Wikipedia

Human milk oligosaccharide

Human milk oligosaccharides (HMOs), also known as human milk glycans, are short polymers of simple sugars that can be found in high concentrations in human breast milk.[1] Human milk oligosaccharides promote the development of the immune system, can reduce the risk of pathogen infections and improve brain development and cognition.[1] The HMO profile of human breast milk shapes the gut microbiota of the infant by selectively stimulating bifidobacteria and other bacteria.[2]

Functions

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Chemical structure of 2'-fucosyllactose consisting of lactose and fucose subunits

In contrast to the other components of breast milk that are absorbed by the infant through breastfeeding, HMOs are indigestible for the nursing child. However, they have a prebiotic effect and serve as food for intestinal bacteria, especially bifidobacteria.[3] The dominance of these intestinal bacteria in the gut reduces the colonization with pathogenic bacteria (probiosis) and thereby promotes a healthy intestinal microbiota and reduces the risk of dangerous intestinal infections. Recent studies suggest that HMOs significantly lower the risk of viral and bacterial infections and thus diminish the chance of diarrhoea and respiratory diseases.

This protective function of the HMOs is activated when in contact with specific pathogens, such as certain bacteria or viruses. These have the ability to bind themselves to the glycan receptors (receptors for long chains of connected sugar molecules on the surface of human cells) located on the surface of the intestinal cells and can thereby infect the cells of the intestinal mucosa. Researchers have discovered that HMOs mimic these glycan receptors so the pathogens bind themselves to the HMOs rather than the intestinal cells. This reduces the risk of an infection with a pathogen.[1][4] It has also been demonstrated that HMOs can bind to several intestinal viruses, such as norovirus and Norwalk virus, moreover they can reduce the virus load from influenza and RSV.[5]

In addition to this, HMOs seem to influence the reaction of specific cells of the immune system in a way that reduces inflammatory responses.[1][6] It is also suspected that HMOs reduce the risk of premature infants becoming infected with the potentially life-threatening disease necrotizing enterocolitis (NEC).[1]

Some of the metabolites directly affect the nervous system or the brain and can sometimes influence the development and behavior of children in the long term. There are studies that indicate certain HMOs supply the child with sialic acid residues. Sialic acid is an essential nutrient for the development of the child’s brain and mental abilities.[1][6]

In experiments designed to test the suitability of HMOs as a prebiotic source of carbon for intestinal bacteria it was discovered that they are highly selective for a commensal bacteria known as Bifidobacteria longum biovar infantis. The presence of genes unique to B. infantis, including co-regulated glycosidases, and its efficiency at using HMOs as a carbon source may imply a co-evolution of HMOs and the genetic capability of select bacteria to utilize them.[7]

Occurrence

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Milk oligosaccharides seem to be more abundant in humans than in other animals and to be more complex and varied.[8] Oligosaccharides in primate milk are generally more complex and diverse than in non-primates.[1]

Human milk oligosaccharides (HMOs) form the third most abundant solid component (dissolved or emulsified or suspended in water) of human milk, after lactose and fat.[9] HMOs are present in a concentration of 11.3 – 17.7 g/L (1.5 oz/gal – 2.36 oz/gal) in human milk, depending on lactation stages.[10] Approximately 200 structurally different human milk oligosaccharides are known, and they can be categorized into fucosylated, sialylated and neutral core HMOs. The composition of human milk oligosaccharides in breast milk is individual to each mother and varies over the period of lactation. The dominant oligosaccharide in 80% of all women is 2′-fucosyllactose, which is present in human breast milk at a concentration of approximately 2.5 g/L;[4] other abundant oligosacchadies include lacto-N-tetraose, lacto-N-neotetraose, and lacto-N-fucopentaose.[11] It has been found by numerous studies that the concentration of each individual human milk oligosaccharide changes throughout the different periods of lactation (colostrum, transitional, mature and late milk) and depend on various factors such as the mother's genetic secretor status and length of gestation.[10]

