Introduction to Human Milk Oligosaccharides (HMOs)
Human milk is an incredibly complex fluid that provides complete nutrition for infants, but it also contains numerous bioactive components that support their overall health and development. Among these, human milk oligosaccharides, or HMOs, are a highly diverse group of complex carbohydrates present in high concentrations. Unlike lactose, which provides energy directly to the infant, HMOs are mostly indigestible and pass through the infant's digestive system to reach the large intestine largely intact. Here, they serve several crucial functions beyond simple nutrition, acting as powerful prebiotics, anti-adhesive agents, and immune modulators. This dynamic composition changes over the course of lactation and varies significantly between mothers, highlighting the tailored nature of breast milk. Decades of research have illuminated the complex roles of HMOs in infant health, prompting the addition of some synthetic, human-identical HMOs to modern infant formulas to mimic these vital benefits.
The Multifunctional Roles of HMOs
Prebiotic Effect and Gut Microbiome Development
One of the most well-known functions of HMOs is their role as prebiotics. By resisting digestion in the upper gastrointestinal tract, they arrive in the colon to be selectively fermented by beneficial bacteria, most notably Bifidobacterium species. This process gives these good bacteria a significant advantage over potential pathogens, helping to establish and maintain a healthy, balanced gut microbiome. The fermentation of HMOs by Bifidobacteria produces beneficial metabolites called short-chain fatty acids (SCFAs), such as acetate and lactate. SCFAs are essential for strengthening the gut's mucosal barrier, providing energy to colon cells, and creating a low-pH environment that is unfavorable for pathogenic bacteria. The dominance of Bifidobacteria in breastfed infants' guts is a direct result of this selective feeding by HMOs.
Anti-Adhesive 'Decoy' Receptors
Another key mechanism of action for HMOs is their ability to act as soluble decoy receptors. The complex structures of HMOs closely mimic the glycans (sugar chains) found on the surface of the infant's gut epithelial cells. Many pathogens, including specific viruses (like norovirus and rotavirus) and bacteria (like Campylobacter jejuni and enteropathogenic E. coli), must bind to these epithelial glycans to cause an infection. By floating freely in the gut, HMOs can intercept these pathogens, effectively blocking them from binding to the gut lining. The pathogens then pass harmlessly through the digestive tract and are excreted, providing a direct anti-infective defense. The specific decoy function can depend on the HMO structure, which varies widely.
Immunomodulatory and Anti-Inflammatory Effects
Beyond their direct impact on the gut microbiome and pathogens, HMOs also interact directly with the infant's immune system. A small percentage of HMOs is absorbed into the infant's circulation, where they can modulate immune cell responses. Research indicates that HMOs can influence the expression of pro- and anti-inflammatory cytokines, helping to maintain immune homeostasis. This has significant implications for preventing conditions like necrotizing enterocolitis (NEC) in premature infants, where HMOs have been shown to reduce inflammatory responses and strengthen the intestinal barrier. The anti-inflammatory properties are linked to the production of SCFAs by HMO-fermenting bacteria and the direct interaction of HMOs with immune cell receptors.
Role in Brain Development
Emerging research suggests that HMOs may play a role in infant neurodevelopment through the gut-brain axis. Sialylated HMOs, which contain sialic acid, are particularly important in this area. The cell membranes of neurons are rich in gangliosides, which require sialic acid for proper function. By potentially providing a source of sialic acid, or influencing other pathways, HMOs support various aspects of cognitive development, learning, and memory. Animal studies have shown that supplementation with specific HMOs can improve memory and learning abilities. Furthermore, observational studies in human infants suggest that exposure to certain HMOs, like 2'-FL in early life, may be associated with improved cognitive outcomes.
HMOs in Infant Formula
Given the profound benefits of HMOs, the infant formula industry has worked to incorporate them into products to better mimic breast milk. However, recreating the full diversity of over 200 different HMOs found in breast milk is not yet possible. The most common human-identical HMOs (or HiMOs) added to formula are 2'-fucosyllactose (2'-FL) and lacto-N-neotetraose (LNnT). While these additions are a significant step forward and have been shown in some studies to shift the gut microbiome and immune markers closer to that of breastfed infants, formula containing HMOs still lacks the full complexity and dynamic changes of natural breast milk. Nonetheless, for formula-fed infants, the inclusion of these synthetic HMOs represents a valuable nutritional enhancement.
Comparison of HMOs, Probiotics, and Classic Prebiotics
| Feature | Human Milk Oligosaccharides (HMOs) | Probiotics | Classic Prebiotic Oligosaccharides (PBOs) |
|---|---|---|---|
| Source | Naturally in human breast milk; some synthetically produced | Live beneficial bacteria; from fermented foods or supplements | Non-digestible fibers; from plants like chicory root |
| Mechanism | Act as food for specific gut bacteria and as pathogen decoys | Introduce living beneficial bacteria into the gut | Serve as food for a broader range of bacteria |
| Specificity | High; selectively promote the growth of specific beneficial bacteria like Bifidobacterium | Variable; depends on the strains included | Lower; fermented by many types of gut bacteria |
| Role | Diverse; prebiotic, anti-adhesive, immune modulator | Modulate gut flora by introducing new strains | Feed and promote bacterial growth |
| Digestion | Resists digestion in the infant's GI tract | Survived passage through the digestive tract to reach the colon alive | Resists digestion to reach the colon |
Conclusion
What are human milk oligosaccharides? They are complex, indigestible sugars that are far more than just a source of calories. As the third most abundant component of breast milk, HMOs are a testament to the sophisticated design of human lactation, serving as multi-functional agents that profoundly shape an infant's earliest developmental stages. By acting as selective prebiotics, they cultivate a healthy gut microbiome dominated by beneficial bacteria. As soluble decoys, they provide a powerful defense against infections from bacteria, viruses, and parasites. Their systemic effects further modulate the immune system and are increasingly recognized for their role in neurodevelopment. While synthetic versions of some HMOs are now available in infant formulas, they still cannot replicate the full diversity and concentration found in human milk. The ongoing research into HMOs continues to uncover their full range of biological functions and therapeutic potential, not only for infants but potentially for adult health as well.
Learn more about HMOs from a scientific perspective on the ScienceDirect review.
