Human milk oligosaccharides

Abundancy and variation of human milk oligosaccharides

About 12 human milk oligosaccharides (HMO) are the most abundant isoforms in human milk. HMO composition of human milk differs individually because of genetic regulation, based on gene activation of the Lewis positive/negative (Le gene) and secretor/non‑secretor (Se gene) status. Women with Lewis positive gene express the enzyme Fucosyltransferase‑3 producing the isoform 3'‑Fucosyllactose while lewis negative women do not. Women with secretor status express the enzyme Fucosyltransferase‑3 and can produce 2'‑Fucosyllactose (2'‑FL) in high abundancy, while non-secretor women do not.

The most abundant HMO


Several studies identified certain human milk oligosaccharide (HMO) isoforms as the most abundant isoforms in human milk. They are major represents of known HMO categories (Table 412-1). However, the composition of HMO vary individually between women. The abundancy and the even the presence of the following HMO isoforms may differ between human milk of different women. Consequently, it is difficult to state valid concentration ranges of HMO in human milk (Kunz et al., 2017, Thurl et al., 2017).

HMO composition is genetically regulated


Human milk can be sorted into four groups dependent on gene activation – that is on the Lewis positive/negative (Le gene) and secretor/non‑secretor (Se gene) status. These milk groups differ mostly in fucosylated HMO (Kumazaki and Yoshida. 1984⁠; Thurl et al. 1997). Sialylated and neutral non-fucosylated HMO (Figures 412-7 and 412-8) are abundant with relatively stable concentrations in all groups (Kunz et al. 2017⁠; Thurl et al. 2017).

Enzymes define the HMO isoforms. Theoretically a great number of structures are possible. About 200 isoforms are present in human milk because the enzymes for their construction limit the possibilities of what building blocks are added where within the molecule (Figures 412-3, 412-4, and 412-5) (Kobata. 2010⁠; Zivkovic et al. 2010). Generally, 13 core structures are found in human milk (Urashima et al. 2012).

Fucosylated HMO are generated by two different enzymes (Figure 412‑6): Fucosyltransferase‑2 encoded by the secretor (Se) gene (Kumazaki and Yoshida. 1984) and fucosyltransferase‑3 encoded by the Lewis blood group (Le) gene (Xu et al. 1996). Both genes are known to control blood group antigens (Dotz and Wuhrer. 2016⁠; Shen et al. 1968).

Dependent on the genetic phenotype, the Le and Se genes can either be active or inactive (Kumazaki and Yoshida. 1984⁠; Shen et al. 1968). Individuals with active Se gene are “secretors” or "Se+" (Kumazaki and Yoshida. 1984) and individuals with active Le gene are “Le‑positive” or "Le+" (Xu et al. 1996).

Le-positive secretors


Le-positive secretors (Le+/Se+) express high oligosaccharide concentrations and all fucosylated human milk oligosaccharide isoforms from both fucosyltransferase‑2 and ‑3. Le-negative secretors (Le-/Se+) express similar oligosaccharide concentrations but are lacking the human milk oligosaccharides from fucosyltransferase‑3 such as lacto-N-fucopentaose‑II and ‑III. Presence of the HMO isoform 3'-fucosyllactose in this milk group is under debate because recent reports state its absence (Kunz et al. 2017) but older reports stated presence of 3'‑fucosyllactose (Ayechu-Muruzabal et al. 2018⁠; Thurl et al. 2010⁠; Thurl et al. 1997). If fucosyltransferase‑3 is responsible to generate 3'‑fucosyllactose it would be logical to expect its absence from this group.

Non-secretors


Le-positive non-secretors (Le+/Se-) express lower total oligosaccharide concentrations compared to the other groups. Because fucosyltransferase‑2 is absent, this group lacks the 2'-fucosyllactose, the most abundant human milk oligosaccharide isoform in the majority of milk samples (Kunz et al. 2017). Less than 1% of women are Le-negative non‑secretors (Le-/Se-) and compositional data of their milks are scarce. Total HMO concentrations have not been reported to date but are estimated to be comparable to Le-positive non-secretors (Thurl et al. 1997). Fucosylated human milk oligosaccharides are barely traceable and sialylated or acidic HMO take higher precedence in the total oligosaccharide fraction compared to the other milk groups.

Although both enzymes are absent in Le-negative non‑secretors, traces of fucosylated HMO are detectable in these milk samples. This observation indicates that Le and Se-independent fucosyltransferases with very low efficacy exist (Erney et al. 2000⁠; Thurl et al. 1997). Their biological relevance remains to be determined.

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