Human breast milk is known to be associated with a number of health benefits1-4, with recent evidence suggesting that many of these benefits are likely to be associated with human milk oligosaccharides (HMOs).5
Studies indicate that HMOs may play an important role in maintenance of health and prevention of disease.5 One important and abundant HMO, 2’-fucosyllactose (2’-FL), has been investigated in a number of studies, with recent studies in human infants showing supplemental 2’-FL to be well tolerated with promising signs of efficacy.6,7
The composition of HMO (types and quantity of various oligosaccharides) in human milk is influenced by maternal genetics, environmental factors and lactation stage.8,9
The concentration of major HMOs in human milk, except 3-FL, decreases during lactation.10,11 A study in Chinese women found that 2’-FL levels decreased from 2.5 g/L to 1.2 g/L during the first 6 months of lactation;10 another study followed HMO levels in breast milk of Malaysian women up to 1 year of lactation, and found the level of 2’-FL drops from 2.2 g/L at the start to 0.8 g/L after 1 year of lactation.11
Health benefits of 2’-FL
Effects on gut microbiota and infections
Studies suggest that 2’-fucosylated oligosaccharides, among which 2’-FL, drive colonization of the infant gut with bifidobacteria.15-18 (Figure 1). In vitro studies have shown that 2’-FL can be used as a substrate by bifidobacteria in the gut, thereby stimulating their growth16-17. In addition, clinical association studies indicate that infants receiving breast milk lacking 2’-FL show delayed establishment of bifidobacteria in the gut15-18. These data suggest that 2’-FL plays an important role in shaping a healthy gut microbiota composition early in life.
Figure 1. By serving as a substrate, 2’-FL gives bifidobacteria a competitive advantage for growth in the gut.15,16
In vitro studies showed that 2’-FL can inhibit enteric (e.g. norovirus, EPEC, Campylobacter, Salmonella) and respiratory pathogens (Pseudomonas aeruginosa) from adhering to human epithelial cell lines.19 Another study showed 2’-FL reduced the infectivity of human rotaviruses, an effect that was attributed to interaction directly between the oligosaccharide and the virus.20 (Figure 2)
Figure 2. By serving as a decoy receptor, 2’-FL can inhibit binding and infectivity of pathogens.
High levels of 2’-FL in breast milk have been shown to be protective against diarrhoea associated with specific pathogens.12 More specifically, rates of C. jejuni diarrhoea during breastfeeding were shown to be inversely associated with 2’-FL as a percentage of milk oligosaccharides. Compared with infants fed milk with medium and high levels of 2’-FL, infants receiving milk with low levels of 2’-FL had significantly higher rates of Campylobacter diarrhoea during breastfeeding. Overall, a significant inverse association was found between total 2-linked fucosylated oligosacchardes as a percentage of HMO and rates of all moderate-to-severe diarrhoea during breastfeeding.
Effects on allergy
An animal study on food allergy revealed that 2 HMOs—neutral 2’-FL and acidic 6’-sialyllactose—led to significant attenuation of intestinal allergy.21 Additional evidence for a role of HMOs in allergy comes from an association study conducted in infants at elevated risk of allergic disease, with results showing that eczema was more likely at age 2, but not at age 5, among those born by C-section who received milk lacking in 2’-FL.22 It needs to be noted, however, that a recent study did not find such an association between 2’-FL level in human milk and cow’s milk allergy risk in infants.23
Anti-inflammatory effects of 2’-FL
Evidence also suggests that HMOs, especially 2’-FL, may have anti-inflammatory effects.24 A study on necrotizing enterocolitis (NEC) showed that rats receiving HMOs with their formula had an average pathology score that did not differ from disease-free rats, and was significantly lower than the standard formula-fed NEC controls.24 Addition of 2’-FL alone to formula was also associated with significantly lower pathology scores than those in the formula-fed rats, but pathology scores remained higher than those in the disease-free rats and in the HMO group. Although these results look promising, it has to be noted that another recent animal study did not show an effect of 2’-FL on NEC development. In a preterm piglet model, 2’-FL supplementation had no effect on intestinal structure and digestive function, and no effect on NEC incidence.25 A recent association study showed that the DSLNT (disialyl-lacto-N-tetraose) content in human milk is associated with a reduced risk of NEC development in preterms, not the 2’-FL content.26 These results suggest that other HMOs may play a more important role in NEC prevention.
Effects on cognition
Preclinical studies have also demonstrated that 2’-FL is able to enhance memory and learning;27,28 rats fed 2’-FL had increased long-term potentiation at the hippocampus. Moreover, there was evidence in these animals of enhanced memory consolidation, spatial learning and associative learning.
