Human milk oligosaccharides

Structure and terminology of human milk oligosaccharides

Different terms are synonomyously used to describe human milk oligosaccharide structures, and are summarised here. Human milk oligosaccharides are composed of five building blocks and always contain lactose, which is depicted with a residue. Based on the residue, human milk oligosaccharides are classified into different categories: fucosylated human milk oligosaccharides, sialylated or acidic human milk oligosaccharides, and non-fucosylated neutral human milk oligosaccharides.

Terminology of HMO

The literature on human milk oligosaccharides (HMO) is diverse and stretches over many decades. Certain terms are used synonymously. We summarised these terms here:

  • The oligosaccharide fraction of human milk
  • consists of 200+ HMO species or isoforms or molecules or types.
  • Together, these form a HMO profile (e.g. HPLC analysis) or cluster or conglomerate.
  • The cluster/profile/conglomerate can be split into three HMO categories
  • in which HMO with a specific structure are sorted or grouped by their residues.
  • These structures are all built from the same three to five residues or molecules or monomers or building blocks that are monosaccharides and
  • differ in the combination of building blocks and glycosidic bond i.e. connection type.

Building blocks of HMO

All human milk oligosaccharides (HMO) can be described with an equation such as this:

HMO are composed of 5 different mono­saccharides

To break down this complicated seeming equation, we start with the three to five monosaccharides or monomers that are the building blocks of HMO (figure 534_01-03). Depending on the way these five building blocks are combined together with a number of different structural ways to connect, they form more than 200 HMO isoforms (Thurl et al. 2010).

The disaccharide lactose is a combination of D‑glucose (Glu, blue circle figures 534_01-03 and 534_01-04) with D-galactose (Gal, yellow circle, figures 534_01-03 and 534_01-04) connected via a β1-4 bond (figure 534_01-06). As free disaccharide or dimer, lactose is the major carbohydrate in mother's milk and thus called milk sugar. Lactose is a core component of all HMO isoforms. It is located at the terminal end of all HMO and further modified by the addition of galactose, N‑acetyllactosamine, fucose, or sialic acid, elongated and branched in various ways to form the multitude of known HMO isoforms (figure 534_01-03) (Bode. 2012⁠).

Different bonds in HMO cause structural diversity

The type of connection ‑ that is the glucoside bond ‑ plays a crucial role in HMO formation. It can define the 3D structure, thus determine interaction of the HMO to microorganisms (decoy receptor) or access of enzymes and other metabolites, and therefore affect functionality of the HMO isoform that was synthesised.


HMO can be categorisied by their residues

Human milk oligosaccharides structures are described by a basic blueprint (figure 534_01-03): Lactose is a core component linked with at least one further residue or unit. Based on the presence of these residues, HMO can be sorted into three different categories:

  1. Fucosylated HMO (figure 534_01-07) are linked with at least one L-fucose residue.

  2. Sialylated or acidic HMO (figure 534_01-08) are oligosaccharides linked with at least one sialic acid residue.

  3. Non-fucosylated or neutral HMO (figure 534_01-09) are linked with at least one galactose, N‑acetyllactosamine, or lacto‑N‑biose unit. They are neither linked with fucose nor sialic acid (Ayechu-Muruzabal et al. 2018⁠; Kunz et al. 2000).

Non-fucosylated neutral human milk oligosaccharides are the most diverse and extensive category representing between 42 ‑ 55% of the entire human milk oligosaccharide fraction, followed by fucosylated human milk oligosaccharides with 35 ‑ 50%. Sialylated, acidic human milk oligosaccharides are the least extensive category, representing approx. 13% of total human milk oligosaccharides (Donovan and Comstock. 2016).