Human Milk Oligosaccharides: Structure and Functions

Summary 

Human milk is unique when it comes to the high concentrations and structural diversity of oligosaccharides. In fact, human milk oligosaccharides (HMOs) are the third most abundant component of human milk after lactose and lipids, often exceeding the total amount of human milk proteins. HMOs are composed of up to 5 different building blocks: glu- cose, galactose, N-acetylglucosamine, fucose, and sialic acid. More than 150 different HMOs have been identified and characterized so far, and, most intriguingly, the composition varies between women and changes over the course of lactation. Single-nucleotide polymorphisms in genes that encode specific fucosyltransferase enzymes are known to dramatically affect HMO composition. However, how other enzymes and transporters, for example, are involved in HMO biosynthesis remains largely unknown. The combination of genome-wide association studies, human milk transcriptomics, in vitro gene editing, and in silico pathway modeling allows us to reconstruct the HMO biosynthetic pathway and lays the foundation to modulate and optimize it once we fully understand the effects of HMOs on infant and maternal health and development. Once ingested, HMOs resist degradation through the infant, a small percentage is absorbed and reaches the systemic circulation, and the rest reaches the colon where it gets metabolized by the infant gut microbiota or is excreted intact with the feces. HMOs are known to be prebiotics, but they also serve as antimicrobials, antiadhesives, or immune cells modulators – both locally in the gut as well as systemically after absorption. Using
new data-mining approaches and leveraging samples and metadata from large mother-infant cohorts enables us to identify associations between individual HMOs or HMO composition profiles with infant and maternal health outcomes. Suitable preclinical models and clinical intervention studies allow us to corroborate the established associations for causal relationships and test for in vivo efficacy in humans. In some cases, individual HMOs alone are effective, and the effects are highly structure specific
and dose dependent, suggesting mediation through specific receptors either on a host cell or on microbes. For example, we discovered that a specific HMO named disialyllacto-N-tetraose improves survival and reduces pathology scores in an animal model of necrotizing enterocolitis [1]. In human cohort studies, preterm infants that receive human milk with low levels of the same HMO are at higher risk to develop necrotiz- ing enterocolitis [2]. In a second example, specific HMOs increase the
infectivity of a specific rotavirus G10P strain in tissue culture. The same HMOs occur at higher concentrations in the milk given to infants that acquire symptomatic rotavirus infections [3]. Both examples highlight the power of combining data generated from suitable preclinical models with data obtained from mother-infant cohorts. In other cases, the mixture and relative abundance of different HMOs to each other is what makes them most effective, suggesting mediation through complex interactions
of multiple different HMOs on different molecular targets that shape the composition of gut microbial communities or complex multi-cell immune responses. For example, the ratio of 2′-fucosyllactose and lacto-N-neo- tetraose in mother’s milk is associated with height and weight z-scores in a small Danish pilot study as well as in a large Finnish mother-infant cohort [4]. In a second example, not one single HMO alone is associated
with food sensitization when the infant is 1 year of age, but the combination of several HMOs as a specific profile is associated with food sensitization [5]. Overall, the knowledge generated from combining suitable preclinical models, mother-infant cohort association studies, as well as randomized clinical trials will help us establish true structure-function relationships and provide the rigorous evidence required to improve
infant health and development.

References
1 Jantscher-Krenn E, Zherebtsov M, Nissan C, et al: The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotizing enterocolitis in neonatal rats. Gut 2012;61:1417–1425.
2 Autran CA, Kellman BP, Kim JH, et al: Human milk oligosaccharide composition
predicts risk of necrotizing enterocolitis in preterm infants. Gut 2018;67:1064–1073.
3 Ramani S, Stewart CJ, Laucirica DR, et al: Complex interplay between human milk
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4 Larsson MW, Lind MV, Laursen RP, et al: Human milk oligosaccharide composition
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5 Miliku K, Robertson B, Sharma AK, et al: Human milk oligosaccharide profiles and
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