What Is HMO in Formula? Key Facts About Infant Oligosaccharides

Human milk oligosaccharides (HMOs) are complex carbohydrates in breast milk that support infant health by promoting gut microbiota development, enhancing immune function, and protecting against infections. To better replicate human milk, some infant formulas now include HMOs.

As research advances, more HMOs are being synthesized and added to commercial formulas. Understanding their role in infant nutrition requires examining their molecular structure, production methods, and regulatory considerations.

Molecular Characteristics

HMOs are structurally diverse carbohydrates composed of five primary monosaccharides: glucose, galactose, N-acetylglucosamine, fucose, and sialic acid. These non-digestible glycans vary in size, branching, and functional properties. Their molecular weight ranges from 300 to 3000 Daltons, depending on polymerization and glycosidic linkages. Their structural complexity influences stability, solubility, and biological interactions.

Most HMOs have a lactose core as a foundation for modifications. Fucosylation and sialylation contribute to their diversity—fucosylated HMOs like 2′-fucosyllactose (2′-FL) contain fucose, while sialylated HMOs, such as 3′-sialyllactose (3′-SL) and 6′-sialyllactose (6′-SL), incorporate sialic acid, giving them a negative charge that affects biological activity. These modifications classify HMOs as either neutral or acidic, each with distinct properties.

Glycosidic linkages further influence HMO function, affecting resistance to enzymatic degradation in the infant gut. Unlike digestible carbohydrates, HMOs remain intact through digestion, reaching the colon where they interact with microbial communities. Their β-glycosidic bonds resist hydrolysis, ensuring they exert effects in the lower intestine.

Types Found in Infant Formulas

The inclusion of HMOs in infant formulas has expanded, with manufacturers incorporating those structurally similar to those in breast milk and feasible to produce at scale. The most common is 2′-fucosyllactose (2′-FL), a fucosylated HMO abundant in human milk. Studies in The Journal of Nutrition show that 2′-FL is well-tolerated in formula-fed infants and can be synthesized via microbial fermentation using genetically modified Escherichia coli. Due to its prevalence and safety profile, 2′-FL is now standard in many formulas.

Additional HMOs, such as lactodifucotetraose (LDFT) and difucosyllactose (DFL), have been explored but are less commercially available. Sialylated HMOs, including 3′-sialyllactose (3′-SL) and 6′-sialyllactose (6′-SL), are gaining attention due to their structural attributes and potential benefits. These are typically produced using microbial fermentation, similar to 2′-FL.

Some formulas incorporate blends of multiple HMOs to better approximate breast milk composition. Research in Nutrients suggests that multi-HMO blends more closely resemble human milk, though formula still contains fewer oligosaccharides overall. Differences in formulation strategies between brands affect composition, with some opting for single-HMO supplementation while others include multiple types in varying proportions.

Labeling Protocols

Accurate labeling of HMOs in infant formula is essential for regulatory compliance and consumer transparency. Ingredient labels follow systematic carbohydrate nomenclature, listing compounds such as “2′-FL” for 2′-fucosyllactose and “3′-SL” or “6′-SL” for sialylated oligosaccharides. Some brands also include total HMO concentration per serving, though this is not universally required.

Marketing claims about HMOs must be substantiated by compositional analysis. While synthetic HMOs replicate natural structures, they do not encompass the full diversity of breast milk. Regulatory bodies such as the European Food Safety Authority (EFSA) and the U.S. Food and Drug Administration (FDA) evaluate these claims to ensure accuracy. In some regions, manufacturers cannot imply that formula-fed infants receive identical benefits to breastfed infants solely from HMO supplementation.

The order of ingredients on labels reflects their relative concentrations. If 2′-FL appears early in the list, it is present in higher amounts. Some formulas include multiple HMOs, with ratios varying by brand. While no standardized minimum or maximum levels exist, companies must demonstrate that HMO inclusion meets established safety thresholds.

How HMOs Are Manufactured

HMOs are produced using biotechnological methods to replicate their complex structures. Since extracting HMOs from human milk is impractical, synthetic approaches meet commercial demand. One common method is microbial fermentation, where genetically modified bacteria, such as Escherichia coli or Lactococcus lactis, express enzymes for HMO biosynthesis. These microorganisms convert simple sugars into target oligosaccharides in controlled fermentation tanks. Once synthesized, HMOs are purified and tested for structural fidelity.

Enzymatic synthesis is another approach, using glycosyltransferases to add monosaccharides in a controlled sequence. This method ensures high purity but is more expensive than fermentation. Chemical synthesis has been explored but is less viable due to complexity and lower yields.

Brand Differences

HMO inclusion in infant formula varies by manufacturer, with differences in the number, concentration, and types used. Some brands focus on single-HMO formulations, primarily using 2′-FL due to its prevalence and safety profile. Others incorporate multi-HMO blends, including lacto-N-neotetraose (LNnT), 3′-SL, and 6′-SL, to better replicate breast milk diversity.

HMO concentrations also differ, with some brands using levels approximating the lower range of breast milk and others basing amounts on clinical studies. Since human milk contains over 150 different oligosaccharides, even advanced formulas offer only a partial representation. Some companies highlight this limitation, marketing their products as “HMO-enriched” rather than direct substitutes for breast milk. Processing techniques, such as how HMOs are integrated into powdered or liquid formulas, may also affect stability and bioavailability. Parents comparing formulas should review ingredient lists, as formulations vary widely by region and product line.

Regulatory Perspective

Regulatory agencies oversee HMO approval and labeling to ensure safety and accuracy. In the U.S., the FDA evaluates new HMOs under its Generally Recognized as Safe (GRAS) program, requiring manufacturers to provide scientific evidence of safety. The EFSA follows a similar process, reviewing toxicology data and human studies before approval.

Regulations dictate how HMOs can be described on packaging. Claims suggesting formulas provide identical benefits to breast milk are generally prohibited, as human milk contains a complex array of bioactive compounds. Manufacturers must ensure that any statements about HMOs, such as their role in gut microbiota support, are backed by scientific evidence and comply with regional guidelines. Discussions continue on setting standardized inclusion levels for HMOs in formula, ensuring consistency while maintaining safety standards. As research evolves, regulatory agencies may update guidelines to reflect new findings on HMO benefits in infant nutrition.