharides. Trends Microbiol. 2010 Jul;18(7):298-307.
• Jantscher-Krenn E, Bode L. Human milk oligosaccharides and their potential benefits for the breast-fed neonate. Minerva Pediatr. 2012 Feb;64(1):83-99.
• Eiwegger T, Stahl B, Schmitt J, Boehm G, Gerstmayr M, Pichler J et al. Human milk-derived oligosaccharides and plant-derived oligosaccharides stimulate cytokine production of cord blood T-cells in vitro. Pediatr Res. 2004 Oct;56(4):536-40.

Research has shown that breastfed infants have a high abundance of beneficial bacteria, such as bifidobacteria.^1-3 Infants breastfed by secretor mothers with higher levels of 2-fucosylated HMOs, such as 2’FL, in their breast milk had a higher abundance of beneficial bifidobacteria and lower levels of Streptococcus in comparison with infants of non-secretor mothers.⁴

References:

• Collado MC, Cernada M, Baüerl C, Vento M, Pérez-Martínez G. Microbial ecology and host-microbiota interactions during early life stages. Gut Microbes. 2012 Jul-Aug;3(4):352-65.
• Rodríguez JM, Murphy K, Stanton C, Ross RP, Kober OI, Juge N et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015 Feb;26:26050.
• Davis JC, Lewis ZT, Krishnan S, Bernstein RM, Moore SE, Prentice AM et al. Growth and morbidity of Gambian infants are influenced by maternal milk oligosaccharides and infant gut microbiota. Sci Rep. 2017 Jan;7:40466.
• Lewis ZT, Totten SM, Smilowitz JT, Popovic M, Parker E, Lemay D et al. Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants. Microbiome. 2015 Apr;3:13.

At birth, the baby’s immune system is still immature. A protective commensal gut microbiota is one of the key factors responsible for the maturation of the baby’s immune system. Breastfeeding is known to establish beneficial gut microbiota in infants.^1-3

References:

• Martin R, Nauta AJ, Ben Amor K, Knippels LM, Knol J, Garssen J. Early life: gut microbiota and immune development in infancy. Benef Microbes. 2010 Nov;1(4):367-82.
• Walker WA. Intestinal colonization and programming of the intestinal immune response. J Clin Gastroenterol. 2014 Nov-Dec;48 Suppl 1:S8-11.
• Rodríguez JM, Murphy K, Stanton C, Ross RP, Kober OI, Juge N et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015 Feb;26:26050.

Two clinical studies have shown that breastfed infants who received human breast milk abundant in fucosylated HMOs, like 2’FL, had a lower risk of developing diarrhoea due to Campylobacter jejuni or to enterotoxigenic E. coli. Also, moderate to severe diarrhoea of all causes were less frequent in these infants.^1,2

References:

• Morrow AL, Ruiz-Palacios GM, Altaye M, Jiang X, Guerrero ML, Meinzen-Derr JK, et al. Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. J Pediatr. 2004 Sep;145(3):297-303.
• Newburg DS, Ruiz-Palacios GM, Morrow AL. Human milk glycans protect infants against enteric pathogens. Annu Rev Nutr. 2005 Jul;25:37-58.

HMOs may have an impact on the development of some allergies in children during the first two years of life. First evidence from a clinical study indicates that an abundance of 2’ fucosylated HMOs, especially 2ʹFL, in human breast milk may reduce the risk of immunoglobulin E (IgE)-associated eczema in breastfed infants with high risk of allergy at the age of 2 years, when born by C-section.¹

Reference:

• Sprenger N, Odenwald H, Kukkonen AK, Kuitunen M, Savilahti E, Kunz C. FUT2‑dependent breast milk oligosaccharides and allergy at 2 and 5 years of age in infants with high hereditary allergy risk. Eur J Nutr. 2016 Apr;56(3):1293-301.

Research suggests that human milk oligosaccharides (HMOs) serve as food to specifically promote the growth of certain beneficial gut bacteria. Furthermore, certain species of bifidobacteria and several other commensal gut bacteria ferment HMOs to short-chain fatty acids (SCFAs) and other metabolites like lactate and acetate, which contribute to an environment in the gut, favouring the growth of beneficial bacteria over potential pathogens.^1,2

References

• Sela DA and Mills DA. Nursing our microbiota: molecular linkages between bifidobacteria and milk oligosaccharides. Trends Microbiol. 2010 Jul;18(7):298-307.
• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep;22(9):1147-62.