Clinical studies show 2’-FL safe, well-tolerated
While much of the evidence for the health benefits of 2’-FL comes from in vitro and in vivo studies, there is also a number of clinical studies involving children and adults that showed the first evidence of both good tolerability and potential efficacy of 2’-FL supplementation.6,7,29,30
In a study involving 420 infants, 2’-FL supplementation (0.2 or 1.0 g/L) was found to be well-tolerated.7 Post-hoc analysis on this study revealed that infants receiving 0.2 g/L 2’-FL had a significantly reduced incidence of respiratory infections as compared to the control group7. This effect was not seen in the group receiving 1.0 g/L 2’-FL.31 In a further analysis of the same study, the effect of 2’-FL on plasma inflammatory markers was examined. Compared with infants who received the control formula, those who received 2’-FL-containing formula had significantly lower plasma inflammatory cytokines, which resembled closely the levels found in breastfed infants.29 In another multi-center, randomized, double-blind trial, 2 parallel groups of formula-fed infants received control formula or formula supplemented with 2’-FL and lacto-N-neotetraose (LNnT).6 2’-FL and LnNT were shown to be safe, well-tolerated and to support age-appropriate growth. Moreover, secondary outcome findings of lower morbidity (particularly bronchitis) and medication use (antipyretics and antibiotics) were reported in infants fed supplemented formula. Also, this study showed that the addition of 2’FL and LNnT to infant formula shifted the stool microbiota towards that observed in breastfed infants, both in composition and function.32
Recently, 2 short tolerance trials with formula containing 2′-FL were reported in infants.31,33 Both of the 1 month-studies showed that a formula supplemented with 2′-FL was safe and well tolerated.
In addition to these studies in infants, a randomized, double-blind, placebo-controlled study examined the effect of HMO supplementation in healthy adults (2’-FL, LNnT or their combination). When given at daily doses of up to 20 g for 2 weeks, 2’-FL and LNnT were safe and well tolerated. Furthermore, HMO supplementation led to modifications in gut microbiota: in this study, 2’-FL increased actinobacteria and Bifidobacterium, and more specifically increased Bifidobacterium adolescentis.30
To conclude, current clinical evidence on the benefits of 2′-FL looks promising. It is expected that additional studies will be performed in the near future to try and confirm the beneficial effects of 2′-FL on microbiota composition, infection and inflammation, cognition and allergy prevention that were observed in preclinical studies.
Early clinical trials indicate that 2’-FL is safe and well tolerated. 6,7,29,30,31,33
Preclinical and human association studies suggest that 2’-FL may contribute to:
- Reduction of infections12,19,20
- Stimulation of healthy gut microbiota (prebiotic effect)15-18
- Reduction of the risk of developing allergy21,22
Currently, there is limited evidence available from clinical studies in infants on the health benefits of 2’-FL:
- 1 g/L 2’-FL (in combination with LNnT) may reduce lower respiratory tract infections and medication use6
- 1 g/L 2’-FL (in combination with LNnT) may stimulate a healthy gut microbiota6,32
- 2 g/L 2’-FL may reduce respiratory infections, whereas 1.0 g/L 2’-FL may not7,31
- Blaymore Bier, J.A., et al., Human milk reduces outpatient upper respiratory symptoms in premature infants during their first year of life. J Perinatol, 2002. 22(5): p. 354-9.
- Duijts, L., et al., Prolonged and exclusive breastfeeding reduces the risk of infectious diseases in infancy. Pediatrics, 2010. 126(1): p. e18-25.
- Ip, S., et al., Breastfeeding and maternal and infant health outcomes in developed countries. Evid Rep Technol Assess (Full Rep), 2007(153): p. 1-186.
- Sisk, P.M., et al., Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants. J Perinatol, 2007. 27(7): p. 428-33.
- Bode, L., Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology, 2012. 22(9): p. 1147-62.
- Puccio, G., et al., Effects of Infant Formula With Human Milk Oligosaccharides on Growth and Morbidity: A Randomized Multicenter Trial. J Pediatr Gastroenterol Nutr, 2017. 64(4): p. 624-631.
- Marriage, B.J., 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): p. 649-58.
- Bode, L. and E. Jantscher-Krenn, Structure-function relationships of human milk oligosaccharides. Adv Nutr, 2012. 3(3): p. 383S-91S.
- McGuire, M.K., et al., What’s normal? Oligosaccharide concentrations and profiles in milk produced by healthy women vary geographically. Am J Clin Nutr, 2017. 105(5): p. 1086-1100.
- Austin, S., et al., Temporal Change of the Content of 10 Oligosaccharides in the Milk of Chinese Urban Mothers. Nutrients, 2016. 8(6).
