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Burnham Institute for Medical Research, Glycobiology and Carbohydrate Chemistry Program, La Jolla, CA
* To whom correspondence should be addressed. Email: Lbode{at}burnham.org.
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ABSTRACT |
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 TOP ABSTRACT IntroductionLITERATURE CITED |
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5–10 g unbound oligosaccharides, and >130 different HMO have been identified. Both their high amount and structural diversity are unique to humans. Only trace amounts of these oligosaccharides are present in mature bovine milk and, as a consequence, in bovine milk–based infant formula. The potential health benefits of HMO that were uncovered over the years may affect breast-fed infants both locally and systemically. Recent advances in glycobiology and nutrition, including the use of stable isotopes, frontal-affinity chromatography, glycan microarrays, MS, and automated solid-phase carbohydrate synthesis, will help verify hypotheses and unravel the mysteries behind HMO.
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Introduction |
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TOPABSTRACTIntroductionLITERATURE CITED |
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5–10 g unbound oligosaccharides, which is similar to the amount of proteins and exceeds the amount of lipids. The building blocks of milk oligosaccharides are the 5 monosaccharides D-glucose (Glc),3 D-galactose (Gal), N-acetylglucosamine (GlcNAc), L-Fucose (Fuc), and sialic acid (N-acetyl neuraminic acid (Neu5Ac) in humans, and both Neu5Ac and N-glycolyl neuraminic acid (Neu5Gc) in all other species). Lactose (Galß1-4Glc) forms the reducing end and can be elongated with up to 15 N-acetyllactosamine repeat units (Galß1-3/4GlcNAc). Lactose or the polylactosamine backbone can be sialylated in 
2-3 and/or 2-6 linkages and/or fucosylated in 1-2, 1-3, and/or 1-4 linkages. More than 130 different human milk oligosaccharides (HMO) have been identified. Infant formula contains only trace amounts of less complex oligosaccharides [reviewed in (1)]. Whether these significant differences cause physiological distinctions between breast-fed and formula-fed infants remains speculative, but may very well be possible considering the putative physiological effects of HMO outlined below (Table 1).
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Adhesion to the host's epithelial surface is essential for the virulence of most pathogenic microorganisms, e.g., Campylobacter jejuni, Escherichia coli, Vibrio cholera, and Shigella and Salmonella strains. The adhesion-related virulence factors are often lectins, carbohydrate-binding proteins, which dock to oligosaccharides on the epithelial cell surface [reviewed in (7)]. These carbohydrate-binding determinants are also often part of HMO, suggesting that HMO serve as soluble ligand analogs, block pathogen adhesion, and protect breast-fed infants against infections and diarrhea [reviewed in (8)]. For example, C. jejuni, one of the most predominant causes of diarrhea worldwide (9), adheres to intestinal 2'-fucosyllactosamine (10), which is also present on HMO. In fact, fucosylated HMO inhibit Campylobacter binding to human intestinal mucosa ex vivo (10), and the incidence of Campylobacter diarrhea in breast-fed infants is inversely related to the amount of 2'-fucosyllactose in the mother's milk (11). Antimicrobial effects of HMO were also described for calicivirus diarrhea (11) and infections with heat-stable enterotoxin of E. coli (12).
In addition to ligand mimicry, HMO may change the glycome of intestinal epithelial cells. Micro-array glycan profiling of Caco-2 intestinal epithelial cells reveals significant changes in specific glycan epitopes upon exposure to 3'sialyllactose (3'SL) (13), one of the predominant sialylated HMO. 3'SL reduces the expression of various glycosyltransferases, which diminishes the content of cell surface sialic acid, fucose, and galactose (13). Such glycocalyx modifications may alter the ability of certain pathogens to adhere. In fact, 3'SL exposure of Caco-2 cells reduces the adhesion of enteropathogenic E. coli (EPEC) by 50% (13). This correlates with reduced cell surface sialic acid and lactosamine, which are key glycans for EPEC adhesion (14).
HMO rinse the laryngopharyngeal region and may also reduce pathogen adhesion at the entry to the upper respiratory tract. Human milk inhibits adhesion of Streptococcus pneumoniae and Haemophilus influenzae to human pharyngeal or buccal epithelial cells (15). These pathogens attach to sialylated glycans on the host's epithelium and are responsible for most of the otitis media cases and respiratory tract infections in newborn infants (15). Sialylated glycans are also part of HMO and may partially account for the beneficial effects of human milk (16).
