The Power of Human Milk Oligosaccharides: Nature’s Secret to Infant Health

Human milk oligosaccharides (HMOs) are the third most abundant solid human breast milk component behind lactose and lipids, and occur in total concentrations during colostrum of about 20 25 g/L and mature milk of 5 15g /L as reported by several studies, including a 2020 cohort analysis by Pediatric Research. This group of non-digestible carbohydrates is constructed on a lactose base and is decorated with fucose, sialic acid, N-acetylglucosamine and galactose to make a very wide repertoire: more than 200 different molecular species have been described, of which around 50 contain the majority (more than 99%) of the total abundance in human milk. Depending on the stage of lactation (colostrum, transitional, and mature milk production), concentrations and profiles of HMOs vary and are also subject to maternal genetics (secretor and Lewis blood group status, FUT2 and FUT3), geography, diet, and health. In this example, secretor-positive mothers synthesize 2-fucosyl transferase modified HMOs such as 2- 2-fucosyllactose, which accounts for up to 30 percent of all HMOs, and can be 3-fucosyllactose in non-secretors, demonstrating high levels. The changing levels of HMOs throughout lactation, which are high early on and decrease steadily, match the changing developmental requirements of the gut, the immune system. This has been increased by the fact that infants are subjected to this abundance, complexity, and individualized variation, all of which highlight the importance of utilizing HMOs in influencing infant health and have led to a recent explosion of both literature and novel formula formulations meant to recreate such unique bioactive properties.

**Fig.1.** Basic Structure of Human Milk Oligosaccharides.
**Source:** Adapted from mdpi.com

What are Human Milk Oligosaccharides?

Human Milk Oligosaccharides (HMOs) are a complex and diverse mixture of non-digestible carbohydrates and usually have backbone lengths of 3 to 20 monosaccharide units and typically have 5 to 20 monosaccharide residues. Oligosaccharides constitute the third most abundant solid component of human milk after lactose and lipids, and structurally can be divided into neutral and acidic. Neutral types include: fucosylated or non-fucosylated. The glycans cannot be digested by the infant, rather that the ability to act as prebiotics, immune modulators, and anti-pathogenic by developing the infant gut microbiota and resembling the host cell surface receptors to block the pathogen adherence. It is worth mentioning that now more than 200 different HMO structures are identified, and their content can drastically change according to the genetics of the mother (e.g., FUT2 and FUT3 gene expression), lactation stage, and even based on geography. As an example, secretors (carrying the FUT2 gene) have greater concentrations of some fucosylated HMOs such as 2 26; fucosyllactose (2 26; FL), which has been associated with decreased occurrence of neonatal diarrhea and necrotizing enterocolitis. Scientific research has indicated that HMOs are vital in early immune establishment, such as the development of the gut microbiome, encouragement of the growth of useful bacteria, such as Bifidobacterium longum subsp. infantis, and associating with epithelial and immune cells. The direct antimicrobial activity, lack of adherence to pathogens, and decoys to viruses like norovirus and rotavirus are functions attributed to the HMOs (Bode et al., 2012). Also, a study published by Zivkovic et al. (2011) emphasizes the evolution of HMO structure during lactation and considers the time-dependence of infant health outcomes.

Human Milk Oligosaccharides

The Importance of HMOs in Infant Health

The third most abundant solid compound of human breast milk, besides lactose as well as lipids, is Human Milk Oligosaccharides (HMOs). HMOs also provide effective biological properties, although they are not digestible by the infants and form the foundation of lifelong health. These polysaccharides help to strengthen the microbial growth in the gut of the baby, the immune system, brain growth, and physiological fortification against illness.

1. Prebiotic Effects:

Among the most studied functions of HMOs, prebiotics is one of them. They act as selective nutrition for beneficial bacteria, particularly the Bifidobacterium longum subsp. Infants that inhabit the infant’s intestines. These are good bacteria that beat other bad microorganisms, thus preventing the sharp instances of infections and inflammation. The 2023 randomized controlled trial (RCT) showed a 45-fold increase in bifidobacteria in infants who were fed a five-HMO-containing formula and a significant reduction in the pathogenic genera, such as Clostridioides difficile. These results help to highlight the influence of HMOs on building the microbiota and maintaining a healthy gut in the stages of life when a person is exposed to the largest number of new species, and their role in the setting of a healthy gut environment during early life.

