Human milk oligosaccharides: 130 reasons to breast-feed.

Many nutrition scientists are not yet aware that human milk contains significant quantities of carbohydrates other than lactose. If you’ve never heard of lacto-N-tetraose or sialyllactose, you are not alone. The role of oligosaccharides in other fields has attracted widespread excitement but curiously little interest has been shown in the oligosaccharides of human milk. Many of the 130 different human milk oligosaccharides may be important in infant brain development and resistance to infection. Their presence may be one of the reasons that breast-fed infants appear to have higher intelligence quotients and greater resistance to infection than formula-fed infants. Quantitatively, oligosaccharides are the third largest solute in human milk after lactose and fat. Mature milk contains over 15 g human milk oligosaccharides/l compared with only about 9 g protein/l (Coppa et al. 1993). The oligosaccharide content of human milk varies with the duration of lactation, diurnally and with the genetic makeup of the mother (Viverge et al. 1990; Coppa et al. 1993). Oligosaccharides vary greatly, both within and between individuals, more so than any other component of human milk. Marsupial and monotreme milks are also known to contain significant amounts of oligosaccharides (Messer & Kerry, 1973; Messer & Mossop, 1977) but cows’ milk and infant formulas contain very little (Neeser et al. 1991). We used to say that the structural complexity of human milk oligosaccarides was unique. However, in this month’s issue of the British Journal of Nutrition, we learn that elephant milk and human milk have much in common (Kunz et al. 1999). It may not be coincidental that elephants secrete large quantities of oligosaccharides containing sialic acid in their milk and are said to have a memory ‘that never forgets’ (more on this later). Over the past two decades the chemical structures of human milk oligosaccharides have been studied using NMR spectroscopy and mass spectrometry (Stahl et al. 1994). Each individual oligosaccharide is based on a variable combination of glucose, galactose, sialic acid (also known as N-acetylneuraminic acid), fucose and/or N-acetylglucosamine with many and varied linkages between them, thus accounting for the enormous number of different oligosaccharides in human milk (at least 130, and still counting). Almost all of them have a lactose moiety at their reducing end while fucose and sialic acid (when present) occur at the non-reducing end (Kobata et al. 1978). The large quantity of sialylated oligosaccharides in both human and elephant milk is fascinating. Sialic acid is a nine-C sugar that is a vital structural and functional component of brain gangliosides. It is thought to play an essential role in nerve cell transmission, memory formation and cell-to-cell communication (Rosenberg, 1995). Most importantly, studies in rat pups indicate that early supplementation with sialic acid improves both brain ganglioside sialic acid and learning ability in well-nourished and malnourished animals, and that these changes persist into adulthood (Morgan & Winick, 1980a,b). Human milk contains large numbers of sialylated oligosaccharides that are not found in significant amounts in cows’ milk or infant formulas. The immature liver may not be capable of synthesizing all the sialic acid needed by the infant during this peak period of brain growth. Over the last few years we have explored the hypothesis that sialic acid accretion may be enhanced by breast-feeding. Apart from brain gangliosides, saliva is a rich source of sialic acid and, unlike blood or brain tissue, can be obtained non-invasively from young infants. The high concentration of sialic acid in saliva and other mucins is responsible for their slippery, viscous nature and thus their protective function. In our recent study, breast-fed infants were found to have nearly 50 % more total sialic acid in saliva compared with formula-fed infants (Tram et al. 1997). It is possible that the sialic acid derived from human milk contributes to higher levels of sialic acid in saliva. One of the important questions is whether human milk oligosaccharides are digested and absorbed in the small intestine, providing energy and important molecules such as galactose, fucose and sialic acid. The marsupial smallintestinal mucosa has several enzymes that split oligosaccharides into their component monosaccharides. This makes oligosaccharides nutritionally available to the animal in a form that is less osmotically active than if lactose or monosaccharides were the only carbohydrates. Human milk oligosaccharides may be a similar low-osmolar source of energy for the infant. However, the glycosidic linkages between the monosaccharide residues of human milk oligosaccharides are unlikely to be hydrolysed by lactase and other known brush-border disaccharidases. These enzymes have no action on linkages involving fucose, sialic acid or N-acetylglucosamine (Rings et al. 1994). Furthermore, the brush-border neutral lactase cannot hydrolyse the lactose moiety of trisaccharides or higher oligosaccharides. Recently, we demonstrated using breath H2 methodology that human milk oligosaccharides resist digestion in the small intestine of the majority of breast-fed infants and undergo fermentation in the colon (Brand Miller et al. 1998). We found that the peak rise and overall production of breath H2 after a human milk oligosaccharide load was similar to that after an equivalent load of lactulose, in six of eight infants studied. The implication is that human milk oligosaccharides are not digested and absorbed in the small intestine but are readily fermented in the large intestine. British Journal of Nutrition (1999), 82, 333–335 333