Milk Oligosaccharides: Every Mammal Has a Different Sugar Mama

Written by: Lauren Milligan Newmark, Ph.D. | Issue # 116 | 2023

The scientific literature on mammalian milk oligosaccharides just got a glow up thanks to a team of milk and food scientists from University of California—Davis and the U.S. Department of Agriculture. MilkOligoDB [1] brings together 50 years of research results on milk oligosaccharides from nearly 80 mammal species. The team standardized the available data on milk oligosaccharides and transformed them into a searchable and open access database—no easy feat considering the sheer number of oligosaccharides in mammalian milks and the heterogeneity of data reporting on their identification and concentration. 

Necessity drives invention, so it shouldn’t be surprising that the team that created MilkOligoDB includes researchers interested in understanding how other mammals’ milks compare with human milk in types and quantities of oligosaccharides. Of particular interest to the team was the identification of nonhuman milks that could be a source of oligosaccharides for supplementing human infant formula. 

Oligosaccharides are complex carbohydrates made from between three and twenty single sugar molecules. Unlike the milk sugar lactose, which is digested in the small intestine and provides energy for infant growth and development, milk oligosaccharides are generally intact when they reach the large intestine. Once they get there, however, they get to work by providing food for beneficial bacteria that line the infant gut. This well-fed probiotic gut population increases and their consumption of oligosaccharides produces short-chain fatty acids, which have anti-inflammatory properties [1-3]. Some human milk oligosaccharides (HMOs) are also doppelgängers for sugars found on the surface of gut epithelial cells. In an act of biological trickery, they act as decoy receptors for pathogens; pathogens bind to oligosaccharides instead of gut cells and are removed from the gut instead of causing infection [1-4]. HMOs may even support brain development as a source of sialic acid [1-3]

It is these prebiotic and anti-microbial actions of HMOs that make them highly desirable ingredients for infant formula. But the very thing that makes them so effective in keeping infants healthy—a high degree of structural diversity—makes them difficult to replicate. For reference, researchers have identified over 300 different oligosaccharides across human mothers, each unique structure associated with a potentially unique function [5]. Currently, some formulas do include synthetic oligosaccharides, but they are difficult and expensive to produce and may have functional differences from HMOs [1]. Researchers have also isolated HMOs from human milk for formula supplementation, but this process is also difficult and costly, and only feasible with smaller, less complex oligosaccharides [1]. 

With these roadblocks, researchers turned to nonhuman mammal milks as potential sources of biologically active carbohydrates. MilkOligoDB was specifically designed to facilitate species comparisons that were not possible with the scattered and heterogenous data from the literature. Pulling from a total of 113 different publications and representing 77 mammal species, the database has 3,193 entries for 783 unique oligosaccharides [1]. But users do not have to go through entry by entry to compare profiles. 

If a researcher is interested in comparing milk oligosaccharide profiles between two different mammal species (or even a group of species), the database transforms their unique and shared carbohydrates into a concept map that clearly labels and color codes oligosaccharides that are shared, and those that are unique to a species [1]. Did the concept maps from MilkOligoDB reveal any mammal species that produce milks with oligosaccharides that match the structural features in human milk? 

The short answer is no. But the longer, and infinitely more interesting answer is that all mammals appear to have unique oligosaccharide profiles that reflect species’ adaptations, including their reproductive strategies and pathogen exposure. Because of this, you wouldn’t expect to find a perfect replicate for human milk but rather groups of species with similar oligosaccharide patterns due to similar life history strategies or similar ecological niches. 

In a perfect example of “one of these things is not like the other,” the team found that milk from chimpanzees, bonobos, and Asian elephants had the best balance of the three key features that typify HMOs [1]. The MilkOligoDB team hypothesized these species converge on this shared suite of features because they all produce offspring with an extended lactation period and have infants that need more immune support due to a slower immune maturation. 

Human infants are needy in other ways as well. Because of their extended period of brain growth during their first 18 months of life, human infants are considered altricial, or less mature and in need of more parental care. In another fascinating instance of convergent evolution, MilkOligoDB revealed that human milk shares a similar feature in oligosaccharide composition—more fucosylated structures—with other mammals that produce altricial young, including bears, dogs, skunks, and some primates [1]. Fucosylated oligosaccharides, oligosaccharides where a fucose sugar molecule is linked onto the carbohydrate chain, are the largest fraction of HMOs [6]. Fucosylated oligosaccharides may act as decoy receptors and fucose on its own has been shown to have a protective effect on infection and inflammation, features that may be particularly important for immature neonates [1, 6]. 

Unfortunately, none of these species that humans shared similarities with were reasonable sources (i.e., commercially milked) for milk oligosaccharide isolation [1]. However, some camel and goat breeds did have high concentrations of fucosylated oligosaccharides. In particular, the whey fraction from these milks—the liquid part of milk that separates from the curd during cheese production—could be useful in creating supplements for infants or even as additives to other foods to improve human nutrition [1]. Analyzing milk from domestic species commonly milked outside of the U.S., such as yaks and llamas, for oligosaccharide profiles could reveal additional sources for supplements. Looking for a perfect match for HMOs may be fruitless, but extracting bioactive carbohydrates with known prebiotic and anti-microbial properties from multiple domestic species could provide health benefits to formula-fed infants. 

MilkOligoDB is far from complete. The concept map format highlights gaps in the literature, indicating a handful of mammalian orders without any corresponding data (anyone have access to flying lemur milk?). And the MilkOligoDB creators are still working hard to improve the functionality of the database by developing a graphical interface to visually see comparisons across species, standardized identifiers for all terms, and even add a programming interface that would allow users to include data from MilkOligoDB in their own databases.

MilkOligoDB may have been created with a particular research question in mind, but ultimately it will move milk science forward by helping other researchers generate new hypotheses about the evolutionary origins of milk oligosaccharides, why milk oligosaccharides are so structurally variable across species, and even milk’s role in the infant’s immune system.

References

1. Durham SD, Wei Z, Lemay DG, Lange MC, Barile D. Creation of a milk oligosaccharide database, MilkOligoDB, reveals common structural motifs and extensive diversity across mammals. Scientific Reports. 2023 Jun 26;13(1): 10345.
2. Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep 1;22(9): 1147-62.
3. German JB, Freeman SL, Lebrilla CB, Mills DA. Human milk oligosaccharides: evolution, structures and bioselectivity as substrates for intestinal bacteria. Personalized nutrition for the diverse needs of infants and children. Nestle Nutr Workshop Ser Pediatr Program 2008; 62: 205-22.
4. Morrow AL, Ruiz-Palacios GM, Jiang X, Newburg DS. Human-milk glycans that inhibit pathogen binding protect breast-feeding infants against infectious diarrhea. The Journal of Nutrition. 2005 May 1;135(5): 1304-7.
5. Ayechu-Muruzabal V, Van Stigt AH, Mank M, Willemsen LE, Stahl B, Garssen J, Van’t Land B. Diversity of human milk oligosaccharides and effects on early life immune development. Frontiers in Pediatrics. 2018 Sep 10; 6: 239.
6. Orczyk-Pawiłowicz M, Lis-Kuberka J. The impact of dietary fucosylated oligosaccharides and glycoproteins of human milk on infant well-being. Nutrients. 2020 Apr 16;12(4): 1105.

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