Systemic effects. HMO are partially absorbed intact in the infant's intestine and appear in the urine of breast-fed, but not formula-fed infants (17–19). These very important results provide the basis for 2 other hypotheses. First, HMO serve as antiadhesive receptor analogs for urinary pathogens. Second, the appearance of HMO in the urine indirectly proves their presence in the systemic circulation, although the direct detection of HMO in the infant's blood has not yet been reported. However, a blood concentration of 100–200 mg/L can be calculated based on the HMO concentration in human milk, the daily intake, the infant's blood volume, and the amount excreted with the urine over time (17).
Assuming that HMO reach the systemic circulation, they may alter protein-carbohydrate interactions also on a systemic level. Selectins, for example, are involved in cell-cell interactions in the immune system (20). P- and E-selectin mediate leukocyte deceleration (rolling) on activated endothelial cells and initiate leukocyte extravasation at sites of inflammation (21). P-selectin is also involved in the formation of platelet-neutrophil complexes (PNC), a subpopulation of highly activated neutrophils primed for adhesion, phagocytosis, and enhanced production of reactive oxygen species (ROS) (22). Selectins bind to specific fucosylated and sialylated oligosaccharides, e.g., sialyl Lewis x (sLex), on their respective glycoconjugate ligands (23). Some HMO resemble these binding determinants (24). In fact, physiologically relevant concentrations of sialylated HMO reduce rolling and adhesion of human leukocytes on activated endothelial cells, whereas nonsialylated HMO have no effects (25). Remarkably, the total fraction of sialylated HMO decreases leukocyte adhesion even more than the physiological binding determinant, sLex, suggesting that some complex HMO carry multivalent binding sites, which were reported to enhance selectin-ligand binding (26). Furthermore, HMO inhibited PNC formation and reduced subsequent neutrophil activation in an ex vivo assay (27).
These immunmodulatory effects can certainly be looked upon as a two-edged sword. Do HMO compromise the infant's immune defense and harm the breast-fed infant or do they keep the immune system in check and protect the breast-fed infant against overshooting immune responses such as necrotizing enterocolitis (NEC)? In fact, the incidence for NEC is 85% lower in breast-fed than in formula-fed infants (28). Although NEC pathomechanisms are not yet fully understood, it seems to be the infant's own invading leukocytes and their excessive ROS production that propagate NEC pathogenesis after a primary insult [reviewed in (29)]. Because HMO inhibit leukocyte adhesion at sites of inflammation and reduce formation of highly active PNCs, they may contribute to the protection of breast-fed infants against NEC and other inflammatory diseases (1,24,25,27,28).
Due to structural similarities, HMO may also interfere with other protein-carbohydrate interactions (Table 2). Galectins (galactoside-binding lectins), for example, bind ß-galactosides and poly-N-acetyllactosamine–enriched glycans. The backbone of HMO is formed by these poly-N-acetyllactosamines (1). Galectins regulate cell growth, proliferation, and apoptosis, as well as cell-cell and cell-matrix interactions (30). Siglecs (sialic acid binding Ig-like lectins) bind to terminal sialic acid (2-3 or/and 2-6-bound) (31) which is also present on some HMO.
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Screening for "bioactive" HMO. HMO are a heterogenic group of at least 130 different compounds. Which of these oligosaccharides interact with a given lectin is currently unknown. Recent advances in MS, including Fourier transform ion cyclotron resonance MS (34), will help to fully profile the HMO glycome and describe interindividual differences as well as intraindividual changes during the time of lactation. To screen for potentially bioactive HMO, at least 2 approaches are imaginable: on the one hand, oligosaccharides can be passed over a column-bound lectin in frontal-affinity chromatography-MS. Oligosaccharides with higher affinity will elute later and can be detected on-line (35). On the other hand, HMO can be immobilized on glyco-chips (36,37) and the binding specificities of lectins can be determined. However, binding under these artificial conditions does not guarantee bioactivity. Carefully chosen biological systems will be required to verify that the identified oligosaccharides also interact with the lectin in a physiological setting.
Once individual "bioactive" HMO are identified, they can be chemically synthesized and used to supplement infant formula for clinical trials. The recent development of automated solid-phase oligosaccharide synthesis (38) has been a milestone for efficient and fast chemical HMO synthesis. In solid-phase synthesis, the oligosaccharides being synthesized are linked to an insoluble material (beads or resins), which allows the rapid separation of reaction products from excess reagents, soluble reaction by-products, and solvents (39). The synthesis of complex oligosaccharides, such as the nonasaccharide Lewis x-Lewis y, required more than 1 y using solution-phase synthesis; it can now be accomplished in <1 d using automated solid-phase synthesis (40).
