Why are human milk oligosaccharides added to infant formula and food products?

Human milk oligosaccharides (HMOs) are a special type of low-degree polysaccharides. Their addition to formulas such as infant formula and food products aims to mimic the nutritional components and biologically active molecules found in breast milk. This comprehensive approach promotes gut health, immune system development, and overall well-being. HMOs interact with microorganisms to produce beneficial metabolites, enhance gut barrier function, and reduce intestinal inflammation. Additionally, they regulate the balance of gut microbiota, promote the growth of beneficial bacteria, and potentially contribute to infant brain development. Therefore, the addition of HMOs enriches food products with valuable functional ingredients, offering comprehensive support for the health of both infants and adults.

Human milk oligosaccharides are the oligosaccharides present in human breast milk. They are formed by the combination of five monomers (D-glucose, D-lactose, N-acetylglucosamine, L-fucose, and N-acetylneuraminic acid or sialic acid) in varying proportions.

Classification of Human Milk Oligosaccharides

Human milk oligosaccharides (HMOs) can be categorized into neutral HMOs and acidic HMOs. Neutral HMOs include fucosylated oligosaccharides, while acidic HMOs include sialylated oligosaccharides and their sulfate esters. To date, more than 200 different types of HMOs have been identified in human milk.

Application and Function of Human Milk Oligosaccharides in Infant Foods

Currently, there are two approved HMOs for use in infant formula: 2'-fucosyllactose (2'-FL) and lacto-N-neotetraose. These HMOs play a significant role in promoting gut health, supporting immune system development, and providing valuable nutrients for infants.

(I) By preventing pathogens from attaching to epithelial cells, exerting anti-inflammatory and anti-infectious effects, serving as guardians of the infant gut.
(II) Promoting the maturation of intestinal mucosa and the barrier function of intestinal epithelium, acting as regulators of intestinal epithelial cells and balancing microbial flora.
(III) Serving as a prebiotic, directly and indirectly regulating immune cells, acting as immune modulators.
(IV) Lowering colonic pH, promoting the absorption of minerals such as calcium, magnesium, and iron.
(V) Providing essential nutrition for infant growth and development.

In addition to being used in the infant formula industry, infant cereal products, and infant nutritional supplements, human milk oligosaccharides (HMOs) can also be utilized as dietary supplements or functional foods for children, adults, the elderly, and breastfeeding women. For more information on HMO products, please call our ordering hotline at 400-021-8158!

Infant Formula Applications:

Human milk oligosaccharides (HMOs) have attracted widespread interest due to their potential in promoting health benefits for both infants and adults. Through in vitro, in vivo, and clinical studies, the benefits of HMOs for gastrointestinal and immune systems have been confirmed. Recent research has also revealed the impact of HMO intake on multiple organ systems such as respiratory, central nervous, circulatory, and urinary systems. HMOs support the development of the infant immune system by interacting with intestinal epithelial cells or modulating gut microbiota, indirectly providing protection against infectious diseases. Clinical data suggests that adding HMOs to infant formulas appears to be safe and well-tolerated, contributing to health promotion. Experts believe that HMOs positively influence allergy prevention through various mechanisms such as microbial regulation and immune development. Therefore, adding HMOs to infant formulas is expected to play a positive role in managing cow's milk protein allergy.

The review "Human Milk Oligosaccharides: 2'-Fucosyllactose (2'-FL) and Lacto-N-Neotetraose (LNnT) in Infant Formula" discusses the presence of HMOs and their benefits in in vivo and in vitro studies. It emphasizes the application of the major HMO, 2'-fucosyllactose (2'-FL), in infant formulas. HMOs directly interact with intestinal epithelial cells or modulate gut microbiota, particularly stimulating bifidobacteria, supporting immune function development, and indirectly protecting infants from infectious diseases. Limited clinical data suggests that adding HMOs to infant formulas is safe and contributes to normal growth and health promotion. There are differences between HMOs in human milk and cow's milk, but adding one or two of these components to infant formulas is safe and makes the formula composition closer to human milk.

The article "Human milk oligosaccharides as bioactive compounds in infant formula: recent advances and trends in synthetic methods" points out that HMOs have gained broad interest for their potential to promote health in infants and adults. In vitro, in vivo, and clinical studies have confirmed the benefits of HMOs on gastrointestinal and immune physiological systems. Research over the past decade has also revealed the impact of HMO intake on various other organ systems such as respiratory, central nervous, circulatory, movement, and urinary systems. Due to their positive health effects, incorporating HMOs into infant formulas or other functional foods has become an urgent need. However, large-scale production is currently limited to the commercially obtained 2'-fucosyllactose (2'-FL) and lacto-N-neotetraose (LNnT) obtained through fermentation.

