Human Milk Oligosaccharides

After lactose and fat, HMOs are the third largest component of human milk solids, at 8 percent

Soyyilmaz, B., Mikš, M. H., Röhrig, C. H., Matwiejuk, M., Meszaros‐matwiejuk, A., & Vigsnæs, L. K. (2021). The mean of milk: A review of human milk oligosaccharide concentrations throughout lactation. Nutrients, 13(8), 1–22. https://doi.org/10.3390/nu13082737.



. HMOs are non-digestible carbohydrates that help provide the optimum conditions for beneficial bacteria to thrive in the infant gut and play an important role in supporting the immune system and contributing to brain development

Bode, L. (2012). Human milk oligosaccharides: Every baby needs a sugar mama. In Glycobiology. https://doi.org/10.1093/glycob/cws074  and inhibits in vitro binding of viral and bacterial pathogens associated with childhood diarrhoea, like norovirus, rotavirus and ETEC
Bode, L., Kuhn, L., Kim, H.-Y., Hsiao, L., Nissan, C., Sinkala, M., Kankasa, C., Mwiya, M., Thea, D. M., & Aldrovandi, G. M. (2012). Human milk oligosaccharide concentration and risk of postnatal transmission of HIV through breastfeeding. The American Journal of Clinical Nutrition, 96(4), 831–839. https://doi.org/10.3945/ajcn.112.039503
Bode, L., & Jantscher-Krenn, E. (2012). Structure-function relationships of human milk oligosaccharides. Advances in Nutrition. https://doi.org/10.3945/an.111.001404



. So far, more than 200 different HMOs have been identified at various concentrations and combinations in breast milk

German, J., Freeman, S., Lebrilla, C., & Mills, D. (2008). Human milk oligosaccharides: Evolution, structures and bioselectivity as substrates for intestinal bacteria. Nestle Nutrition Workshop Series: Pediatric Program. https://doi.org/10.1159/000146322



. These include 2’-FL, 3’-SL and LNT, each of which is expected to have its own potential benefits for infant health.

Research shows that HMOs have an important role to play by supporting infant health in various ways. These include influencing the gut microbiome, reducing the risk of infection and supporting the brain development of infants

Bode, L. (2012). Human milk oligosaccharides: Every baby needs a sugar mama. In Glycobiology. https://doi.org/10.1093/glycob/cws074  and inhibits in vitro binding of viral and bacterial pathogens associated with childhood diarrhoea, like norovirus, rotavirus and ETEC
Bode, L., Kuhn, L., Kim, H.-Y., Hsiao, L., Nissan, C., Sinkala, M., Kankasa, C., Mwiya, M., Thea, D. M., & Aldrovandi, G. M. (2012). Human milk oligosaccharide concentration and risk of postnatal transmission of HIV through breastfeeding. The American Journal of Clinical Nutrition, 96(4), 831–839. https://doi.org/10.3945/ajcn.112.039503
Bode, L., & Jantscher-Krenn, E. (2012). Structure-function relationships of human milk oligosaccharides. Advances in Nutrition. https://doi.org/10.3945/an.111.001404



