Human milk oligosaccharide

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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]

Contents

Functions

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

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]
AbbreviationNameColostrum (0–5 days)Transitional (6–14 days)Mature (15–90 days)Late (>90 days)
2'FL 2'-Fucosyllactose 3.182.072.281.65
LNDFH-I Lacto-N-difucohexaose I 1.031.061.100.87
LNFP-I Lacto-N-fucopentaose I 0.831.110.830.41
LNFP-II Lacto-N-fucopentaose II 0.780.330.780.27
LNT Lacto-N-tetraose 0.731.070.740.64
3-FL 3-Fucosyllactose 0.720.590.720.92
6'-SL 6'-Sialyllactose 0.400.710.400.30
DSLNT Disialyllacto-N-tetraose 0.380.670.380.22
LNnT Lacto-N-neotetraose 0.370.470.370.19
DFL Difucosyllactose 0.290.560.290.27
FDS-LNH Fucosyldisialyllacto-N-hexaose I 0.28N/A0.290.12
LNFP-III Lacto-N-fucopentaose III 0.260.370.260.23
3'SL 3'-Sialyllactose 0.190.130.190.13

Applications

Synthesis

Biosynthesis in humans

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 groupGenetic classificationLewis status (FUT3 enzyme presence)Secretor status (FUT2 enzyme presence)Main HMOs secretedEstimated global frequency
1Lewis positive, SecretorYesYes2'FL, 3-FL, DFL, LNT, LNnT, LNFP-I, LNFP-II, LNDFH-I, LNDFH-II70%
2Lewis positive, Non-secretorYesNo3-FL, LNT, LNnT, LNFP-II, LNFP-III, LNDFH-II20%
3Lewis negative, SecretorNoYes2'FL, 3-FL, DFL, LNT, LNnT, LNFP-I, LNFP-III9%
4Lewis negative, Non-secretorNoNo3-FL, LNT, LNnT, LNFP-III, LNFP-V1%

Industrial large-scale synthesis

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

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]

Related Research Articles

<span class="mw-page-title-main">Infant formula</span> Manufactured food designed for feeding infants

Infant formula, also called baby formula, simply formula, baby milk or infant milk, is designed and marketed for feeding to babies and infants under 12 months of age, usually prepared for bottle-feeding or cup-feeding from powder or liquid. The U.S. Federal Food, Drug, and Cosmetic Act (FFDCA) defines infant formula as "a food which purports to be or is represented for special dietary use solely as a food for infants by reason of its simulation of human milk or its suitability as a complete or partial substitute for human milk".

<span class="mw-page-title-main">Oligosaccharide</span> Saccharide polymer

An oligosaccharide is a saccharide polymer containing a small number of monosaccharides. Oligosaccharides can have many functions including cell recognition and cell adhesion.

<span class="mw-page-title-main">Breast milk</span> Milk produced by the mammary glands in the breast of a female human

Breast milk or mother's milk is milk produced by the mammary glands in the breasts of women. Breast milk is the primary source of nutrition for newborn infants, comprising fats, proteins, carbohydrates, and a varying composition of minerals and vitamins. Breast milk also contains substances that help protect an infant against infection and inflammation, such as symbiotic bacteria and other microorganisms and immunoglobulin A, whilst also contributing to the healthy development of the infant's immune system and gut microbiome.

Prebiotics are compounds in food that foster growth or activity of beneficial microorganisms such as bacteria and fungi. The most common environment concerning their effects on human health is the gastrointestinal tract, where prebiotics can alter the composition of organisms in the gut microbiome.

Necrotizing enterocolitis (NEC) is an intestinal disease that affects premature or very low birth weight infants. Symptoms may include poor feeding, bloating, decreased activity, blood in the stool, vomiting of bile, multi-organ failure, and potentially death.

<span class="mw-page-title-main">Gut microbiota</span> Community of microorganisms in the gut

Gut microbiota, gut microbiome, or gut flora are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota. The gut is the main location of the human microbiome. The gut microbiota has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut–brain axis.

A bifidus factor is a compound that specifically enhances the growth of bifidobacteria in either a product or in the intestines of humans and/or animals. Several products have been marketed as bifidogenic factors, such as several prebiotics and methyl-N-acetyl D-glucosamine in human milk.

<span class="mw-page-title-main">Galactooligosaccharide</span> Class of prebiotics

Galactooligosaccharides (GOS), also known as oligogalactosyllactose, oligogalactose, oligolactose or transgalactooligosaccharides (TOS), belong to the group of prebiotics. Prebiotics are defined as non-digestible food ingredients that beneficially affect the host by stimulating the growth and/or activity of beneficial bacteria in the colon. GOS occurs in commercially available products such as food for both infants and adults.