Mean concentrations of the most abundant HMOs by lactation stage in [g/L] (pooled HMO means from 31 countries) [10]
Abbreviation Name Colostrum (0–5 days) Transitional (6–14 days) Mature (15–90 days) Late (>90 days)
2'FL 2'-Fucosyllactose 3.18 2.07 2.28 1.65
LNDFH-I Lacto-N-difucohexaose I 1.03 1.06 1.10 0.87
LNFP-I Lacto-N-fucopentaose I 0.83 1.11 0.83 0.41
LNFP-II Lacto-N-fucopentaose II 0.78 0.33 0.78 0.27
LNT Lacto-N-tetraose 0.73 1.07 0.74 0.64
3-FL 3-Fucosyllactose 0.72 0.59 0.72 0.92
6'-SL 6'-Sialyllactose 0.40 0.71 0.40 0.30
DSLNT Disialyllacto-N-tetraose 0.38 0.67 0.38 0.22
LNnT Lacto-N-neotetraose 0.37 0.47 0.37 0.19
DFL Difucosyllactose 0.29 0.56 0.29 0.27
FDS-LNH Fucosyldisialyllacto-N-hexaose I 0.28 N/A 0.29 0.12
LNFP-III Lacto-N-fucopentaose III 0.26 0.37 0.26 0.23
3'SL 3'-Sialyllactose 0.19 0.13 0.19 0.13

Applications

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  • Infant formula: Historically HMOs were not part of infant formula, and bottle-fed babies could not benefit from their positive health effects. However recently more and more HMOs, including 2'-Fucosyllactose and Lacto-N-neotetraose, are being added as supplements to modern infant formula.[12][13] Recently an infant formula with a combination of 5 different HMOs (2′-fucosyllactose, 2′,3-di-fucosyllactose, lacto-N-tetraose, 3′-sialyllactose, and 6′-sialyllactose) was tested in a clinical trial with positive effects on gut microflora.[14] However it is important to note that even this type of infant formula is far from the natural abundance of nearly 200 HMOs present in human milk.
  • Irritable bowel syndrome: Human milk oligosaccharides are also used to treat the symptoms of irritable bowel syndrome (IBS), which is a gastrointestinal disorder affecting 10–15% of the developed world. A 12-week treatment with an orally taken HMO mixture showed significant improvement of the life quality of IBS patients.[15]

Synthesis

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Biosynthesis in humans

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All HMOs derive from lactose, which can be decorated by four monosaccharides (N-acetyl-D-glucosamine, D-galactose, sialic acid and/or L-fucose) to form an oligosaccharide.[10] The HMO variability in human mothers depend on two specific enzymes, the α1-2-fucosyltransferase (FUT2) and the α1-3/4-fucosyltransferase (FUT3).[16] The milk of mothers with inactivated FUT2 enzyme do not contain α1-2-fucosylated HMOs, and likewise with inactivated FUT3 enzyme there can be almost no α1-4-fucasylated HMOs found. Typically 20% of the global population of mothers do not have active FUT2 enzyme, but still have an active FUT3 enzyme, whereas 1% of mothers express neither FUT2 nor FUT3 enzymes.[17]

Milk groups according to Lewis and Secretor status [17]
Milk group Genetic classification Lewis status (FUT3 enzyme presence) Secretor status (FUT2 enzyme presence) Main HMOs secreted Estimated global frequency
1 Lewis positive, Secretor Yes Yes 2'FL, 3-FL, DFL, LNT, LNnT, LNFP-I, LNFP-II, LNDFH-I, LNDFH-II 70%
2 Lewis positive, Non-secretor Yes No 3-FL, LNT, LNnT, LNFP-II, LNFP-III, LNDFH-II 20%
3 Lewis negative, Secretor No Yes 2'FL, 3-FL, DFL, LNT, LNnT, LNFP-I, LNFP-III 9%
4 Lewis negative, Non-secretor No No 3-FL, LNT, LNnT, LNFP-III, LNFP-V 1%

Industrial large-scale synthesis

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Human milk oligosaccharides can be synthesized in large quantities using precision industrial fermentation methods e.g. by the commonly used, non-pathogenic bacteria Escherichia coli.[18] During the fermentation process the bacteria are fed with a carbon-source (e.g. glucose), salts, minerals and trace elements under aseptic conditions in a stainless steel bioreactor, while lactose is added to the process as precursor molecule. Bacteria are then converting the lactose into human milk oligosaccharides by decorating it with other sugar monomers. After the fermentation process the HMOs are completely separated from the bacteria, proteins and DNA using different filtration techniques.[18] Subsequently the HMOs are purified, crystallized, dried, packaged and delivered to infant formula manufacturers where they are mixed with other components of infant formula.[18]