. Different individual HMOs have been shown to have different effects

Asakuma S, Hatakeyama E, Urashima T, et al. Physiology of consumption of human milk oligosaccharides by infant gut-associated ifidobacterial. J Biol Chem. Published online 2011. Doi:10.1074/jbc.M111.248138
Bode, L., & Jantscher-Krenn, E. (2012). Structure-function relationships of human milk oligosaccharides. Advances in Nutrition. https://doi.org/10.3945/an.111.001404
Lin, A. E., Autran, C. A., Szyszka, A., Escajadillo, T., Huang, M., Godula, K., Prudden, A. R., Boons, G. J., Lewis, A. L., Doran, K. S., Nizet, V., & Bode, L. (2017). Human milk oligosaccharides inhibit growth of group B Streptococcus. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.M117.789974
Salli K, Hirvonen J, Siitonen J, Ahonen I, Anglenius H, Maukonen J. Selective Utilization of the Human Milk Oligosaccharides 2′-Fucosyllactose, 3-Fucosyllactose, and Difucosyllactose by Various Probiotic and Pathogenic Bacteria. J Agric Food Chem. Published online 2021. doi:10.1021/acs.jafc.0c06041
Watson D, O’Connell Motherway M, Schoterman MHC, van Neerven RJJ, Nauta A, Van Sinderen D. Selective carbohydrate utilization by lactobacilli and bifidobacteria. J Appl Microbiol. Published online 2013. doi:10.1111/jam.12105
Yu, Z. T., Chen, C., Kling, D. E., Liu, B., McCoy, J. M., Merighi, M., Heidtman, M., & Newburg, D. S. (2013). The principal fucosylated oligosaccharides of human milk exhibit prebiotic properties on cultured infant microbiota. Glycobiology. https://doi.org/10.1093/glycob/cws138



, so they may complement each other in supporting infant health.

At FrieslandCampina Ingredients, we believe that delivering a larger variety of non-digestible oligosaccharides (e.g. a combination of GOS and HMOs) can be of key importance for the establishment of the gut microbiota and its metabolism, thereby feeding into many different health aspects in early life and beyond. As a unique provider of both GOS and HMO solutions, we can offer a wider diversity of structures to bring the concept of gut health to the next level.

• 2’-Fucosyllactose (2’-FL) is a fucosylated HMO
• Most abundant HMO in human milk
  
  Chaturvedi, P., Warren, C. D., Altaye, M., Morrow, A. L., Ruiz-Palacios, G., Pickering, L. K., & Newburg, D. S. (2001). Fucosylated human milk oligosaccharides vary between individuals and over the course of lactation. Glycobiology, 11(5), 365–372.
  
  
  
• Stimulation of the growth of beneficial Bifidobacteria in vitro
  
  Yu, Z. T., Chen, C., & Newburg, D. S. (2013). Utilization of major fucosylated and sialylated human milk oligosaccharides by isolated human gut microbes. Glycobiology, 23(11), 1281–1292.https://doi.org/10.1093/glycob/cwt065
  
  
  
• An association study demonstrated that infants receiving breast milk with high 2’-FL content show enhanced gut colonisation with Bifidobacterium as compared with infants receiving milk without 2’-FL
  
  Lewis, Z. T., Totten, S. M., Smilowitz, J. T., Popovic, M., Parker, E., Lemay, D. G., Van Tassell, M. L., Miller, M. J., Jin, Y.-S., German, J. B., Lebrilla, C. B., & Mills, D. A. (2015). Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants. Microbiome, 3(1), 13.https://doi.org/10.1186/s40168-015-0071-z
  
  
  
• Pre-clinical research has shown that 2’-FL can inhibit adhesion and infectivity of the diarrhea pathogens norovirus, rotavirus, EPEC, Campylobacter jejuni and Salmonella enterica serovar fyris, as well as the respiratory tract infection pathogen Pseudomonas aeruginosa
  
  Laucirica, D. R., Triantis, V., Schoemaker, R., Estes, M. K., & Ramani, S. (2017). Milk Oligosaccharides Inhibit Human Rotavirus Infectivity in MA104 Cells. Journal of Nutrition, 147(9), 1709–1714.
  Weichert, S., Jennewein, S., Hüfner, E., Weiss, C., Borkowski, J., Putze, J., & Schroten, H. (2013). Bioengineered 2’-fucosyllactose and 3-fucosyllactose inhibit the adhesion of Pseudomonas aeruginosa and enteric pathogens to human intestinal and respiratory cell lines. Nutrition Research (New York, N.Y.), 33(10), 831–838. https://doi.org/10.1016/j.nutres.2013.07.009
  Weichert, S., Koromyslova, A., Singh, B. K., Hansman, S., Jennewein, S., Schroten, H., & Hansman, G. S. (2016). Structural Basis for Norovirus Inhibition by Human Milk Oligosaccharides. Journal of Virology, 90(9), 4843–4848. https://doi.org/10.1128/JVI.03223-15
  Yu, Z.-T., Nanthakumar, N. N., & Newburg, D. S. (2016). The Human Milk Oligosaccharide 2’ Fucosyllactose Quenches Campylobacter jejuni – Induced Inflammation in Human Epithelial Cells HEp-2 and HT-29 and in Mouse. J Nutr, Epub.https://doi.org/10.3945/jn.116.230706.The
  