Human milk oligosaccharides (HMOs) serve as metabolic substrates for specific beneficial gut bacteria and provide them with a growth advantage over potential pathogens.^1,2,3 Evidence from experimental studies indicates that HMOsdo not allow the growth of potentially pathogenic strains of Enterobacteriaceae, Escherichia coli and Clostridia.^2-4

References

• Sela DA, Mills DA. Nursing our microbiota: molecular linkages between bifidobacteria and milk oligosaccharides. Trends Microbiol. 2010 Jul;18(7):298-307.
• Yu ZT, Chen C, Newburg DS. Utilization of major fucosylated and sialylated human milk oligosaccharides by isolated human gut microbes. Glycobiology. 2013 Nov;23(11):1281-92.
• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep;22(9):1147-62.
• Hoeflinger JL, Davis SR, Chow J and Miller MJ. In vitro impact of human milk oligosaccharides on Enterobacteriaceae growth. J Agric Food Chem. 2015 Apr;63(12):3295-302.

Human milk oligosaccharides (HMOs) resemble glycans on the mucosa cell surface to which pathogens adhere. Due to this structural similarity, HMOs can act as decoy receptors by preventing pathogens from binding to the host cells, thus help reduce the risk of infection.^1-4As shown in observational studies, an abundance of 2’fucosylated HMOs in breast milk was associated with a lower risk of infectious diarrhoea in breast-fed infants.^5-6

References

• Jantscher-Krenn E. Human milk oligosaccharides and their potential benefits for the breast-fed neonate. Minerva Pediatr. 2012 Feb;64(1):83-99.
• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep;22(9):1147-62.
• Smilowitz J, Lebrilla C, Mills D, German J and Freeman S. Breast milk oligosaccharides: structure-function relationships in the neonate. Annu Rev Nutr. 2014;34(1):143-69.
• Ruiz-Palacios G, Cervantes L, Ramos P, Chavez-Munguia B, Newburg D. Campylobacter jejuni binds Intestinal H(O) antigen (Fuc 1, 2Gal 1, 4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. J Biol Chem. 2003;278(16):14112-20.
• Newburg D, Ruiz-Palacios GM, Altaye M, Chaturvedi P, Meinzen-Derr J, Guerrero M et al. Innate protection conferred by fucosylated oligosaccharides of human milk against diarrhea in breastfed infants. Glycobiology. 2004;14(3):253-263.
• Morrow A, Ruiz-Palacios G, Altaye M, Jiang X, Lourdes Guerrero M, Meinzen-Derr J et al. Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. J Pediatr. 2004;145(3):297-303.

An accumulating body of evidence shows that human milk oligosaccharides (HMOs) directly and indirectly influence infant mucosal and systemic immune function.^1-3 HMOs may act locally on the gut associated immune system or can directly modulate infants’ systemic immune function, such as by affecting immune cell populations and cytokine secretion ^4-5

References

• Donovan S and Comstock S. Human milk oligosaccharides influence neonatal mucosal and systemic immunity. Ann Nutr Metab. 2016;69 Suppl 2:42-51.
• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012;22(9):1147-62.
• Jantscher-Krenn E. Human milk oligosaccharides and their potential benefits for the breast-fed neonate. Minerva Pediatr. 2012;64(1):83-99.
• Eiwegger T, Stahl B, Schmitt J et al. Human milk-derived oligosaccharides and plant-derived oligosaccharides stimulate cytokine production of cord blood T-cells in vitro. Pediatr Res. 2004;56(4):536-40.
• Comstock SS, Li M, Wang M, Monaco MH, Kuhlenschmidt TB, Kuhlenschmidt MS, et al. Dietary human milk oligosaccharides but not prebiotic oligosaccharides increase circulating natural killer cell and mesenteric lymph node memory T Cell populations in noninfected and rotavirus-infected neonatal piglets. J Nutr. 2017 Jun;147(6):1041-7.

Frist evidence from a randomised, clinical study suggests that t addition of the human milk oligosaccharide 2’fucosyllactose (2’FL) to infant formulae influences immune biomarkers similar to that of breastfed infants, in comparison to formulae without this HMO.¹

Reference

• Goehring KC, Marriage BJ, Oliver JS, Wilder JA, Barrett EG, Buck RH. Similar to those who are breastfed, infants fed a formula containing 2′-fucosyllactose have lower inflammatory cytokines in a randomized controlled trial. J Nutr. 2016 Dec;146:2559-66.

