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How do the oligosaccharides in human milk help protect babies and adults from infection?

October 17, 2022 8 min read

How Do the Oligosaccharides in Human Milk Help Protect Babies From Infection?

 As we enter the world we are instantly at risk from a large list of potentially life-threatening infections. There is also a risk of initiating the foundations of what could go on to be a chronic debilitating disease later in life. However, this risk can be greatly reduced.

As we grow and prepare for birth, an assortment of bacteria, mainly in the gastrointestinal tract, is being made ready to stand guard and fend off potential invaders. These bacteria are then reinforced as we receive an additional coating from mum as we come through the birthing canal[i]. Once we are out and vulnerable, this protection is then reinforced and sustained by human milk oligosaccharides (HMOs) we receive from our mother’s milk[ii].

These complex glycans are present in most mammals, but humans have a unique concentration in comparison[iii]. The milk we receive from our mother, nourishes our gut bacteria, so they can protect us from infection. In short, HMOs are incredibly important prebiotics that help to lay the foundations for our immune system and health as we grow.

A review study by Ayechu-Muruzabal et al. (2018) is the central focus of this article, as we aim to offer a detailed overview of the importance of HMOs, in nutrition, in early life and its impact on immune development.

What are human milk oligosaccharides?

HMOs are a very complex group of indigestible glycans (sugars). They are the third most abundant biomolecules found in human milk and are the main players in modulating the immune system and developing the microbiota of the gastrointestinal (GI) tract. Human milk gives us protection from birth while our own B cell repertoire develops. It could take the first few years of life for our B cells to mature before being adequate enough to defend against opportunistic pathogensii.

The concentrations of HMOs are influenced by several factors. These include:

  • the lactational stage
  • maternal nutrition
  • genetic predisposition

The mother’s own pathogen-specific maternal antibodies are passed to baby and offer almost instant protection in the early months of lifeii. Consumption of HMOs results in health benefits that would not be possible without them, and their interaction with bacteria, protozoa and viruses could reduce the risk of specific infections[iv].

The importance of HMOs being consumed in the diet of infants is such, that there are research programs being conducted to show just how important it is to be added to formula milk[v].

How do HMOs affect early life immune development?

One of the first ways the HMOs begin to offer protection can be seen in the inhibitory effect that it offers to our cells in the intestinal mucosa. Here the cells are given a form of protection that will see the prospective invader being unable to attach or adhere to the mucosa cells, without which they cannot cause harm[vi].

Further protection is given from the HMOs as they inhibit the growth of pathogens by producing bacteriocins and organic acids. Both of which are instrumental in producing functional metabolites, an umbrella term that translates into various roles such as, acting as fuel, signalling, maintaining the cell structure, producing antioxidants, and antimicrobial compounds. All of which go towards protecting us from harm[vii].

The effect on our immune system is such that cases of pneumonia and diarrhoea are lower in breastfed and partially breastfed infants, as is diarrhoea mortality, compared to formula-fed babies.

Furthermore, this protection extends into prevention against allergic reactions, influencing behaviour at our optimum level, cognitive development, gastrointestinal development and even possible protection against chronic diseases[viii].

How does the interaction take place?

The HMOs act like a go-between. As communication between the epithelial cells and the mucosal surface interact, the HMOs counterbalance the deficiencies like low IgA production, lack of epithelial chemokine secretion, defective antimicrobial peptide secretion, and increased permeability that may occur during this early stageii.

It is during these early stages, after the birth and the consumption of milk, that the neonate encounters a mass of different microorganisms. In order for these microorganisms to work in their own and our best interests, they need food, and once again, the HMOs are there ready to be offered up. Amongst this mass of numbers are Lactobacillus and Bifidobacteria, both of which are important big players in the gut microbiome, not least because they are examples of probiotics.

These microorganisms, once determined and established, will form part of the microbiome that will be instrumental in creating a balanced metabolic response that will be carried into adult life. Depending on several other additional factors, your microbiota help to determine a pain-free existence or a life of painii.

Diversity and biological function of HMOs

The diversity and abundance of HMOs are exclusive to humans. Although there are only 5 different monosaccharides that makeup HMOs, their structural complexity is unique. These 5 monosaccharides are the building blocks from which HMOs are formed. They are:

  1. Glucose
  2. Galactose
  3. N-Acetyl-Glucosamine
  4. Fucose
  5. Sialic acid

Different HMOs are formed depending on how many of these building blocks are used and how they link together. So far, more than 100 different HMOs have been discovered with 19 core structures described[ix].