  
  
  . Association studies have shown that infants receiving breast milk with high 2’-FL content have a lower risk of Campylobacter jejuni-induced diarrhea
  
  Morrow, A. L., Ruiz-Palacios, G. M., Altaye, M., Jiang, X., Guerrero, M. L., Meinzen-Derr, J. K., Farkas, T., Chaturvedi, P., Pickering, L. K., & Newburg, D. S. (2004). Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. The Journal of Pediatrics, 145(3), 297–303.https://doi.org/10.1016/j.jpeds.2004.04.054
  
  
  
• Recent clinical studies have shown that addition of 2’-FL to infant formula is safe and well tolerated by healthy infants
  
  Marriage, B. J., Buck, R. H., Goehring, K. C., Oliver, J. S., & Williams, J. A. (2015). Infants Fed a Lower Calorie Formula with 2 ′ FL Show Growth and 2 ′ FL Uptake Like Breast-Fed Infants. Journal of Pediatric Gastroenterology and Nutrition.https://doi.org/10.1097/MPG.0000000000000889
  Puccio, G., Alliet, P., Cajozzo, C., Janssens, E., Corsello, G., Sprenger, N., Wernimont, S., Egli, D., Gosoniu, L., & Steenhout, P. (2017). Effects of infant formula with human milk oligosaccharides on growth and morbidity: A randomized multicenter trial. Journal of Pediatric Gastroenterology and Nutrition.https://doi.org/10.1097/MPG.0000000000001520
  Vandenplas, Y., de Halleux, V., Arciszewska, M., Lach, P., Pokhylko, V., Klymenko, V., Schoen, S., Abrahamse-Berkeveld, M., Mulder, K. A., & Rubio, R. P. (2020). A partly fermented infant formula with postbiotics including 3′-GL, specific oligosaccharides, 2′-FL, and milk fat supports adequate growth, is safe and well-tolerated in healthy term infants: A double-blind, randomised, controlled, multi-country trial. Nutrients.https://doi.org/10.3390/nu12113560
  
  
  
• First efficacy outcomes from safety studies in infants suggest that 2’-FL can contribute to reducing the risk of respiratory tract infections
  
  Puccio, G., Alliet, P., Cajozzo, C., Janssens, E., Corsello, G., Sprenger, N., Wernimont, S., Egli, D., Gosoniu, L., & Steenhout, P. (2017). Effects of infant formula with human milk oligosaccharides on growth and morbidity: A randomized multicenter trial. Journal of Pediatric Gastroenterology and Nutrition.https://doi.org/10.1097/MPG.0000000000001520
  
  
  
  and can have immunomodulatory activity
  
  Goehring, K. C., Marriage, B. J., Oliver, J. S., Wilder, J. A., Barrett, E. G., & Buck, R. H. (2016). Similar to those who are breastfed, infants fed a formula containing 2’-fucosyllactose have lower inflammatory cytokines in a randomized controlled trial. Journal of Nutrition.https://doi.org/10.3945/jn.116.236919
  
  
  
• Pre-clinical research has shown a potential role of 2’-FL in brain development, cognition and learning
  