Due to their highly complex structure, the replication of HMOs was not possible until recently. Breakthrough advances in biotechnology after almost 30 years of research and development activities by Nestlé along with their partners, has enabled the production of HMOs, such as 2’fucosyllactose (2’FL) and lacto-N-neotetraose (LNnT), identical to those present in human breast milk on an industrial scale to introduce into infant formulae.^1-3

References

• Bode L, Contractor N, Barile D, Pohl N, Prudden AR, Boons GJ, et al. Overcoming the limited availability of human milk oligosaccharides: challenges and opportunities for research and application. Nutrition Reviews. 2016;74(10):635-644.
• EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Safety of 2ʹ-O-fucosyllactose as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA J. 2015 Jul;13(7):4184.
• EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Safety of lacto-N-neotetraose as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA J. 2015 Jul;13(7):4183.

Human milk oligosaccharides (HMOs) can be either chemically synthesized or produced using a fermentation process for the addition to infant and follow-on formulae. Both these processes have been approved to be safe by the United States Food and Drug Administration (US-FDA) [Generally recognized as safe (GRAS)] and the European Food Safety Authority (EFSA). ^1-4

References

• GRAS Notices [Internet]. Accessdata.fda.gov. 2015 [cited 2017 Jun 25, 2017]. Available from: https://www.accessdata.fda.gov/scripts/fdcc/?set=GRASNotices&id=546
• GRAS Notices [Internet]. Accessdata.fda.gov. 2015 [cited 2017 Jun 25, 2017]. Available from: https://www.fda.gov/downloads/food/ingredientspackaginglabeling/gras/noticeinventory/ucm517673.pdf
• EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Safety of 2′-O-fucosyllactose as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA J. 2015;13(7):4184
• EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Safety of lacto-N-neotetraose as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA J. 2015;13(7):4183.

The HMOs 2’fucosyllactose (2’FL) and lacto-N-neotetraose (LNnT) are among the 10 most abundant HMOs in human breast milk and also the most researched.^1-7 So far, the HMOs 2’FL and LNnt have been approved to be safe by the United States Food and Drug Administration (US-FDA) [Generally recognized as safe (GRAS)] and the European Food Safety Agency(EFSA) for the use in infant formulae and follow-on formulae.^8-11 First clinical studies have shown positive effects of these HMOs on babies’ immunity, gut microbiota development, tolerance and normal growth when added to infant formulae.^4-7

References:

• Zivkovic AM, German BJ, Lebrilla CB, Mills DA. Human milk glyycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci.2011 Aug; 108(11):4653-4658. .
• Austin S, De Castro C, Bénet T, Hou Y, Sun H, Thakkar S et al. Temporal change of the content of 10 oligosaccharides in the milk of Chinese urban mothers. Nutrients. 2016 Jun;8(6):346.
• Urashima T, Asakuma S, Leo F, Fukuda K, Messer M and Oftedal OT. The predominance of type I oligosaccharides is a feature specific to human breast milk. Adv Nutr. 2012 May;3(3):473S-82S.
• Goehring K, Marriage B, Oliver J, Wilder J, Barrett E, Buck R. Similar to those who are breastfed, infants fed a formula containing 2'-fucosyllactose have lower inflammatory cytokines in a randomized controlled trial. J Nutr. 2016 Dec;146(12):2559-66.
• Steenhout P, Sperisen P, Martin FP et al. Term infant formula supplemented with human milk oligosaccharides (2′ fucosyllactose and lacto-N-neotetraose) shifts stool microbiota and metabolic signatures closer to that of breastfed infants. FASEB J. 2016 Apr;30(1) Suppl:275-7.
• Puccio G, Alliet P, Cajozzo C et al. Effects of infant formula with human milk oligosaccharides on growth and morbidity: a randomized multicenter trial. J Pediatr Gastroenterol Nutr. 2017 Apr;64(4):624-31.
• Marriage B, Buck R, Goehring K, et al. Infants fed a lower calorie formula with 2′FL show growth and 2′FL uptake like breast-fed infants. J Pediatr Gastroenterol Nutr. 2015;61(6):649-58.
• GRAS Notices [Internet]. Accessdata.fda.gov. 2015 [cited 2017 Jun 25, 2017]. Available from: https://www.accessdata.fda.gov/scripts/fdcc/?set=GRASNotices&id=546
• GRAS Notices [Internet]. Accessdata.fda.gov. 2015 [cited 2017 Jun 25, 2017]. Available from: https://www.fda.gov/downloads/food/ingredientspackaginglabeling/gras/noticeinventory/ucm517673.pdf
• EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Safety of 2ʹ-O-fucosyllactose as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA J. 2015 Jul;13(7):4184.
• EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Safety of lacto-N-neotetraose as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA J. 2015 Jul;13(7):4183.