Enzymatic synthesis

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Enzymatic synthesis of HMOs through transgalactosylation is an efficient way for production. Various donors, including p-nitrophenyl-β-galactopyranoside, uridine diphosphate galactose and lactose, can be used in transgalactosylation. In particular, lactose may act as either a donor or an acceptor in a variety of enzymatic reactions and is available in large quantities from the whey produced as a co-processing product from cheese production. There is a lack of published data, however, describing the large-scale production of such galacto-oligosaccharides.[19]

References

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  1. ^ a b c d e f g Bode, L. (2012). "Human milk oligosaccharides: every baby needs a sugar mama". Glycobiology. 22 (9): 1147–1162. doi:10.1093/glycob/cws074. PMC 3406618. PMID 22513036.
  2. ^ Bezirtzoglou, Eugenia; Tsiotsias, Arsenis; Welling, Gjalt W. (December 2011). "Microbiota profile in feces of breast- and formula-fed newborns by using fluorescence in situ hybridization (FISH)". Anaerobe. 17 (6): 478–482. doi:10.1016/j.anaerobe.2011.03.009. ISSN 1075-9964. PMID 21497661.
  3. ^ Doare, K. Le; Holder, B.; Bassett, A.; Pannaraj, P. S. (2018). "Mother's Milk: A Purposeful Contribution to the Development of the Infant Microbiota and Immunity". Frontiers in Immunology. 9: 361. doi:10.3389/fimmu.2018.00361. PMC 5863526. PMID 29599768.
  4. ^ a b Katja Parschat, Bettina Gutiérrez (November 2016), "Fermentativ erzeugte humane Milch-Oligosaccharide wirken präbiotisch.", Dei – die Ernährungsindustrie (in German), p. 38
  5. ^ Triantis, Vassilis; Bode, Lars; van Neerven, R. J. Joost (2018). "Immunological Effects of Human Milk Oligosaccharides". Frontiers in Pediatrics. 6: 190. doi:10.3389/fped.2018.00190. ISSN 2296-2360. PMC 6036705. PMID 30013961.
  6. ^ a b Newburg, D. S.; He, Y. (2015). "Neonatal Gut Microbiota and Human Milk Glycans Cooperate to Attenuate Infection and Inflammation". Clinical Obstetrics and Gynecology. 58 (4): 814–826. doi:10.1097/GRF.0000000000000156. PMID 26457857.
  7. ^ German, JB; Lebrilla, CB; Mills, DA (18 Apr 2012). Human milk oligosaccharides: evolution, structures and bioselectivity as substrates for intestinal bacteria. Nestlé Nutrition Workshop Series: Pediatric Program. Vol. 62. pp. 205–22. doi:10.1159/000146322. ISBN 978-3-8055-8553-8. PMC 2861563. PMID 18626202. {{cite book}}: |journal= ignored (help)
  8. ^ Nannan Tao; et al. (Apr 1, 2012). "Evolutionary Glycomics: Characterization of Milk Oligosaccharides in Primates". J Proteome Res. 10 (4): 1548–1557. doi:10.1021/pr1009367. PMC 3070053. PMID 21214271.
  9. ^ Chen, X. (2015). "Human Milk Oligosaccharides (HMOS): Structure, Function, and Enzyme-Catalyzed Synthesis". Advances in Carbohydrate Chemistry and Biochemistry. 72: 113–190. doi:10.1016/bs.accb.2015.08.002. PMC 9235823. PMID 26613816.
  10. ^ a b c d Soyyılmaz, Buket; Mikš, Marta Hanna; Röhrig, Christoph Hermann; Matwiejuk, Martin; Meszaros-Matwiejuk, Agnes; Vigsnæs, Louise Kristine (2021-08-09). "The Mean of Milk: A Review of Human Milk Oligosaccharide Concentrations throughout Lactation". Nutrients. 13 (8): 2737. doi:10.3390/nu13082737. ISSN 2072-6643. PMC 8398195. PMID 34444897.