<i>Bifidobacterium</i> Genus of bacteria

Bifidobacterium is a genus of gram-positive, nonmotile, often branched anaerobic bacteria. They are ubiquitous inhabitants of the gastrointestinal tract though strains have been isolated from the vagina and mouth of mammals, including humans. Bifidobacteria are one of the major genera of bacteria that make up the gastrointestinal tract microbiota in mammals. Some bifidobacteria are used as probiotics.

FODMAPs or fermentable oligosaccharides, disaccharides, monosaccharides, and polyols are short-chain carbohydrates that are poorly absorbed in the small intestine and ferment in the colon. They include short-chain oligosaccharide polymers of fructose (fructans) and galactooligosaccharides, disaccharides (lactose), monosaccharides (fructose), and sugar alcohols (polyols), such as sorbitol, mannitol, xylitol, and maltitol. Most FODMAPs are naturally present in food and the human diet, but the polyols may be added artificially in commercially prepared foods and beverages.

<span class="mw-page-title-main">2'-Fucosyllactose</span> Chemical compound

2′-Fucosyllactose (2′-FL) is a fucosylated neutral trisaccharide composed of L-fucose, D-galactose, and D-glucose units. It is the most prevalent human milk oligosaccharide (HMO) naturally present in human breast milk, making up about 30% of all of HMOs. It was first discovered in the 1950s in human milk. The oligosaccharide's primary isolation technique has been in use since 1972.

<i>Akkermansia muciniphila</i> Species of bacterium

Akkermansia muciniphila is a human intestinal symbiont, isolated from human feces. It is a mucin-degrading bacterium belonging to the genus Akkermansia, discovered in 2004 by Muriel Derrien and Willem de Vos at Wageningen University of the Netherlands. It belongs to the phylum Verrucomicrobiota and its type strain is MucT. It is under preliminary research for its potential association with metabolic disorders.

<i>Bifidobacterium bifidum</i> Species of bacterium

Bifidobacterium bifidum is a bacterial species of the genus Bifidobacterium. B. bifidum is one of the most common probiotic bacteria that can be found in the body of mammals, including humans.

Microbiota-accessible carbohydrates (MACs) are carbohydrates that are resistant to digestion by a host's metabolism, and are made available for gut microbes, as prebiotics, to ferment or metabolize into beneficial compounds, such as short chain fatty acids. The term, ‘‘microbiota-accessible carbohydrate’’ contributes to a conceptual framework for investigating and discussing the amount of metabolic activity that a specific food or carbohydrate can contribute to a host's microbiota.

https://journals.sbmu.ac.ir/afb/issue/view/2622

<span class="mw-page-title-main">Human milk microbiome</span> Community of microorganisms in human milk

The human milk microbiota, also known as human milk probiotics (HMP), encompasses the microbiota–the community of microorganisms–present within the human mammary glands and breast milk. Contrary to the traditional belief that human breast milk is sterile, advancements in both microbial culture and culture-independent methods have confirmed that human milk harbors diverse communities of bacteria. These communities are distinct in composition from other microbial populations found within the human body which constitute the human microbiome.

<i>Bacteroides thetaiotaomicron</i> Species of bacterium

Bacteroides thetaiotaomicron is a Gram-negative, obligate anaerobic bacterium and a prominent member of the human gut microbiota, particularly within the large intestine. B. thetaiotaomicron belongs to the Bacteroides genus – a group that is known for its role in the complex microbial community of the gut microbiota. Its proteome, consisting of 4,779 members, includes a system for obtaining and breaking down dietary polysaccharides that would otherwise be difficult to digest for the human body.

<span class="mw-page-title-main">Human milk immunity</span> Protection provided to immune system via human milk

Human milk immunity is the protection provided to the immune system of an infant via the biologically active components in human milk. Human milk was previously thought to only provide passive immunity primarily through Secretory IgA, but advances in technology have led to the identification of various immune-modulating components. Human milk constituents provide nutrition and protect the immunologically naive infant as well as regulate the infant's own immune development and growth.

Lacto-<i>N</i>-tetraose Chemical compound

Lacto-N-tetraose is a complex sugar found in human milk. It is one of the few characterized human milk oligosaccharides (HMOs) and is enzymatically synthesized from the substrate lactose. It is biologically relevant in the early development of the infant gut flora.

Breast milk-mediated drug delivery refers to the use of breast milk to transport a pharmaceutical compound, protein, or other treatment to achieve a desired effect. Delivery of these substances via milk provides an oral alternative for transport of a compound to the gut, specifically in infants. Breast milk-mediated drug delivery provides a way for pharmaceuticals and proteins to travel through the gastrointestinal system of an infant while minimizing the potential for irritation within gastrointestinal tissue.

References

  1. 1 2 3 4 5 6 7 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. 1 2 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. 1 2 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. 1 2 3 4 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. 1 2 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. 1 2 3 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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