Despite the possibilities of chemically synthesizing individual HMO, the "bioactive" power may lie in heterogeneity. Most pathogens use more than one lectin to adhere to and invade host cells and different pathogens use lectins with different oligosaccharide-binding determinants. The more diverse the soluble analogs, the better the defense mechanisms.
Natural sources for HMO-like oligosaccharides. Instead of chemical synthesis, naturally occurring oligosaccharides isolated from the milk of other species could be used. Although HMO are considered unique, milk oligosaccharides from elephants closely resemble those of human milk (41). However, large-scale use of these oligosaccharides is impossible for obvious reasons. Goat's milk is a rich source of HMO-like oligosaccharides and may be suitable for supplementing formula. These oligosaccharides separate as by-products in goat cheese production and can be isolated by membrane technology on a large scale (42). Their effect on human infant physiology remains to be evaluated.
Next to these potential natural sources, insights into HMO biosynthesis in the mammary gland might pave the way for effective and inexpensive in vitro or in vivo techniques to synthesize vast amounts of HMO, e.g., in bioreactors. Several approaches are possible to study HMO biosynthesis, including tissue culture models (43), transgenic animals (44), or the use of stable isotopes (45). The use of human breast carcinoma cells to mimic lactating mammary epithelial cells is often limited because of dedifferentiation and loss of expression of relevant genes. However, PMC42 cells grown on matrigel and incubated with hormones express several milk-specific genes (43). Whether these cells synthesize HMO has not been determined. If so, specific knockdowns of key enzymes in glycosylation pathways may provide insights into HMO biosynthesis.
Immunogenic nonhuman sialic acid. Unlike most other mammals, including our closest relatives the great apes, humans are unable to synthesize the sialic acid derivative Neu5Gc due to an inactivating mutation in the CMAH-gene encoding for the enzyme CMP-Neu5Ac hydroxylase, which catalyzes the hydroxylation of CMP-Neu5Ac to generate CMP-Neu5Gc (46). Hence, HMO and other milk glycans contain only Neu5Ac, whereas both Neu5Ac and Neu5Gc are part of milk oligosaccharides from other species, including cows and goats. Despite the lack of the CMP-Neu5Ac hydroxylase, Neu5Gc is present in various human tissues (47). An alternative pathway to synthesize Neu5Gc in humans is not known, and it was shown both in vitro and in vivo that the presence of Neu5Gc in human tissues stems from the incorporation of exogenous, dietary Neu5Gc (47,48). Because Neu5Gc in human tissues is of nonhuman origin, it must be considered as a non-self epitope. Indeed, circulating anti-Neu5Gc-antibodies can be found in humans (47,49) and are associated with several diseases (50,51). Epidemiological studies are required to address whether the amount of ingested dietary Neu5Gc correlates with Neu5Gc tissue incorporation and disease.
Neu5Gc incorporation is enhanced in various tumors and fetal tissues (48) and might also be increased in the fast-growing tissues in newborns. The extensive Neu5Gc supply through infant formula may increase the Neu5Gc tissue content compared with breast-fed infants. Whether such differences affect infant physiology or even predispose for diseases later on in life remains elusive but may be a significant drawback for the use of milk oligosaccharides from other species, such as goats, to supplement infant formula.
HMO: Why so unique and complex? Milk oligosaccharides are synthesized exclusively in the mammary gland and only during lactation, which makes it difficult to study their biosynthetic pathway. Oligosaccharides in human milk are distinct from those of other species with respect to quantity and diversity, which limits the use of animal models to mimic HMO absorption, metabolism, pharmacokinetics, and function. Despite these hurdles, it is this particular uniqueness and the lack of HMO in infant formula that warrants further investigations into their ability to affect human health and disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 The author is supported by Deutsche Forschungsgemeinschaft, Germany (BO 2488/1-1) and declares no conflict of interest.
3 Abbreviations used: DC-SIGN, dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin); EPEC, enteropathogenic E. Coli; FAC, frontal-affinity chromatography; Fuc, fucose; Gal, galactose; Glc, glucose; GlcNAc, N-acetylglucosamine; HMO, human milk oligosaccharides; NEC, necrotizing enterocolitis; Neu5Ac, N-acetyl neuraminic acid; Neu5Gc, N-glycolyl neuraminic acid; PNC, platelet-neutrophil complexes; ROS, reactive oxygen species; 3'SL, 3'sialyllactose.
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