European Journal of Clinical Nutrition (2003) 57, 1351–1369 & 2003 Nature Publishing Group All rights reserved 0954-3007/03 $25.00 www.nature.com/ejcn REVIEW The role and potential of sialic acid in human nutrition B Wang1* and J Brand-Miller1 1Human Nutrition Unit, School of Molecular and Microbial Biosciences, University of Sydney, NSW, Australia Sialic acids are a family of nine-carbon acidic monosaccharides that occur naturally at the end of sugar chains attached to the surfaces of cells and soluble proteins. In the human body, the highest concentration of sialic acid (as N-acetylneuraminic acid) occurs in the brain where it participates as an integral part of ganglioside structure in synaptogenesis and neural transmission. Human milk also contains a high concentration of sialic acid attached to the terminal end of free oligosaccharides, but its metabolic fate and biological role are currently unknown. An important question is whether the sialic acid in human milk is a conditional nutrient and confers developmental advantages on breast-fed infants compared to those fed infant formula. In this review, we critically discuss the current state of knowledge of the biology and role of sialic acid in human milk and nervous tissue, and the link between sialic acid, breastfeeding and learning behaviour. European Journal of Clinical Nutrition (2003) 57, 1351–1369. doi:10.1038/sj.ejcn.1601704 Keywords: sialic acid; ganglioside; sialyl-oligosaccharides; human milk; infant formula; breastfeeding Introduction promising new candidate is sialic acid (also known as The rapid growth and development of the newborn infant N-acetylneuraminic acid), a nine-carbon sugar that is a puts exceptional demands on the supply of nutrients. Any structural and functional component of brain gangliosides deficit has profound effects on somatic growth and organ and correlates with the amounts of DHA and total long- structural and functional development, especially the brain. chain polyunsaturated fatty acids in the ceramide tail of Brain growth, including cell number, organ structural and brain gangliosides. Sialic acid may be a conditionally synaptic connectivity, etc, reaches its peak at 26 weeks essential nutrient in infancy, if demand outstrips the rate gestation and then continues at a high rate throughout the of endogenous synthesis. first year of life (Uauy and Peirano, 1999; Uauy et al, 2001). The rapid initial growth of the brain exceeds that of other body tissues. At 6th month gestation, it comprises 21% of Breastfeeding and cognition total body weight and 15% at term (Friede, 1989). The brain Several studies show that children who were breast-fed as weight more than doubles during the first 9 postnatal babies attain higher scores on intelligence tests than those months to reach over 90% of the adult weight by the 6th who were bottle-fed (Rodgers, 1978; Fergusson et al, 1982; year. Once the time for the critical period of brain growth has Lucas et al, 1992, 1998). On average, scores are 2–9 points passed, it cannot be restarted. The challenge is accentuated higher, a difference that is considered biologically signifi- in the premature infants, particularly in relation to nutri- cant. The difference becomes more pronounced as the tional support for brain growth. duration of breastfeeding increases (Dewey et al, 1995). Recently, neurodevelopmental research has focused atten- Lucas et al (1992) reported that preterm infants fed human tion on the role of long-chain polyunsaturated fatty acids milk in the first month of life have an 8-point advantage in (LCPUFAs), and particularly docosahexaenoic acid (DHA) in verbal IQ at 7–8 y of age compared with infants fed standard improving visual acuity and cognitive ability in preterm infant formulas. In a large cohort study of several thousand infants (Carlson et al, 1996; Gibson, 1999). There are many adults, sentence completion, reading ability, and vocabulary factors, however, that may support brain growth. One were all related to patterns of infant feeding (Richards et al, 1998). In a retrospective study, Menkes (1977) found a significantly greater incidence of bottle feeding among *Correspondence: B Wang, Human Nutrition Unit, School of Molecular learning-disabled children than among controls being and Microbial Biosciences, G08 University of Sydney, NSW 2006, Australia. followed for other neurological symptoms. Rodgers (1978) E-mail: [email protected] described a large, stratified sample of British children. The role and potential of sialic acid B Wang and J Brand-Miller 1352 Covariates included social class, parental interest in educa- but also in physiological, biochemical, and psychological tion, material home conditions, parental education, family parameters, early nutrition may modulate nervous system size and birth rank, and age at weaning. After control of development. Infant formulas are the sole source of nutri- confounding variables, there was a significant advantage to tion for infants who are not breast-fed and differences breast-fed children on a picture vocabulary test at 8 y of age between them may be important. In