Human milk contains more than 150 unique types of HMOs, of these 2’fucosyllactose (2’FL) and lacto-N-neotetraose (LNnT) are among the 10 most abundant.^1-4 A randomised controlled clinical trial showed that infant formula added with a combination of 2′FL and LNnT is well tolerated and supports normal growth.⁵

Moreover, 2´FL can be added to infant formulae either alone or in combination with LNnT, as stated in a recently published European Union (EU) regulation.⁶

Reference:

• Bode L, Contractor N, Barile D, Pohl N, Prudden AR, Boons GJ, et al. Overcoming the limited availability of human milk oligosaccharides: challenges and opportunities for research and application. Nutrition Reviews. 2016;74(10):635-644.
• Zivkovic AM, German BJ, Lebrilla CB, Mills DA. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci.2011 Aug; 108(11):4653-4658.
• Austin S, De Castro C, Bénet T, Hou Y, Sun H, Thakkar S et al. Temporal change of the content of 10 oligosaccharides in the milk of Chinese urban mothers. Nutrients. 2016 Jun;8(6):346.
• Urashima T, Asakuma S, Leo F, Fukuda K, Messer M and Oftedal OT. The predominance of type I oligosaccharides is a feature specific to human breast milk. Adv Nutr. 2012 May;3(3):473S-82S.
• Puccio G, Alliet P, Cajozzo C, Janssens E, Corsello G, Sprenger N et al. Effects of infant formula with human milk oligosaccharides on growth and morbidity: a randomized multicenter trial. J Pediatr Gastroenterol Nutr. 2017 Apr;64(4):624-31.
• Commission Implementing Regulation (EU) 2017/2470 of 20 December 2017 establishing the Union list of novel foods in accordance with Regulation (EU) 2015/2283 of the European Parliament and of the Council on novel foods. Off J Eur Union. L 351. 2017

There are over 150 different human milk oligosaccharides (HMOs) in human milk, which are synthesised by the mammary gland.¹ Scientists do not yet know if specific structures of HMOs have unique or similar or overlapping functions for the infant. Initial evidences are promising that an abundance of2’fucosyllactose (2’FL) in breast milk reduces the risk of Campylobacter -induced diarrhoea in infants, whereas lacto-N-neotetraose (LNnT) has shown to reduce the colonisation of S. pneumoniae in the lungs and to attenuate the course of pneumococcal pneumonia. ^2-3 Hence, the effect of adding 2’FL alone to formula may differ from that when a combination of 2’FL and LNnT is provided in an infant formula.
 

Reference:

• Bode L, Contractor N, Barile D, Pohl N, Prudden AR, Boons GJ et al. Overcoming the limited availability of human milk oligosaccharides: challenges and opportunities for research and application. Nutr Rev. 2016 Sep;74(10):635-44.
• Morrow A, Ruiz-Palacios G, Altaye M, Jiang X, Lourdes Guerrero M, Meinzen-Derr J et al. Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. J Pediatr. 2004;145(3):297-303..
• Idänpään‐Heikkilä I, Simon P, Zopf D, Vullo T, Cahill P, Sokol K. Oligosaccharides interfere with the establishment and progression of experimental pneumococcal pneumonia. J Infect Dis. 1997 Sep;176(3):704-12.

The three main considerations for Nestlé selecting 2’fucosyllactose (2’FL) and lacto-N-neotetraose (LNnT) are as follows: Firstly, 2ʹFL and LNnT are among the 10 most abundant HMOs in human breast milk.^1-3 Secondly, the HMOs 2ʹFL and LNnT are the most researched HMOs in preclinical and clinical studies, providing evidence for their positive effects on immunity. ^4-8 Furthermore, infant formulae supplemented with 2′FL, alone or in combination with LNnT, support normal growth and are well tolerated.^5-8. Thirdly, 2ʹFL and LNnT are approved as safe by the European Food Safety Agency (EFSA) and the United States Food and Drug Administration [Generally recognized as safe (GRAS)]).^9-12

