Sialic Acid in Brain Development of Newborn Infants

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Sialic Acid in Brain Development of Newborn Infants

Human milk is composed of many things that impact embryo development. It consists of different ingredients such as oligosaccharides, glycolipids, glycoproteins, and antibodies that play huge roles as a nutrient for newborn infants or different bioactivity factors in growth factors. Even it is accepted that it has its microbiome1. Human milk oligosaccharides (HMOs) are one of the most important bioactive molecules that constitute the quality of human milk. In unbound form, HMOs are found as the higher percentage in the human milk after water, lactose, and fat. Human milk has some unique specialties due to differences that newborn infant’s needs2. That means, different kinds of HMOs can be observed in mammal milk, which some of them are especial for humans.

One of the important types of HMO is an acidic sugar called sialic acid. It is composed of nine carbon sugar that capable of attaching to the sugar chains with different types of linkages3. They have essential roles on the neural tissue, both structural and functional, alongside their ability to act as decoys for the pathogens as an immune response, making them very important for humans4. Despite the many functions of sialic acids, humans are not the only one that uses these. Some human and animal pathogens can use the sialic acids on the cell surface for grappling the cell itself. Even further, they can also mimic these acids and covers their cell surface with them for avoiding the immune system3. Every mammal can synthesize the sialic acid from simple sugar in their tissues or in their milk due to its requirement for brain development.5

HMOs are rich in sialic acids, and the most abundant one is N-Acetylneuraminic acid (Neu5Ac). They are known for improving infants’ brain development, especially the Neu5Ac itself. For example, it was recorded that the infants who breastfed for at least three months had higher intelligence scores than the infants who were formula-fed6. The reason behind this is the human’s specific glycan composition, which it makes harder to create a similar formula for infants2. There is another type of sialic acid called N-Glycolylneuraminic acid (Neu5Gc). It is commonly synthesized with hydroxylates, adding a hydroxy group to the Neu5Ac for synthesizing Neu5Gc7. It is recorded that they exist in dairy milk or other mammal milk, but surprisingly not in human milk. Every mammalian species requires sialic acids for developing their brain, but due to our high brain/body mass ratio, human neonates require high sialic acid quantity than other species during the development process2.

Figure 1: Structure of Neu5Gc and Neu5Ac (a)

Figure: Structure of Neu5Gc and Neu5Ac (a)

Even though the only main difference occurs with the additional oxygen atom addition3 (FIG.1), their function impacts more differences. It has been mentioned in the previous paragraph that HMOs are rich in Neu5Ac for infant brain development, but research showed that it was different in past. Previously, humans themselves could syntheses the Neu5Gc too. There are lots of thoughts about the reason behind this, but the most accepted cause is an inactivated mutation that occurred on the CMAH gene which is responsible for the synthesis of Neu5Gc.7 The mutation occurred after the last ape-human common ancestor. It was observed the percent of Neu5Gc that found in apes, which is between %20-90 of all sialic acids while it is almost impossible to detect in humans3. Right now, it is widely accepted that an increase occurred in the amount of Neu5Ac, with the inactivation of the CMAH gene, resulted in a huge improvement in our brain development.

To sum up, sialic acid has an important function for mammalian brain improvement. Throughout our evolution road, somehow, we managed to choose our sialic acid source that was easily observed in our kind’s milk, which eventually led our brain development to the current stage.


  1. Lyons KE, Ryan CA, Dempsey EM, Ross RP, Stanton C. Breast milk, a source of beneficial microbes and associated benefits for infant health. Nutrients. Published online 2020. doi:10.3390/nu12041039
  2. Georgi G, Bartke N, Wiens F, Stahl B. Functional glycans and glycoconjugates in human milk. Am J Clin Nutr. Published online 2013. doi:10.3945/ajcn.112.039065
  3. Varki A. Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution. Yearb Phys Anthropol. Published online 2001. doi:10.1002/ajpa.10018
  4. Wang B. Sialic acid is an essential nutrient for brain development and cognition. Annu Rev Nutr. Published online 2009. doi:10.1146/annurev.nutr.28.061807.155515
  5. Wang B, Brand-Miller J. The role and potential of sialic acid in human nutrition. Eur J Clin Nutr. Published online 2003. doi:10.1038/sj.ejcn.1601704
  6. Eidelman AI, Schanler RJ. Breastfeeding and the use of human milk. Pediatrics. Published online 2012. doi:10.1542/peds.2011-3552
  7. Chou HH, Hayakawa T, Diaz S, et al. Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution. Proc Natl Acad Sci U S A. Published online 2002. doi:10.1073/pnas.182257399

Figure References: Varki A. Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution. Yearb Phys Anthropol. Published online 2001. doi:10.1002/ajpa.10018


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