Human Milk Oligosaccharides as Essential Tools for Basic and Application Studies on Galectins

It is now recognized that human milk oligosaccharides (HMOs) can function both as prebiotics and as decoy receptors that inhibit the attachment of pathogenic microorganisms to the colonic mucosa. They can also act as immune modulators and as colonic maturation stimulators in breast-fed infants. These functions could be mediated by biological interaction between a variety of HMOs and lectins including galectins, selectins and siglecs. There are more than 100 HMOs; they have structural units such as H type 1: Fucα1-2Galβ1-3GlcNAc, Lewis a: Galβ1-3(Fucα1-4)GlcNAc, Lewis b: Fucα1-2Galβ1-3(Fucα1-4)GlcNAc, Lewis x: Galβ1-4(Fuc α1-3)GlcNAc, sialyl Lewis a: Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAc, and sialyl Lewis x: Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAc. It can be expected that these units may be utilized as tools for studies on the sugar-binding specificities of lectins including galectins, monoclonal antibodies, virus capsid proteins and bacterial toxins. This mini-review presents the dataset of comprehensive HMO structures, including recently clarified ones, in tabular form, for its utilization in such studies, including those of carbohydratebinding specificity of galectins. In addition, this review introduces recent in vivo and clinical studies, which may be relevant to the biological functions and future utilization of HMOs. A. Introduction Human milk contains around 60 g/L of lactose (Galβ1-4Glc), as well as 12–13 g/L of a variety of milk oligosaccharides in mature milk and 22–24 g/L in colostrum. Whereas human milk oligosaccharides (HMOs) comprise several monosaccharide components, such as glucose (Glc), N-acetylglucosamine (GlcNAc), galactose (Gal), fucose (Fuc) and N-acetylneuraminic acid (Neu5Ac), they always have a lactose unit at their reducing ends. Although by 2009 the structures of about 115 HMOs had been characterized and clarified based on 13 core series (1, 2), a comprehensive database, including large novel structures, had not been described. When breast-fed infants consume their mother’s milk, the majority of the HMOs are not digested and absorbed within the small intestine and therefore reach the infant’s colon. It has been suggested from in vitro studies that the HMOs function as prebiotics and decoy receptors, inhibiting the attachment of certain types of pathogenic microorganisms to the colonic mucosa, and as modulators of colonic epithelial maturation (1, 3–5). It has been also shown that some strains of Bifidobacterium bifidum, B. longum ssp. infantis, and B. breve are able to grow in medium containing HMOs as the only carbon source (6–8). It has been also clarified that B. bifidum is characterized by a unique metabolic pathway in which HMOs are digested by several extracellular and intracellular glycosidases (7). Notably, low concentrations of some HMOs are detected in plasma from venous blood after the consumption of breast milk (9, 10). Thus, it appears that a minor part of HMOs is absorbed within the small intestine and enters the circulation. It is possible that those HMOs have immune modulation effects such as anti-inflammation, as suggested by in vitro studies using blood leukocytes (11), platelets and endothelial cells (12). It can be assumed that the recognition of those HMOs by some endogenous lectins including galectins, selectins and siglecs is related to those biological activities of HMOs. Therefore, studies on the interaction between HMOs and lectins may generate useful information relating to the utilization of HMOs in therapy, such as immunomodulation and inhibition of the establishment of infection. Notably, as some HMOs have been recently produced on an industrial scale (13), these studies combined with advances in the industrial production of HMOs may in near future open up the possibility of the utilization of HMOs for the treatment and/or prevention of human diseases. HMOs consist of more than 100 individual molecules. They have been so far utilized as tools for studies on the sugar binding MINIREVIEW doi: 10.4052/tigg.1734.1SE (Article for special issue on Galectins)