• Zivkovic AM, German BJ, Lebrilla CB, Mills DA. Human milk glyycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci.2011 Aug; 108(11):4653-4658. .
• Austin S, De Castro C, Bénet T, Hou Y, Sun H, Thakkar S et al. Temporal change of the content of 10 oligosaccharides in the milk of Chinese urban mothers. Nutrients. 2016 Jun;8(6):346.
• Urashima T, Asakuma S, Leo F, Fukuda K, Messer M and Oftedal OT. The predominance of type I oligosaccharides is a feature specific to human breast milk. Adv Nutr. 2012 May;3(3):473S-82S.
• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep;22(9):1147-62
• Puccio G, Alliet P, Cajozzo C et al. Effects of infant formula with human milk oligosaccharides on growth and morbidity: a randomized multicenter trial. J Pediatr Gastroenterol Nutr. 2017 Apr;64(4):624-31.
• Steenhout P, Sperisen P, Martin F-P, Sprenger N, Wernimont S, Pecquet S et al. Term infant formula supplemented with human milk oligosaccharides (2ʹFL and LNnT) shifts stool microbiota and metabolic signatures closer to that of breastfed infant. FASEB J. 2016;30 Suppl 1:275:7.
• Goehring KC, Marriage BJ, Oliver JS, Wilder JA, Barrett EG, Buck RH. Similar to those who are breastfed, infants fed a formula containing 2′-fucosyllactose have lower inflammatory cytokines in a randomized controlled trial. J Nutr. 2016 Dec;146:2559-66.
• Marriage BJ, Buck RH, Goehring KC, Oliver JS, Williams JA. Infants Fed a Lower Calorie Formula With 2'FL Show Growth and 2'FL Uptake Like Breast-Fed Infants. J Pediatr Gastroenterol Nutr. 2015;61(6):649-458
• EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Safety of 2ʹ-O-fucosyllactose as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA J. 2015;13(7):4184.
• EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Safety of lacto-N-neotetraose as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA J. 2015;13(7):4183.
• GRAS Notices [Internet]. Accessdata.fda.gov. 2015 [cited 2017 Jun 25, 2017]. Available from:https://www.accessdata.fda.gov/scripts/fdcc/?set=GRASNotices&id=546

GRAS Notices [Internet]. Accessdata.fda.gov. 2015 [cited 2017 Jun 25, 2017]. Available from: https://www.fda.gov/downloads/food/ingredientspackaginglabeling/gras/noticeinventory/ucm517673.pdf

HMOs are the third most abundant component of human breast milk, after lactose and lipids, and are synthesized by the mammary gland.^1,2HMOs are highly complex structures, while other oligosaccharides, which are added to infant formulae to mimic HMOs, are less complex, like GOS and FOS.¹  HMOs are structurally similar to glycans on the surface of intestinal cells.² Therefore, some HMOs can deceive pathogens and their toxins to bind to them instead to the intestinal wall, thereby serving as soluble decoy receptors.¹ As the decoy effect is dependent on the structure of the HMOs, it is unlikely that non-human oligosaccharides can offer the same benefits as HMOs.^1,2

References

• Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012;22(9):1147-62.
• Bode L, Jantscher Krenn E. Structure-Function Relationships of Human Milk Oligosaccharides. Adv Nutr. 2012 May; 3(3):383S-391S.

The complex structures of HMOs may explain the additional functions of HMOs beyond what those oligosaccharides traditionally added to formulae can provide¹. A clinical study provides first evidence that galacto-oligosaccharides (GOS) when added to infant formulae is not able to induce immune biomarkers similar to that of breastfed babies, in comparison to formulae with the HMO- 2’ fucosyllactose (2’FL).² Furthermore, HMOs were more effective than a mixture of GOS and fructo-oligosaccharides (FOS) in changing systemic and gastrointestinal immune cells in an animal model.^2-3  While GOS and FOS have shown to promote the growth of beneficial gut bacteria, the European Food and Safety Agency (EFSA) concluded in 2014 that further evidence is required to translate this to a health benefit.⁴