  11. ^ Miesfeld, Roger L. (July 2017). Biochemistry. McEvoy, Megan M. (First ed.). New York, NY. ISBN 978-0-393-61402-2. OCLC 952277065.{{cite book}}: CS1 maint: location missing publisher (link)
  12. ^ Ralph Ammann (May 2017), "Achieving the impossible", European Dairy Magazine (in German), pp. 30 f
  13. ^ Wiciński, Michał; Sawicka, Ewelina; Gębalski, Jakub; Kubiak, Karol; Malinowski, Bartosz (2020-01-20). "Human Milk Oligosaccharides: Health Benefits, Potential Applications in Infant Formulas, and Pharmacology". Nutrients. 12 (1): 266. doi:10.3390/nu12010266. ISSN 2072-6643. PMC 7019891. PMID 31968617.
  14. ^ Bosheva, Miroslava; Tokodi, Istvan; Krasnow, Aleksander; Pedersen, Helle Krogh; Lukjancenko, Oksana; Eklund, Aron C.; Grathwohl, Dominik; Sprenger, Norbert; Berger, Bernard; Cercamondi, Colin I.; 5 HMO Study Investigator Consortium (2022-07-06). "Infant Formula With a Specific Blend of Five Human Milk Oligosaccharides Drives the Gut Microbiota Development and Improves Gut Maturation Markers: A Randomized Controlled Trial". Frontiers in Nutrition. 9: 920362. doi:10.3389/fnut.2022.920362. ISSN 2296-861X. PMC 9298649. PMID 35873420.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  15. ^ Palsson, Olafur S.; Peery, Anne; Seitzberg, Dorthe; Amundsen, Ingvild Dybdrodt; McConnell, Bruce; Simrén, Magnus (2020-12-07). "Human Milk Oligosaccharides Support Normal Bowel Function and Improve Symptoms of Irritable Bowel Syndrome: A Multicenter, Open-Label Trial". Clinical and Translational Gastroenterology. 11 (12): e00276. doi:10.14309/ctg.0000000000000276. ISSN 2155-384X. PMC 7721220. PMID 33512807.
  16. ^ M. Tonon, Karina; B. de Morais, Mauro; F. V. Abrão, Ana Cristina; Miranda, Antonio; B. Morais, Tania (2019-06-17). "Maternal and Infant Factors Associated with Human Milk Oligosaccharides Concentrations According to Secretor and Lewis Phenotypes". Nutrients. 11 (6): 1358. doi:10.3390/nu11061358. ISSN 2072-6643. PMC 6628139. PMID 31212920.
  17. ^ a b Stahl, B.; Thurl, S.; Henker, J.; Siegel, M.; Finke, B.; Sawatzki, G. (2001), "Detection of Four Human Milk Groups with Respect to Lewis-Bloodgroup-Dependent Oligosaccharides by Serologic and Chromatographic Analysis", Bioactive Components of Human Milk, Advances in Experimental Medicine and Biology, vol. 501, Boston, MA: Springer US, pp. 299–306, doi:10.1007/978-1-4615-1371-1_37, ISBN 978-1-4613-5521-2, PMID 11787693, retrieved 2021-12-10
  18. ^ a b c Bych, Katrine; Mikš, Marta Hanna; Johanson, Ted; Hederos, Markus Jondelius; Vigsnæs, Louise Kristine; Becker, Peter (2019-04-01). "Production of HMOs using microbial hosts — from cell engineering to large scale production". Current Opinion in Biotechnology. Food Biotechnology • Plant Biotechnology. 56: 130–137. doi:10.1016/j.copbio.2018.11.003. ISSN 0958-1669. PMID 30502637. S2CID 56149182.
  19. ^ Karimi Alavijeh, M.; Meyer, A.S.; Gras, S.L.; Kentish, S.E. (February 2020). "Simulation and economic assessment of large-scale enzymatic N-acetyllactosamine manufacture" (PDF). Biochemical Engineering Journal. 154: 107459. doi:10.1016/j.bej.2019.107459. S2CID 214143153.
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