Introduction

The structural makeup of gut mucus oligosaccharides has a significant impact on the composition of early microbe colonisers, who themselves can shape the diversity of these glycans during a baby's intestinal development (Newburg2015). Interestingly, the structural motifs observed in Human milk oligosaccharides (HMOs), produced by the mother, are analogous to the exposed carbohydrate residues found on the surface of host intestinal mucus layers. A consequence of this similarity is that HMOs can act as prebiotics for mutualistic bacteria that dampen pro-inflammatory signals by providing a nutritional advantage during their establishment phase. Encouragement of mutualists, such as members of the Bifidobacterium genus, reduces the impact of pathogens and facilitates a state of homeostasis.

Milk Composition

Human milk is unique among mammals in that it contains a large number (200+) of oligosaccharides (Kobata2010). These HMOs represent between ~4-11% of the dry weight of normal breastmilk (5-15 g/L, Bode2012) and up to 24 g/L in colostrum (Urashima2012). This contrasts sharply with cow's milk, which contains about 50 mg/L (Table 1).

Table 1. Composition of human milk compared to cow's milk (from Bode2012 and references cited therein).

HMOs Promote the Growth of a Handful of Bacteria and Inhibit Others

It has been recognised for many years that undigestible HMOs (originally called Bifido Factor) promote the growth of Bifidobacterium spp. in the gut of the newborn (Bezirtzoglou2011). These bacteria ferment the oligosaccharides and any undigested lactose to produce lactic and acetic acids, and help transition the gut from an oxidising environment to a reducing one that supports the growth of obligately anaerobic bacteria. The resulting acidic environment discourages the growth of many other microorganisms, and thus protects the baby from the over-colonisation of opportunistic bacteria.

HMOs have also been shown to act as decoys for pathogenic bacteria that normally bind to intestinal epithelial cells. The shape of these oligosaccharides mimics that of the intestinal cell glycan receptor binding sites resulting in the bacteria latching onto the decoy rather than the cell (Bode2012) and a reduction in risk of infection (Newburg2015). In addition, HMOs appear to be beneficial by influencing the immune system's inflammatory response, by reducing the incidence of necrotising colitis, and by providing sialic acid metabolites important for the development of the brain and nervous system of infants.

Not all women produce the same set of HMOs. Some lack the fucosyltransferase enzyme responsible for glycosylating the oligosaccharide core with a fucose sugar.

The Most Common HMOs

Soyyilmaz and colleagues compiled the HMO composition of breast milk from 31 countries and pooled the results (Soyyilmaz2021). Wikipedia have abbreviated the data, which is presented in the table below (Table 2, Wikipedia2022a). Although several hundred HMOs have been identified, about a dozen account for the majority of oligosaccharides produced. The concentrations of HMOs change during lactation and are dependent on the mother's genetic secretor status and length of gestation.

Table 2. Mean concentrations of the most abundant HMOs by lactation stage. Concentration in grams of HMO per litre of breastmilk (g/L; Wikipedia2022a).

Biosynthesis and the Diversity of Oligosaccharides in Women

Around 80% of mothers worldwide have a gene that allows for the 2'-glycosylation of many HMOs with L-fucose (Table 3). The expression of this enzyme, α1-2-fucosyltransferase (FUT2), can result in the production of the most prevalent HMO in milk, namely 2'-FL (Table 2). Women who possess this gene (Se/-) are called 'Secretors'.

Another gene encoding for the enzyme, α1-3/4-fucosyltransferase (FUT3), is able to transfer L-fucose to the 3- or 4-positions of several hexose sugars. Women who express this gene are said to have a positive Lewis status and around 90% of mothers have this ability.

Around 20% of the global population of mothers do not have active FUT2 enzyme, but still have an active FUT3 enzyme. Mothers who cannot express either enzymes are relatively rare (~1%).

Table 3. Lewis and Secretor status of women globally (Wikipedia2022a)

HMO Structures and Graphical Representations

The vast majority of HMOs are derivatives of lactose. Four monosaccharides, D-galactose, N-acetylglucosamine, L-fucose and sialic acid, are then used to extend the lactose unit. For a guide to the graphical representation of HMO structures, see the HMO Structural Guide.

For a (mostly) comprehensive list of HMOs based on core structures, select from the following tables:

➙ Di- & Trisaccharides

➙ Tetraose & Tetrasaccharides

➙ Pentaose

➙ Hexaose

➙ Octaose

➙ Decaose

➙ Miscellaneous