The article "Recent Advances on Lacto-N-neotetraose, a Commercially Added Human Milk Oligosaccharide in Infant Formula" highlights human milk oligosaccharides as important prebiotics with unique health effects in infant nutrition. Lacto-N-neotetraose (LNnT) as a rich HMO has attracted wide attention not only for its special benefits for infants but also for its commercial value. While LNnT is present in various types of breast milk, its concentration typically decreases as lactation progresses. However, LNnT exhibits excellent prebiotic properties in infants and has been verified to have other health effects, including immune regulation, anti-inflammatory, prevention of necrotizing enterocolitis, anti-adhesive antibacterial effects, antiviral activity, and promotion of intestinal epithelial cell maturation. LNnT has been proven safe and well-tolerated for infants through safety assessments and clinical trials, leading to its commercial addition to infant formulas.

The "An Expert Panel Statement on the Beneficial Effects of Human Milk Oligosaccharides (HMOs) in Early Life and Potential Utility of HMO-Supplemented Infant Formula in Cow’s Milk Protein Allergy" summarizes the opinions of experts in pediatric gastroenterology and allergy immunology, aiming to explore the biological role of HMOs and their potential applications in allergy prevention, especially cow's milk protein allergy (CMPA). Experts consider HMOs as key bioactive components in breast milk, capable of exerting anti-microbial and antiviral effects by preventing pathogens from attaching to epithelial cells. Additionally, HMOs promote the maturation of intestinal mucosa and the barrier function of intestinal epithelial cells, regulate healthy microbial composition, function as prebiotics, and directly and indirectly regulate immune cells as immune modulators. Thus, experts believe that the link between HMOs and allergy prevention depends on their effects on gut microbiota, intestinal mucosal barrier, immune regulation, and immune development. Besides reducing the risk of respiratory and gastrointestinal infections, formula with added HMOs appears promising in CMPA management. Further research is needed to fully understand the immune regulatory mechanisms and potential of HMOs in preventing allergic diseases and CMPA.

The article "Analysis of Six Human Milk Oligosaccharides (HMO) in Infant Formula and Adult Nutritionals by 2AB Labeling and Quantification with HILIC-FLD: First Action 2022.02" discusses the application of human milk oligosaccharides (HMOs) in enhancing infant immune function and supporting brain development. HMOs have been widely applied in infant formulas and adult nutritional products. The study aims to develop and validate a method in accordance with the AOAC International Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) Standard Method Performance Requirements (SMPR). It details a method to analyze six different HMOs, including 2'-fucosyllactose, 3'-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-tetraose, and lacto-N-neotetraose. The study involves labeling HMOs with 2-aminobenzamide (2AB) and performing derivatization. After review by the AOAC SPIFAN Expert Review Panel, the method was confirmed to meet the SMPR for the six HMOs.

Food Industry Applications:

In 2018, human milk oligosaccharides (HMOs) successfully obtained Novel Food Approval from the European Union and Generally Recognized as Safe (GRAS) status in the United States, signifying their recognition within the industry. Research has confirmed the potential of HMOs to alleviate food allergy symptoms in mouse models. With the increasing prevalence of global food allergy disorders, finding new methods to mitigate allergy symptoms holds significant importance. As the commercial production scale of HMOs expands, they are being introduced into various food applications. Consequently, the development of a reliable and accurate method to measure HMO content in different foods has become increasingly urgent and crucial.

In the article "New Human Milk Oligosaccharide Ingredient Approved for Infant Formulas in Europe, U.S.," it is mentioned that the HMO ingredient received Novel Food Approval from the European Union and GRAS status in the United States in 2018.

The study titled "Attenuation of food allergy symptoms following treatment with human milk oligosaccharides in a mouse model" investigated the reduction of food allergy symptoms in a mouse model after treatment with HMOs. Over the past 30 years, the incidence of food allergies has been steadily increasing. One of the most common allergens in children is cow's milk protein (CMP) allergy. Due to the diverse manifestations of CMP allergy, its diagnosis and treatment pose challenges. Children with CMP allergy need to avoid dairy products, seeking alternatives with components similar to breast milk. The use of extensively hydrolyzed and amino acid-based formulas is suitable for children with CMP allergy, as these formulas gradually approach breast milk composition. Additionally, utilizing HMOs to promote the development of early oral tolerance can help improve CMP allergy symptoms.