The varying structures and diversity of HMOs present in human breast milk suggest they have different biological functions and use varying methods to influence the microbiome of the infant.

For example, Ayechu-Muruzabal et al. (2018) demonstrates that the structural diversity of HMOs produces different roles in the epithelial cell layer, surrounding mucosa and the immune system within the digestive tract of babies.

Let’s take a closer look at some of the biological functions offered by HMOs outlined in the aforementioned review.

Antimicrobial and antiviral effects

In breastfed children, HMOs play an important role in preventing both bacterial and viral infections. They do this by binding to the invading toxin, virus, or bacteria or by copying cell entry receptors to prevent them from adhering directly to the mucosal surface. By doing so, HMOs prevent the pathogen from replicating (growing in numbers) and causing infection.

Research has shown that HMOs have lessened the infectivity of rotavirus by mediating an effect directly on the virus[x]. Rotaviruses are responsible for causing some nasty, infectious tummy bugs that cause symptoms such as sickness and diarrhoea. Moreover, a study by Lin et al. (2017) found that non-sialylated HMOs can inhibit the growth of Streptococcus B infections. This means that HMOs could have an antibacterial effect against these infections, which are a leading neonatal pathogen[xi].

Prebiotic effects

It’s unlikely we’d get through an article without mentioning the prebiotic effects of HMOs, and it’s hard not to since HMOs provide superb nourishment for many Bifidobacteriastrains. Bifidobacteriaare one of the early colonisers of the human gut, and so HMOs provide initial nourishment for them, helping them to increase their abundance (and protective activities) in infants.

But that’s not all. The growth of Bifidobacteria,influenced by the metabolism of HMOs, has a wider effect on the infant’s immunity. That’s because the growth of commensal bacteria comes at a cost for pathogens because they are unable to use HMOs, so their growth is suppressed.

Mucosal barrier maturation

Lining your gut is an elite team of epithelial cells, and these play a vital role in keeping toxins, food, waste, undigested food particles, and even pathogens away from your bloodstream and the rest of your body. HMOs have a special relationship with these cells because they can interact with the carbohydrate molecules called glycans present within them. Alternatively, they can also interact with the dendritic cells which project out of the gut lumen.

This impressive interaction helps to support the maturation of the gut lining and contributes to its integrity by modulating the composition of the gut microbiome and increasing short-chain fatty acid production (SCFAs). Remember, SCFAs, like butyrate, are vital for maintaining the integrity of the gut lining, and this is particularly important in babies whose immune system is still developing.

HMOS can recognise pathogens

When a microbe enters your body, special receptors are deployed to recognise and find them. An example of these receptors is toll-like receptors, and these are thought to be modulated by HMOs.

For example, a study conducted by He et al. (2016) analysed whether HMOs could influence the release of Escherichia coli-induced interleukin-8 (IL-8) by intestinal epithelial cells. It found that the HMO 2'-fucosyllactose (2'-FL) could modulate the expression of CD14, weakening inflammation caused by lipopolysaccharide (LPS), a potent bacterial toxin[xii]. Furthermore, exposure to HMOs increased TLR signal transduction, contributing to an effective immune response and offering protection from infections.

Immune system development

Several HMOs have been found in the gut and blood of breastfed babies, including 2’-FL. Research shows that breastfed babies are better protected against infections, particularly through the first years of life[xiii]. Therefore, HMOs may help with protection by supporting the development of the mucosal and systemic immune systems.

2’-FL, for example, is known to have an anti-inflammatory effect because it reduces the release of interleukin-8, a key mediator in inflammation, in response to E-coli.Further studies have shown that this HMO can also regulate the release of other cytokines and other anti-inflammatory mediators.

HMOs are also believed to bind to another type of lectin (a protein that can bind to carbohydrates) called galectins. Galectins are also involved in the immune and inflammatory response of the body. According to Ayechu-Muruzabal et al. (2018), after exposure to HMOs, galectins can induce an immune response by increasing the production of IFNγ and IL-10.

Summary

HMOs are abundantly available in human breast milk and are believed to play a key role in protecting breastfed babies against invading pathogens and subsequent infections. The review by Ayechu- Muruzabal et al. (2018) demonstrates that the diversity of structures in HMOs contributes to early immune development in several ways, including through antimicrobial activity, prebiotic effects, and by influencing the maturation of the intestinal lining.

If you want to reap the benefits of HMOs, as an adult, without the need for real human milk, then our Pure HMO range is for you. Discover it here.  