a randomised multi- and on nonverbal ability, mathematics, and sentence center study (Lucas et al, 1990), preterm infants fed a completion at 15 y. A few studies have examined reading standard term formula for 1 month performed more poorly ability or school attainment, and breast-fed children tended at 18 months than those given a nutrient-enriched preterm to do better (Ounsted et al, 1984; Rogan & Gladen, 1993; formula. Those infants given the enriched formula had 15 Horwood & Fergusson, 1998). The most recent follow-up points higher score than those infants given standard term study in a New Zealand cohort of 1000 children reported formula. Recently, neurodevelopmental research has focused that breastfeeding is associated with small but detectable on the role of LCPUFAs, and particularly, docosahexaenoic increases in cognitive ability and academic achievement, acid (DHA) (Makrides et al, 1994, 1995; Lanting & Boersma, extending from 8 to 18 y (Horwood & Fergusson, 1998). The 1996). Clinical studies in which infant formula was supple- difference was significant after adjustment for social and mented with DHA suggested possible improvements in family history, including maternal age, education, social visual acuity and cognitive ability in preterm infants economic status, marital status, smoking during pregnancy, (Carlson et al, 1994, 1996). Infants fed with formula family living conditions, and family income, and perinatal containing DHA had significantly better visual-evoked factors, including gender, birth weight, child’s estimated potential scores than infants fed with control formula gestational age, and birth order in the family. Not all studies without DHA at both 16 and 30 weeks (Makrides et al, yield significant differences after adjustment (Sandra et al, 1995). DHA may be the limiting factor in milk formula 1999). A meta-analysis of 20 controlled studies showed that because the brain, in particular the visual cortex, lays down breastfeeding was associated with a 3.2 point higher large amounts in the first year of life. However, if diet is a key cognitive development score than formula feeding after to mental development, then there are many factors besides adjusting for significant covariates. The IQ advantage DHA that may be important, such as enzymes, hormones, increased with duration of breastfeeding, reaching a plateau growth factors, and sialic acid, which are found in human at 4–6 months of age. Low birth weight infants received the milk but poorly represented in the milk of other species and greatest benefits (Anderson et al, 1999). More recently, in infant formulas (Goldman & Garza, 1987). Of these, sialic Mortensen et al (2002) also reported that duration of acid is most intriguing because of its simultaneous presence breastfeeding was associated with significantly higher scores in large amounts in both human milk and human grey on all components of the Wechsler adult intelligence scale. matter. There is little direct evidence for a causative mechanism whereby breastfeeding might enhance or, conversely, bottle feeding might impair cognitive growth. Rodgers (1978) Structure and state of sialic acid in nature suggested possible mediating factors might be differences It is now known that sialic acids comprise a family of 43 between breast and bottle milk osmotic load or protein and naturally occurring derivatives of the nine-carbon sugar lipid concentrations or differences in the feeding situation neuraminic acid (5-amino-3,5-dideoxy-D-glycero-D-galacto- such as infection risk and psychological effects. Menkes nonulsonic acid) (Schauer et al, 1995; Schauer & Kamerling, (1977) proposed that tyrosinemia due to increased protein 1997). One branch of the sialic acid family is N-acetylated to levels in formula milk might produce an increased incidence form N-acetylneuraminic acids (Neu5Ac, NANA, Sia), which of learning disabilities in bottle-fed children. Improved are the most widespread form of sialic acid and almost the maternal–child interaction and reduced morbidity could only form found in humans (Figure 1). The other branch is account for the effect or contribute to it (Grantham- based on N-glycolylneuraminic acids (Neu5Gc) which are McGregor et al, 2000). Interpretation is further complicated common in many animal species (best investigated in by associations between breastfeeding, social status and porcine tissues), but not found in humans except in the education of parents. Women who make a decision to case of a particular cancer (Schauer et al, 1995) (Figure 1). breastfeed are often better educated with positive health Sialic acid molecules can be substituted in more than one attitudes concerning immunisation and smoking, and may position. O-substitution at C4, -7, -8 and -9 (O-acetyl, O- provide a more desirable environment for their young to methyl, O-sulphate, and phosphate groups) or the introduc- develop intellectually (Lucas et al, 1990, 1992). Statistical tion of a double bond between C-2 and C-3 can give rise to a adjustment for these associations may not remove the full wide variety of possible isomers (Varki & Diaz, 1984).