2. Support to the immune system:

HMOs have a twofold role in the development of the immune system. On the one hand, they inhibit adhesion of pathogens to the cell surface, since they imitate cell-surface glycans that pathogens normally clone. In other words, they serve as decoys to prevent infection. Secondly, they regulate Immune cell activity and inflammation. The same 2023 RCT reported that infants fed the five-HMO formula had increased secretory IgA (a main antibody in mucosal immunity) and reduced levels of the fecal calprotectin marker of inflammation. These findings indicate improvements in mucosal immunity and less gut inflammation in the infants fed with HMO, which led to the conclusion that they contribute to a strong and balanced immune system.

3. Brain Development:

Subgroups of HMOs are sialylated HMOs, which have sialic acid, a macronutrient with brain development implications during infancy when neurons multiply rapidly. Sialic acid is necessary in the production of gangliosides and glycoproteins, which are involved in neuronal connections, the creation of synapses, and the use of memory. They indicate that infants have greater cognitive performance later in childhood when they are fed on breast milk that has high levels of sialylated HMOs. These neurodevelopmental advantages in early life might imply upshot difficulties in studying and conduct.

4. Disease Prevention:

HMOs play an essential role in disease prevention as they mold the gut microflora and empower the gut wall, as well as micro-regulate immune responses. HMO consumption has been associated with a decreased infection rate, a decrease in the allergic reaction, and a lowered chance of necrotizing enterocolitis (NEC), which is a deadly bowel illness in preterm babies. In addition to that, new findings indicate HMOs can play a role in programming metabolism and making it less prone to obesity and insulin resistance during adulthood. They have anti-inflammatory and immunomodulatory effects, which provide a basis of long-term health in infancy.

Types of Human Milk Oligosaccharides

HMOs are widely grouped regarding their chemical structure and the existence of charged groups:

1. Neutral HMOs:

Neutral-core HMOs consist of a lactose backbone and additional N-acetylglucosamine and galactose epitopes, but do not contain fucose any sialic acid groups. Over 225 different neutral-core HMOs have now been identified shipped19 Examples are lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT), which are mainly prebiotic substrates that favor the growth of beneficial gut flora. 

2. Fucosylated HMOs:

Fucose forms one or more fucose residues attached by -1,2, -1,3, or -1,4 bonds to the core structure on these HMOs. The most prevalent of them is 2 2 fucosyllactose (2 2 FL), which makes up approximately 30 percent of the HMOs in mothers who are secretors. 2 2 FL 2 Others are lacto N fucopentaose I (LNFP I), 3-fucosyllactose (3-FL)

3. Sialylated (Acidic) HMOs:

HMOs are modified by the addition of sialic acid (Neu5Ac), and this makes these HMOs negatively charged. Notable ones are 3 219벤 immediately without sialyllactose (3 219 quantum SL) and 6 219 quantum sialyllactose (6 219 quantum SL), which contribute to about 12 14 percent of HMOs. Partido system unpunctuated weird HMOs like sialylated sialylated help in brain development and immune modulation .

Structure Foundations and Variety:

Each of the HMOs contains a lactose core (galactoseglucose) which is extended by either 1,3 or 1,4-linked 1X units to result in type-1 (LNB) or type-2 (LacNAc) chains. These basic chains are further glycosylated to add fucose or sialic acid to create more than 200 different HMOs, but only a minority of 2025 structures are the major form of HMOs 95 percent total HMO composition . The secretor (FUT2) and Lewis (FUT3) status of a mother influences the presence and abundance of fucosylated HMOs due to the changes in the structures.

Key Characteristics of Human Milk Oligosaccharides:

Human milk oligosaccharides are more than just complex sugars; they are highly specific molecules with unique functions that have no parallel or equivalent. Here are two main properties that make HMOs biochemically unique:

1. HMOs Are Non-Absorbable by Infants

An in-depth study in Microbial Cell Factories indicates that the HMO is actually not digestible by infant digestive enzymes and thus about 99 percent of it reaches the colon in the intestines, undigested, where it acts as a selective prebiotic to Bifidobacteria and other favorable microorganisms.

