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How Human Milk Oligosaccharides support Immunity?

Breast milk plays an important role in the development of mature immune responses in babies during early life.(1) Human milk oligosaccharides (HMOs), which are the third largest solid component in breast milk(2, 3), are thought to be partly responsible for some of the immune benefits, which are associated with breastfeeding, including diarrhoea and respiratory infections.(4-6)
What is known about the mechanisms how HMOs support immunity? Among their various functions, research suggests that HMOs support immunity in 4 main ways as listed below:

1.Promote the growth of certain beneficial bacteria, including certain bifidobacteria

During early life, the development of a protective commensal gut microbiota is necessary for the maturation of the infants’ immature immune system.(1, 7, 8) Breastfed infants have a high abundance of beneficial gut bacteria, such as bifidobacteria.(1, 9)
Research suggests that HMOs serve as food for the selective growth and metabolic activity of certain beneficial gut bacteria and provide them with a growth advantage over potential pathogens.(3, 10-12) From experimental studies, it is known that potentially pathogenic strains of Enterobacteriaceae, Escherichia coli and Clostridia do not grow on HMOs.(3, 11, 13)

2. Prevent pathogens from binding to the intestinal wall, which reduce their ability to infect the infant

Many viruses, bacterial pathogens or toxins need to adhere to receptors on mucosal surfaces like the intestinal or respiratory epithelial cells, to colonise or invade the infant and cause diseases.(14) Some HMOs, especially fucosylated HMOs, are structurally similar to these receptors, and serve as decoy receptors to prevent pathogen binding and enhance pathogen clearance.(3, 12) This unique decoy effect depends on the structure of HMOs(15), and the effect has been shown for 2′FL and LNnT in experimental studies.(16, 17)

3.Assist gut barrier function, which improve innate immunity

HMOs can increase intestinal cell barrier function, reduce cell growth, induce cell differentiation, cell maturation and cell death, as shown in experimental studies.(14, 18, 19) HMOs can directly affect intestinal cells and modulate their receptors on the cell surface. This can be an alternative mechanism to prevent pathogen attachment, thereby strengthening gut barrier function.(3) Intestinal health and intestinal barrier function are the first defence line in innate immunity.(14)

4.Directly modulate the immune system, which helps educate the developing immune system

An increasing number of experimental studies suggest that HMOs not only affect the infants’ immune system indirectly by changing gut microbiota, but also directly modulate immune responses by affecting immune cell populations and cytokine secretion.(20, 21) HMOs may either act locally on cells of the gut mucosa-associated lymphoid tissues or on a systemic level, thereby driving immune maturation.(3, 20)

In conclusion, HMOs support the development of babies’ immature immune system in many ways, which seem to be specific to the unique structure of HMOs.

Professor Clemens Kunz, University Giessen, Germany

The current research interest is focused on potential systemic functions of HMOs, beyond their local effects on the gastrointestinal tract. This interest is based on the discovery that multiple HMOs can be detected in the urine of breastfed infants. By applying the stable isotope technique, it is possible to mark HMOs and track their metabolic pathway in the infant. This has allowed us to show that small amounts of certain HMOs are absorbed in quantities that may be sufficient for inducing systemic effects. Therefore, the potential of HMOs to influence diseases, such as allergies or infections, is intriguing and should be investigated as it offers a new preventive strategy for certain diseases.

References

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2.Zivkovic AM, German JB, Lebrilla CB, Mills DA. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci USA. 2011;108 (Suppl 1):4653-8.
3.Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012;22(9):1147-62.
4.Horta BL, Victora CG. Short-term effects of breastfeeding: a systematic review on the benefits of breastfeeding on diarrhoea and pneumonia mortality.: World Health Organisation; 2013.
5.Bachrach VR, Schwarz E, Bachrach LR. Breastfeeding and the risk of hospitalization for respiratory disease in infancy: a meta-analysis. Arch Pediatr Adolesc Med. 2003;157(3):237-43.
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11.Yu ZT, Chen C, Newburg DS. Utilization of major fucosylated and sialylated human milk oligosaccharides by isolated human gut microbes. Glycobiology. 2013;23(11):1281-92.
12.Morozov V, Hansman G, Hanisch FG, Schroten H, Kunz C. Human Milk Oligosaccharides as Promising Antivirals. Mol Nutr Food Res. 2018;62(6):e1700679.
13.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.
14.Vandenplas Y, Berger B, Carnielli VP, Ksiazyk J, Lagstrom H, Sanchez Luna M, et al. Human milk oligosaccharides: 2'-fucosyllactose (2'-FL) and lacto-N-neotetraose (LNnT) in infant formula. Nutrients. 2018;10(9):1161.
15.Bode L, Jantscher-Krenn E. Structure-function relationships of human milk oligosaccharides. Adv Nutr. 2012;3(3):383S-91S.
16.Ruiz-Palacios GM, Cervantes LE, Ramos P, Chavez-Munguia B, Newburg DS. Campylobacter jejuni binds intestinal H(O) antigen (Fuc alpha 1, 2Gal beta 1, 4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. J Biol Chem. 2003;278(16):14112-20.
17.Idanpaan-Heikkila I, Simon PM, Zopf D, Vullo T, Cahill P, Sokol K, et al. Oligosaccharides interfere with the establishment and progression of experimental pneumococcal pneumonia. J Infect Dis. 1997;176(3):704-12.
18.Kuntz S, Kunz C, Rudloff S. Oligosaccharides from human milk induce growth arrest via G2/M by influencing growth-related cell cycle genes in intestinal epithelial cells. Br J Nutr. 2009;101(9):1306-15.
19.Kuntz S, Rudloff S, Kunz C. Oligosaccharides from human milk influence growth-related characteristics of intestinally transformed and non-transformed intestinal cells. Br J Nutr. 2008;99(3):462-71.
20.Donovan SM, Comstock SS. Human milk oligosaccharides influence neonatal mucosal and systemic immunity. Ann Nutr Metab. 2016;69 (Suppl 2):42-51.
21.Kunz C, Rudloff S. Compositional analysis and metabolism of human milk oligosaccharides in infants. Nestle Nutr Inst Workshop Ser. 2017;88:137-47.
 

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