Human milk oligosaccharides

Human milk oligosaccharides provide sialic acid

Sialylated human milk oligosaccharides (HMO) are the main source for sialic acid in early life. Sialic acid is important for infants' development as they cannot generate enough for their needs. The sialic acid content of human milk is higher than that of formulas unless specifically enriched. Manufactured sialylated HMO can nowadays be added as formula ingredients because they could be beneficial for brain development. It is unknown how sialylated HMO are digested and absorbed. Preclinical studies show that bacteria release sialic acid, which could then be absorbed and reach the brain.

Infants need sialic acid


Sialic acid is likely an essential nutrient for infants. Sialic acid is present in high concentrations in the human brain. It is a structural component of gangliosides, involved in neural signal transmission, and in the formation of synapses (synaptogenesis) (Wang 2009). The human body can synthesise sialic acid de novo. This endogenous synthesis seems to be immature in infants. Due to their rapidly developing brain, infants require high amounts of sialic acid. It is suggested that the endogenous synthesis is not sufficient to meet physiologic needs. Consequently, dietary intake is needed (Wang 2009; Wang und Brand-Miller 2003).

Human milk contains sialic acid


Human milk is a natural dietary source of sialic acid with a total content of 24 ‑ 136 mg/ 100 ml. Approximately 70 ‑ 80% of sialic acid is bound to sialylated HMO. Of the remaining fraction about 15 ‑ 28% are protein-bound, and 2 ‑ 3% are present in free form. Infant formula traditionally contains much lower concentrations than human milk (about 13 - 26 mg/ 100 ml) (Claumarchirant et al. 2016). This leads to differences in sialic acid intake between breastfed and formula-fed infants and is seen as one potential reason for the higher cognitive development of breastfed infants over exclusively formula-fed infants (Belfort et al. 2013; Cerdó et al. 2019). Nowadays, HMO are permitted as ingredient for infant formula with potential benefits. The most abundant sialylated HMO  in human milk are 3'‑sialyllactose (3'‑SL) and 6'‑sialyllactose (6'‑SL) (Kunz et al. 2017). These isoforms can be manufactured and applications as ingredient for infant formulas in the EU are ongoing (see European Commission). Their use as formula ingredient represents a possibility to add HMO isoforms as “brain nutrients” and to increase the amount of sialic acid informulas. Studies are running whether formulas with HMO blends that include 3'‑SL and 6'‑SL are associated with cognitive benefits (NCT NCT03722550; NCT 003513744).

How does sialic acid get to the brain?


Sialylated or acidic HMO are seen as important for brain development (Wang 2012). They provide sialic acid as substrates for brain cells (Wang 2009). The mechanisms of digestion and absorption of sialylated HMO are under research. It is not well understood how sialic acid is detached from the HMO and reaches the brain. Generally, HMO are resistant to hydrolysis from gastric acid and most digestive enzymes (Brand-Miller et al. 1998; Gnoth et al. 2000). About 50% of sialylated HMO are excreted unmodified in faeces (Gnoth et al. 2000). Only 1 ‑ 2% of sialylated HMO are absorbed in intact form and excreted unmodified in infant urine (Rudloff et al. 2012). Here the potential mechanism may be that absorption occurs via pinocytosis and specific transporter systems (Bruggencate et al. 2014; Brand-Miller et al. 1998).

Whether the human intestine can digest (that is cleave) sialylated HMO is also being investigated. Neuraminidases are enzymes that can release sialic acid from an oligosaccharide. They are expressed in the intestine of rabbits, mice, and guinea pigs (Dickson and Messer 1978). Whether humans express neuraminidase enzymes in the intestine is debated (Bruggencate et al. 2014). As a result the bioavailability of sialic acid from sialylated HMO is still unknown (Claumarchirant et al. 2016). However, certain colonic bacteria (microbiota) species express membrane-bound extracellular neuraminidases that cleave sialylated HMO into sialic acid-free leftover saccharides. The free sialic acid is now available for colonic absorption (Wang 2012). Animal studies indicates that dietary sialic acid is absorbed, transported in the blood, and incorporated in the brain: Feeding radiolabelled sialic acid to newborn rodents and minipigs increased sialic acid content in the brain within 2h (Wang 2009). Like other glycans, the leftover saccharides could serve as energy substrate for less-specific colonic bacteria some of which can produce short-chain fatty acids (SCFA) (Newburg 2000; Yu et al. 2013). SCFA are also beneficial for health (Yu et al. 2013) and brain development (Hauser et al. 2020; Goyal et al. 2015).

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