2. HMOs Exhibit Highly Specific Structures

The review article The structure-function relationship of the human milk oligosaccharide in Advances in Nutrition, provides a thorough analysis of how small structural variations (presence or absence of linear versus branched chains, fucosylation, sialylation) cause a dramatic difference in functional behavior of HMOs (pathogen binding, immune signaling)

3. Neutral vs. Acidic HMOs and Their Complementary Roles

Biological effects of combinations of structurally diverse human milk oligosaccharides note the synergy between neutral (e.g., fucosylated) and acidic (sialylated) HMOs in providing nutrients to gut microbes, preventing pathogen infection via decoy effect, and promoting immune and brain development through released units of monosaccharides (fucose, GlcNAc, Neu5Ac).

4. Genetic and Environmental Variation in HMO Profiles

The HMO composition varies by maternal secretor status (FUT2/FUT3), geography, and diet, and with the stage of lactation, resulting in individualized phenomenon of the human milk HMO signatures in breast milk.

Cutting-Edge Research and Innovations

The exploration of human milk oligosaccharides (HMOs) has broadened significantly beyond their primary function in infant nutrition. As we continue to explore their overall function, HMOs are becoming recognized as bioactive molecules of potential use at various stages of life and within different health contexts.

Functional Formulas for Infant Health:

The potential functional nature of HMOs has attracted interest over the past decade from biotechnological companies and researchers. Advances in biotechnology allow for the production of synthetic, or bioidentical HMOs such as 2′-fucosyllactose (2′-FL) and lacto-N-neotetraose (LNnT), which have been used in HMO-enhanced varieties of infant formula. These formulas aim to reproduce the beneficial effects of breast milk for infants who are not being breastfed. Infants consuming HMO-enhanced formulas have measurable immune responses, gut microbiota composition, and lower rates of and risk for infection, as compared to infants consuming partially hydrolyzed formulas.

Personalizing Infant Nutrition:

The future of infant nutrition is becoming personalized. Scientists are developing customized formulations of HMOs to reflect an individual infant’s genetic makeup, microbiome, along mode of birth. The intent of these formulations, when possible, is to provide the unique combination of HMOs that specific infants may require for the best possible growth, development, immune system, and gut health.

Potential Emerging Medical Applications for All Ages:

Beyond infancy, HMOs are also emerging as a possible form of medical therapy for adults and may potentially be able to help treat gastrointestinal disorders such as irritable bowel syndrome (IBS), ulcerative colitis, and Crohn’s disease, based on their demonstrated anti-inflammatory, antimicrobial, and gut-barrier properties. HMOs may also serve as natural antivirals in that they can help prevent viruses that attach to host cells, such as norovirus and influenza.

Additionally, scientists are investigating HMOs as they relate to metabolic health, potential allergy prevention, and cognitive function, due to their unique immune modulation ability and balancing of the microbiome health. They are particularly exciting as candidates for future functional foods and supplements in preventive and chronic health care, and in the prevention of illness.

Conclusion

Human milk oligosaccharides are a true physiological wonder, something that is unique to humans, non-nutritive, and utterly essential to infant health. These structurally complex biomolecules move beyond traditional nutrition in supplementing infants, acting as biological messengers, immune protectors, and microbial developers in an infant’s body. HMOs play a powerful role in developing the gut microbiota, strengthening the immune system, supporting cognitive development, and preventing future health concerns, making HMOs one of the biggest breakthrough discoveries in maternal and infant health. The most exciting aspect is that this remarkable science is just taking off. As we progress with our understanding of HMOs, they are paving the way for personalized nutrition, new therapies, and prevention, not only for infants but across the human lifespan.HMOs’ unique and multifunctional therapeutic properties provide a significant avenue for innovation in medicine, food science, and biotechnology.

At GlycoDepot, we are committed to supporting this evolution in science by providing high-purity, research-grade HMOs and glycobiology reagents that enable scientists, health innovation leaders, and product developers to expand their frontiers and turn discoveries into practice.

References:

Thurl, Stephan, et al. “Variation of human milk oligosaccharides in relation to milk groups and lactational periods.” British Journal of Nutrition 104.9 (2010): 1261-1271.

https://www.nature.com/articles/s41390-020-01328