  Oliveros, E., Ramirez, M., Vazquez, E., Barranco, A., Gruart, A., Delgado-Garcia, J. M., Buck, R., Rueda, R., & Martin, M. J. (2016). Oral supplementation of 2’-fucosyllactose during lactation improves memory and learning in rats. Journal of Nutritional Biochemistry.https://doi.org/10.1016/j.jnutbio.2015.12.014
  Vazquez, E., Barranco, A., Ramirez, M., Gruart, A., Delgado-Garcia, J. M., Jimenez, M. L., Buck, R., & Rueda, R. (2016). Dietary 2′-fucosyllactose enhances operant conditioning and long-term potentiation via gut-brain communication through the vagus nerve in rodents. PLoS ONE.https://doi.org/10.1371/journal.pone.0166070
  Vázquez, E., Barranco, A., Ramírez, M., Gruart, A., Delgado-García, J. M., Martínez-Lara, E., Blanco, S., Martín, M. J., Castanys, E., Buck, R., Prieto, P., & Rueda, R. (2015). Effects of a human milk oligosaccharide, 2′-fucosyllactose, on hippocampal long-term potentiation and learning capabilities in rodents. Journal of Nutritional Biochemistry. https://doi.org/10.1016/j.jnutbio.2014.11.016.
  
  
  
• 2’-FL in breast milk has been positively associated with cognitive outcomes and motor skill scores in 18-month-old children
  
  Oliveros, E., Martin, M., Torres-Espinola, F. J., Segura-Moreno, T., Ramirez, M., Santos-Fandila, A., Buck, R., Rueda, R., Escudero, M., Catena, A., Azaryah, H., & Campoy, C. (2021). Human Milk Levels of 2´-Fucosyllactose and 6´-Sialyllactose are Positively Associated with Infant Neurodevelopment and are Not Impacted by Maternal BMI or Diabetic Status. Nutrition & Food Science.
  
  
  

• Lacto-N-Tetraose (LNT) is a non-fucosylated HMO
• Most abundant neutral non-fucosylated HMO in human milk
  
  Soyyilmaz, B., Mikš, M. H., Röhrig, C. H., Matwiejuk, M., Meszaros‐matwiejuk, A., & Vigsnæs, L. K. (2021). The mean of milk: A review of human milk oligosaccharide concentrations throughout lactation. Nutrients, 13(8), 1–22. https://doi.org/10.3390/nu13082737.
  
  
  
• Enhancement of beneficial Bifidobacteria growth in vitro
  
  Asakuma S, Hatakeyama E, Urashima T, et al. Physiology of consumption of human milk oligosaccharides by infant gut-associated ifidobacterial. J Biol Chem. Published online 2011. Doi:10.1074/jbc.M111.248138
  
  
  
• Pre-clinical research has shown that LNT can reduce growth, biofilm production and infectivity of Streptococcus Group B and Entamoeba histolytica
  
  Craft, K. M., Thomas, H. C., & Townsend, S. (2019). Sialylated Variants of Lacto-N-Tetraose Exhibit Antimicrobial Activity Against Group B Streptococcus. Organic & Biomolecular Chemistry, 17(7), 1893–1900. http://pubs.rsc.org/en/Content/ArticleLanding/2018/OB/C8OB02080A
  Lin, A. E., Autran, C. A., Szyszka, A., Escajadillo, T., Huang, M., Godula, K., Prudden, A. R., Boons, G. J., Lewis, A. L., Doran, K. S., Nizet, V., & Bode, L. (2017). Human milk oligosaccharides inhibit growth of group B Streptococcus. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.M117.789974
  
  
  
• Sample material available

• 3’-Sialyllactose (3’-SL) is an acidic HMO
• In vitro research indicated that 3’-SL has antiviral and antibacterial effects against rotavirus, RSV (respiratory syncytial virus), influenza virus and UPEC
  