References

• Bode L, Jantscher Krenn E. Structure-Function Relationships of Human Milk Oligosaccharides. Adv Nutr. 2012 May; 3(3):383S-391S.
• Goehring KC, Marriage MJ, Jeffery OS, Wilder JA, Barrett ED and Buck RH. Similar to those who are breastfed, infants fed a formula containing 2ʹ-fucosyllactose have lower inflammatory cytokines in a randomized controlled trial. J Nutr. 2016;146:2559-66.
• Comstock SS, Li M, Wang M, Monaco MH, Kuhlenschmidt TB, Kuhlenschmidt MS et al. Dietary human milk oligosaccharides but not prebiotic oligosaccharides increase circulating natural killer cells and mesenteric lymph node memory T cell populations in noninfected and rotavirus-infected neonatal piglets. J Nutr. 2017;147(6):1041-47.
• EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies). Scientific opinion on the essential composition of infant and follow-on formulae. EFSA J. 2014;12(7):3760.

First clinical evidence shows promising results: babies fed infant formula with the HMOs 2’fucosyllactose (2’FL) and lacto-N-neotetraose (LNnT), had stool microbiota closer to that of breastfed infants, in comparison to formula without these HMOs  .^1,2

Further, an observational study could show  that the abundance of 2’ fucosylated HMOs, such as 2’FL, in the milk of secretor mothers promotes the growth of beneficial bifidobacteria in the gut of breastfed infants.³

Reference

• Steenhout P, Sperisen P, Martin FP, Sprenger N, Wernimont S, Pecquet S et al. Term infant formula supplemented with human milk oligosaccharides (2′ fucosyllactose and lacto-N-neotetraose) shifts stool microbiota and metabolic signatures closer to that of breastfed infants. FASEB J. 2016 Apr;30 Suppl 1:275-7.
• Berger B, Sprenger N, Grathwohl D, AllietP, Puccio G, Steenhout P, Lausanne NSA. Stool microbiota in term infants fed formula supplemented with synthetic human milk oligosaccharides is associated with reduced likelihood of medication. World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. Abstract 1190. J Pediatr Gastroenterol Nutr. 2016 Oct;63 Suppl 2:S406.
• Lewis ZT, Totten SM, Smilowitz JT, Popovic M, Parker E, Lemay D et al. Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants. Microbiome. 2015 Apr;3:13.

An observational study of mother-infant pairs found promising results that higher levels of 2’fucosyllactose (2’FL), in mother’s milk was associated with a lower incidence of Campylobacter-induced diarrhoea in their babies during the first year of life.¹ While human milk oligosaccharides (HMOs)  promote the growth of beneficial gut bacteria, evidence from preclinical studies suggests that HMOs do not support  the growth of  potentially pathogenic strains of  Entereobacteriacea,  E. coli and Clostridium perfringens.^2,3 harmful strains of Enterobacteriaceae do not grow on HMOs like 2’FL and lacto-N-neotetraose (LNnT).³

Reference:

• Morrow A, Ruiz-Palacios G, Altaye M et al. Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. J Pediatr. 2004;145(3):297-303.
• Yu ZT, Chen C, Newburg DS. Utilization of major fucosylated and sialylated human milk oligosaccharides by isolated human gut microbes. Glycobiology. 2013 Sep;23(11):1281-92.
• Hoeflinger JL, Davis SR, Chow J, Miller MJ. In vitro impact of human milk oligosaccharides on enterobacteriaceae growth. J Agric Food Chem. 2015;63(12):3295-302.

Two randomised, controlled, clinical studies provide promising first evidence that infant formulae with the HMOs  2’fucosyllactose (2’FL) alone or in combination with lacto-N-neotetraose (LNnT), support the infant’s immune system.

In the study conducted by Goehring and her colleagues, infants who received formulae with the HMO 2’FL hadlevels of immune biomarkers closer to those of breastfed infants, in comparison to formulae without this HMO .¹

In the study of Puccio and his colleagues, infants receiving formula with 2’FL and LNnT had lower incidences of certain parent-reported, respiratory tract infections and less medication use, compared to feeding formula without these HMOs .²

Reference

• Goehring KC, Marriage BJ, Oliver JS, Wilder JA, Barrett EG and Buck RH. Similar to those who are breastfed, infants fed a formula containing 2’-fucosyllactose have lower inflammatory cytokines in a randomized controlled trial. J Nutr. 2016 Oct;146:2559-66.
• Puccio G, Philippe A, Cajazzo C, Janssens E, Corsello G, Sprenger N et al. Effects of infant formula with human milk oligosaccharides on growth and morbidity: a randomized multicenter trial. J Pediatr Gastroenterol Nutr. 2017 Apr;64(4):624-631.