- Ma, L., et al. Lactational changes in the human milk oligosaccharide concentration in Chinese and Malaysian mothers’ milk. Int Dairy J, 2018. 87: p.1-10.
- Morrow, A.L., et al., Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. J Pediatr, 2004. 145(3): p. 297-303.
- Bode, L., The functional biology of human milk oligosaccharides. Early Hum Dev, 2015. 91(11): p. 619-22.
- Donovan, S.M. and S.S. Comstock, Human Milk Oligosaccharides Influence Neonatal Mucosal and Systemic Immunity. Annals of Nutrition and Metabolism, 2016. 69(suppl 2)(Suppl. 2): p. 41-51.
- Lewis, Z.T., et al., Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants. Microbiome, 2015. 3: p. 13.
- Yu, Z.T., et al., The principal fucosylated oligosaccharides of human milk exhibit prebiotic properties on cultured infant microbiota. Glycobiology, 2013. 23(2): p. 169-77.
- Matsuki, T., et al., A key genetic factor for fucosyllactose utilization affects infant gut microbiota develop ment. Nat Commun, 2016. 7: p. 11939.
- Bai, Y., et al., Fucosylated Human Milk Oligosaccharides and N-Glycans in the Milk of Chinese Mothers Regulate the Gut Microbiome of Their Breast-Fed Infants during Different Lactation Stages. mSystems, 2018: 3(6): p. 1-19.
- Weichert, S., et al., Bioengineered 2′-fucosyllactose and 3-fucosyllactose inhibit the adhesion of Pseudomonas aeruginosa and enteric pathogens to human intestinal and respiratory cell lines. Nutr Res, 2013. 33(10): p. 831-8.
- Laucirica, D.R., et al., Milk Oligosaccharides Inhibit Human Rotavirus Infectivity in MA104 Cells. J Nutr, 2017.
- Castillo-Courtade, L., et al., Attenuation of food allergy symptoms following treatment with human milk oligosaccharides in a mouse model. Allergy, 2015. 70(9): p. 1091-102.
- Sprenger, N., et al., FUT2-dependent breast milk oligosaccharides and allergy at 2 and 5 years of age in infants with high hereditary allergy risk. Eur J Nutr, 2017. 56(3): p. 1293-301.
- Seppo, A.E., et al., Human milk oligosaccharides and development of cow’s milk allergy in infants. J Allergy Clin Immunol, 2017: 139(2): p. 708-11.
- Autran, C.A., et al., Sialylated galacto-oligosaccharides and 2′-fucosyllactose reduce necrotising enterocolitis in neonatal rats. Br J Nutr, 2016. 116(2): p. 294-9.
- Cilieborg, M.S., et al., Minimal short-term effect of dietary 2′-fucosyllactose on bacterial colonisation, intestinal function and necrotising enterocolitis in preterm pigs. Br J Nutr, 2016. 116(5): p. 834-41.
- Autran., C.A., et al., Human milk oligosaccharide composition predicts risk of necrotising enterocolitis in preterm infants. Gut, 2017.
- Vazquez, E., et al., Effects of a human milk oligosaccharide, 2′-fucosyllactose, on hippocampal long-term potentiation and learning capabilities in rodents. J Nutr Biochem, 2015. 26(5): p. 455-65.
- Oliveros, E., et al., Oral supplementation of 2′-fucosyllactose during lactation improves memory and learning in rats. J Nutr Biochem, 2016. 31: p. 20-7.
- Goehring, K.C., et al., Similar to Those Who Are Breastfed, Infants Fed a Formula Containing 2′-Fucosyl lactose Have Lower Inflammatory Cytokines in a Randomized Controlled Trial. J Nutr, 2016. 146(12): p. 2559-66.
- Elison, E., et al., Oral supplementation of healthy adults with 2′-O-fucosyllactose and lacto-N-neotetraose is well tolerated and shifts the intestinal microbiota. Br J Nutr, 2016. 116(8): p. 1356-68.
- Reverri, E.J, et al., Review of the Clinical Experiences of Feeding Infants Formula Containing the Human Milk Oligosaccharide 2’-Fucosyllactose. Nutrients: 2018: 10(1346): p. 1-11.
- Alliet. P. et al., Term infant formula supplemented with human milk oligosaccharides (2’fucosyllactose and lactoneotetraose) shifts stoom microbiota and metabolic signatures closer to that of breastfed infants. JPGN, 2016: Volume 63, Supplement 1, p. 55.
- Kajser, J., et al., Gastrointestinal Tolerance of Formula Supplemented with Oligosaccharides. Faseb J 2016: 30, 671.
*Some parts of this article was first published in a FrieslandCampina Ingredients brochure “The Science of HMO and 2-FL”.