References: 

[i] Dunn AB, Jordan S, Baker BJ, Carlson NS. The Maternal Infant Microbiome: Considerations for Labor and Birth. MCN Am J Matern Child Nurs. 2017 Nov/Dec;42(6):318-325. doi: 10.1097/NMC.0000000000000373. PMID: 28825919; PMCID: PMC5648605.

[ii] Ayechu-Muruzabal, V., van Stigt, A. H., Mank, M., Willemsen, E. M., Stahl, B., Garssen, J., Garssen, J., Land, T., & Land, T. (2018). Diversity of Human Milk Oligosaccharides and Effects on Early Life Immune Development. Frontiers in Pediatrics, 6. https://doi.org/10.3389/fped.2018.00239

[iii] Bode L. Human Milk Oligosaccharides: Structure and Functions. Nestle Nutr Inst Workshop Ser. 2020;94:115-123. doi: 10.1159/000505339. Epub 2020 Mar 11. PMID: 32160614.

[iv] Wiciński M, Sawicka E, Gębalski J, Kubiak K, Malinowski B. Human Milk Oligosaccharides: Health Benefits, Potential Applications in Infant Formulas, and Pharmacology. Nutrients. 2020 Jan 20;12(1):266. doi: 10.3390/nu12010266. PMID: 31968617; PMCID: PMC7019891.

 

[v] Hill DR, Chow JM, Buck RH. Multifunctional Benefits of Prevalent HMOs: Implications for Infant Health. Nutrients. 2021 Sep 25;13(10):3364. doi: 10.3390/nu13103364. PMID: 34684364; PMCID: PMC8539508.

[vi] Plaza-Díaz J, Fontana L, Gil A. Human Milk Oligosaccharides and Immune System Development. Nutrients. 2018 Aug 8;10(8):1038. doi: 10.3390/nu10081038. PMID: 30096792; PMCID: PMC6116142.

[vii] Chen J, Pang H, Wang L, Ma C, Wu G, Liu Y, Guan Y, Zhang M, Qin G, Tan Z. Bacteriocin-Producing Lactic Acid Bacteria Strains with Antimicrobial Activity Screened from Bamei Pig Feces. Foods. 2022 Feb 28;11(5):709. doi: 10.3390/foods11050709. PMID: 35267342; PMCID: PMC8909009.

[viii] Plaza-Díaz J, Fontana L, Gil A. Human Milk Oligosaccharides and Immune System Development. Nutrients. 2018 Aug 8;10(8):1038. doi: 10.3390/nu10081038. PMID: 30096792; PMCID: PMC6116142.

[ix] Chen X. Human Milk Oligosaccharides (HMOS): Structure, Function, and Enzyme-Catalyzed Synthesis. Adv Carbohydr Chem Biochem. 2015;72:113-90. doi: 10.1016/bs.accb.2015.08.002. Epub 2015 Nov 11. PMID: 26613816; PMCID: PMC9235823.

[x] Laucirica DR, Triantis V, Schoemaker R, Estes MK, Ramani S. Milk Oligosaccharides Inhibit Human Rotavirus Infectivity in MA104 Cells. J Nutr. 2017 Sep;147(9):1709-1714. doi: 10.3945/jn.116.246090. Epub 2017 Jun 21. PMID: 28637685; PMCID: PMC5572490.

[xi] Lin AE, Autran CA, Szyszka A, Escajadillo T, Huang M, Godula K, Prudden AR, Boons GJ, Lewis AL, Doran KS, Nizet V, Bode L. Human milk oligosaccharides inhibit growth of group B Streptococcus. J Biol Chem. 2017 Jul 7;292(27):11243-11249. doi: 10.1074/jbc.M117.789974. Epub 2017 Apr 17. PMID: 28416607; PMCID: PMC5500792.

[xii] He Y, Liu S, Kling DE, Leone S, Lawlor NT, Huang Y, Feinberg SB, Hill DR, Newburg DS. The human milk oligosaccharide 2'-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut. 2016 Jan;65(1):33-46. doi: 10.1136/gutjnl-2014-307544. Epub 2014 Nov 27. PMID: 25431457

[xiii] Hanson LA, Korotkova M, Lundin S, Håversen L, Silfverdal SA, Mattsby-Baltzer I, Strandvik B, Telemo E. The transfer of immunity from mother to child. Ann N Y Acad Sci. 2003 Apr;987:199-206. doi: 10.1111/j.1749-6632.2003.tb06049.x. PMID: 12727640.


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