Human milk oligosaccharides: every baby needs a sugar mama

Abstract

Human milk oligosaccharides (HMOs) are a family of structurally diverse unconjugated glycans that are highly abundant in and unique to human milk. Originally, HMOs were discovered as a prebiotic "bifidus factor" that serves as a metabolic substrate for desired bacteria and shapes an intestinal microbiota composition with health benefits for the breast-fed neonate. Today, HMOs are known to be more than just "food for bugs". An accumulating body of evidence suggests that HMOs are antiadhesive antimicrobials that serve as soluble decoy receptors, prevent pathogen attachment to infant mucosal surfaces and lower the risk for viral, bacterial and protozoan parasite infections. In addition, HMOs may modulate epithelial and immune cell responses, reduce excessive mucosal leukocyte infiltration and activation, lower the risk for necrotizing enterocolitis and provide the infant with sialic acid as a potentially essential nutrient for brain development and cognition. Most data, however, stem from in vitro, ex vivo or animal studies and occasionally from association studies in mother-infant cohorts. Powered, randomized and controlled intervention studies will be needed to confirm relevance for human neonates. The first part of this review introduces the pioneers in HMO research, outlines HMO structural diversity and describes what is known about HMO biosynthesis in the mother's mammary gland and their metabolism in the breast-fed infant. The second part highlights the postulated beneficial effects of HMO for the breast-fed neonate, compares HMOs with oligosaccharides in the milk of other mammals and in infant formula and summarizes the current roadblocks and future opportunities for HMO research.

Fig. 1.

Pioneers in HMO research in the 20th century. HMO research originates at the end of the 19th century with parallel work by pediatricians and microbiologists that studied the health benefits of human milk (top half of the time-scale) and chemists that characterized the carbohydrates abundant in human milk (bottom half of the time-scale). Toward the middle of the 20th century scientists from both disciplines closely collaborated, which led to the discovery that human milk “gynolactose” is the “bifidus factor” and consists of oligosaccharides. Since then, more than a hundred different HMOs have been isolated and characterized, and accumulating data suggest that HMOs benefit the breast-fed neonate in multiple ways (black arrows indicate direct mentor–mentee relationships over the course of the century).

Fig. 2.

HMO blueprint and selected HMO structures. (A) HMOs follow a basic structural blueprint. (Monosaccharide key is shown at the bottom of the figure.) (B) Lactose can be fucosylated or sialylated in different linkages to generate trisaccharides. (C) Lactose can be elongated by addition of either lacto-N-biose (type I) or N-acetyllactosamine (type II) disaccharides. Addition of disaccharides to each other in the β1-3 linkage leads to linear chain elongation (para-HMO); a β1-6 linkage between two disaccharides introduces chain branching (iso-HMO). (D) Elongated type I or II chains can be fucosylated in different linkages to form a variety of structural isomers, some of which have Le blood group specificity (Figure 3). (E) The elongated chains can also be sialylated in different linkages to form structural isomers. Disialylated lacto-N-tetraose (bottom right) prevents NEC in neonatal rats.

Fig. 3.

Se- and Le-dependent HMO fucosylation. HMO fucosylation highly depends on a woman's Se and Le blood group status and allows for the distinction of four milk groups. FUT2 is encoded by the Se gene (Se) and facilitates the addition of Fuc to terminal Gal in an α1-2 linkage. FUT3 is encoded by the Le gene (Le) and catalyzes the addition of Fuc to subterminal GlcNAc on type I chains in an α1-4 linkage. If both FUT2 and FUT3 are expressed, milk contains HMO with Le b antigens (highlighted). If only FUT3 is expressed, milk contains HMO with Le a antigens (highlighted). If FUT3 is not expressed, HMOs contain neither Le a nor Le b antigens.

Fig. 4.

Postulated HMO biosynthesis. Although lactose synthesis in the Golgi of mammary gland epithelial cells has been well described and is catalyzed by lactose synthase (LS), subsequent HMO biosynthesis remains poorly understood. Speculations on enzymes (shaded background) involved in HMO biosynthesis are based on other known glycan synthesis pathways, but data to prove their involvement in HMO biosynthesis are often missing, which raises many questions that are pointed out in the figure with question marks and are further explained in the text. Enzymes known to be involved are highlighted in bold. Enzymes that are speculated to be involved are italicized.

Fig. 5.

Postulated HMO effects. HMOs may benefit the breast-fed infant in multiple different ways. (A) HMOs are prebiotics that serve as metabolic substrates for beneficial bacteria (green) and provides them with a growth advantage over potential pathogens (purple). (B) HMOs are antiadhesive antimicrobials that serve as soluble glycan receptor decoys and prevent pathogen attachment. (C) HMOs directly affect intestinal epithelial cells and modulate their gene expression, which leads to changes in cell surface glycans and other cell responses. (D) HMOs modulate lymphocyte cytokine production, potentially leading to a more balanced Th1/Th2 response. (E) HMOs reduce selectin-mediated cell–cell interactions in the immune system and decrease leukocyte rolling on activated endothelial cells, potentially leading to reduced mucosal leukocyte infiltration and activation. (F) HMOs provide Sia as potentially essential nutrients for brain development and cognition. (Center photo taken from author's personal collection).