  Duska-McEwen, G., Senft, A. P., Ruetschilling, T. L., Barrett, E. G., & Buck, R. H. (2014). Human Milk Oligosaccharides Enhance Innate Immunity to Respiratory Syncytial Virus and Influenza. Food and Nutrition Sciences, 5(14), 1387–1398.https://doi.org/10.4236/fns.2014.514151
  Laucirica, D. R., Triantis, V., Schoemaker, R., Estes, M. K., & Ramani, S. (2017). Milk Oligosaccharides Inhibit Human Rotavirus Infectivity in MA104 Cells. Journal of Nutrition, 147(9), 1709–1714.
  Martin-Sosa, Samuel, Maria-Jesus, Hueso, M. ;, & Pablo. (2002). The sialylated fraction of milk oligosaccharides is Partially Responsible for Binding to Enterotoxigenic and Uropathogenic Escherichia coli Human Strains. The Journal of Nutrition, 132(10), 3067–3072.
  Pandey, R. P., Kim, D. H., Woo, J., Song, J., Jang, S. H., Kim, J. B., Cheong, K. M., Oh, J. S., & Sohng, J. K. (2018). Broad-spectrum neutralization of avian influenza viruses by sialylated human milk oligosaccharides: in vivo assessment of 3′-sialyllactose against H9N2 in chickens. Scientific Reports, (1), 2563.https://doi.org/10.1038/s41598-018-20955-4
  
  
  
• Reduced inflammatory response was shown in pre-clinical experiments
  
  Hyder, A. (2020). Dietary oligosaccharides attenuate DSS-induced colitis in mice, induce PGlyRP3 expression, and inhibit NF-κB and MEK/ERK signaling. Cellular Immunology, 354(February), 104144.https://doi.org/10.1016/j.cellimm.2020.104144
  Kang, L.-J., Kwon, E.-S., Lee, K. M., Cho, C., Lee, J.-I., Ryu, Y. B., Youm, T. H., Jeon, J., Cho, M. R., Jeong, S., Lee, S.-R., Kim, W., & Yang, S. (2018). 3’-Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis. Br J Pharmacol, Epub.
  
  
  
• 3’-SL contains sialic acid which is involved in early life brain development
  
  Cho, S., Zhu, Z., Li, T., Baluyot, K., Howell, B. R., Hazlett, H. C., Elison, J. T., Hauser, J., Sprenger, N., Wu, D., & Lin, W. (2021). Human milk 3’-Sialyllactose is positively associated with language development during infancy. American Journal of Clinical Nutrition.https://doi.org/10.1093/ajcn/nqab103
  Jacobi, S. K., Yatsunenko, T., Li, D., Dasgupta, S., Yu, R. K., Berg, B. M., Chichlowski, M., & Odle, J. (2016). Dietary Isomers of Sialyllactose Increase Ganglioside Sialic Acid Concentrations in the Corpus Callosum and Cerebellum and Modulate the Colonic Microbiota of Formula-Fed Piglets1–3. The Journal of Nutrition, 146(2), 200–208.https://doi.org/10.3945/jn.115.220152
  Wang, B. (2012). Molecular mechanism underlying sialic acid as an essential nutrient for brain development and cognition. Advances in Nutrition.https://doi.org/10.3945/an.112.001875
  
  
  
• Levels of 3’-SL in breast milk have been associated positively with language development in infants
  
  Cho, S., Zhu, Z., Li, T., Baluyot, K., Howell, B. R., Hazlett, H. C., Elison, J. T., Hauser, J., Sprenger, N., Wu, D., & Lin, W. (2021). Human milk 3’-Sialyllactose is positively associated with language development during infancy. American Journal of Clinical Nutrition.https://doi.org/10.1093/ajcn/nqab103
  
  
  

With over 75 years of expertise in early life nutrition, we offer an industry-leading portfolio of oligosaccharides, along with a complete offering of nutritional ingredients for infant and young child milk formulas. Our fully owned and scalable HMO supply chain ensures the highest quality standards for dry-blend infant formula and has the flexibility to meet your needs as they evolve. We support leading global infant milk formula brands with our strong analytical expertise, helping to develop and validate analytical methods to ensure the right blend of HMOs and other ingredients for your product.