The article titled "Quantifying the human milk oligosaccharides 2’‐fucosyllactose and 3‐fucosyllactose in different food applications by high‐performance liquid chromatography with refractive index detection" discusses the quantitative analysis method of HMOs in various food applications. With the industrial production of HMOs reaching scale, commercial infant formulas containing 2'-fucosyllactose (2'-FL) have emerged. There is a need for a simple and effective analytical method to quantitatively assess HMOs in different food applications. This study proposes a validated high-performance liquid chromatography method with refractive index detection that quantitatively analyzes 2'-FL and 3-FL in whole milk, infant formula, and cereal bars. The method exhibits high linearity within a concentration range of 0.2 to 12 milligrams/mL. The recovery rates for 2'-FL range from 88% to 105%, and for 3-FL, the recovery rates range from 94% to 112%. The detection limits in different food matrices are 0.1 milligrams/mL and 0.6 milligrams/gram, respectively. Successfully applied in stability studies across various dairy products, this method enables simultaneous and stable quantification of 2'-FL and 3-FL in practical applications, demonstrating high accuracy and reliable repeatability.

Antiviral and Immune Modulation Applications:

Extensive research has been conducted on human milk oligosaccharides (HMOs), particularly focusing on their potential roles in combating viral infections. HMOs may not only interfere with the attachment of viruses to host cells by mimicking viral receptor structures, thereby preventing infections, but also show potential in improving immune adaptability and restoring immune balance. These studies provide insights for exploring novel antiviral therapies, offering a deeper understanding of the relationship between HMOs and the immune system. This understanding holds promise for developing more precise and effective immune interventions to address infectious diseases and viral disorders.

The study "Human Milk Oligosaccharides as Promising Antivirals" investigates the potential of HMOs. HMOs may offer immune protection, especially against viral infections. The study emphasizes that HMOs could prevent infection by mimicking the structure of viral receptors, inhibiting the attachment of viruses to host cells. However, due to the complex interaction between viruses and carbohydrates, along with technical challenges in HMO isolation, identification, and manufacturing, their application as antiviral drugs is limited. Recent technological advancements provide a deeper understanding of viral entry mechanisms, paving the way for using HMOs as invasion inhibitors. The research also covers studies on the sugar-based binding of rotaviruses, noroviruses, influenza viruses, and human immunodeficiency viruses, exploring the potential of HMOs as invasion inhibitors for prevention and treatment.

The article "Human Milk Oligosaccharide 2′-Fucosyllactose Improves Innate and Adaptive Immunity in an Influenza-Specific Murine Vaccination Model" focuses on the specific HMO, 2'-fucosyllactose (2'-FL), and its impact on innate and adaptive immunity in a mouse influenza vaccine model. Researchers administered varying doses of 2'-FL through diet before and after vaccination and assessed immune responses. The results indicate that mice receiving 2'-FL demonstrated enhanced vaccine-specific immune responses, including increased antibody levels, immune cell activation, improved T-cell proliferation, and cytokine production. This suggests that dietary intake of 2'-FL may contribute to enhancing both humoral and cellular immune responses, partially attributed to its impact on immune cell differentiation.

"The Human Milk Oligosaccharide 2'-Fucosyllactose Shows an Immune-Enhancing Effect in a Cyclophosphamide-Induced Mouse Model" explores the immune-enhancing effect of 2'-fucosyllactose (2'-FL) in a cyclophosphamide (CCP)-induced immunosuppressive mouse model. The study administered 2'-FL orally to mice and induced immune suppression using CCP. Results showed that mice receiving 2'-FL exhibited better immune responses compared to the CCP-induced group, including increased spleen weight, natural killer cell activity, cytokine levels, and T-cell proliferation. This study suggests that 2'-FL might help alleviate CCP-induced immunosuppression and enhance immune function.

"The human milk oligosaccharide 2'-fucosyllactose attenuates β-lactoglobulin-induced food allergy through the miR-146a-mediated toll-like receptor 4/nuclear factor-κB signaling pathway" delves into the immunomodulatory molecular mechanisms of HMOs. After oral administration of 2'-FL or HMO, specific IgE secretion induced by β-LG decreases, mast cell degranulation is reduced, inflammatory cytokine production (such as TNF-α, IL-4, and IL-6) decreases, and miR-146a expression increases. In vitro experiments further confirm that treatment with 2'-FL or HMO reduces allergen-induced release of inflammatory cytokines and reactive oxygen species. Additionally, 2'-FL dose-dependently inhibits the TLR4/NF-κB inflammatory pathway while enhancing miR-146a expression. Overall, 2'-FL mitigates β-LG-induced food allergy by regulating the miR-146a-mediated TLR4/NF-κB signaling pathway.

Regulation of Gut Microbiota Applications:

Human milk oligosaccharides (HMOs) have a broad impact on the gut microbiota and infant health. HMOs play a role as prebiotics in the gut, promoting the growth of beneficial bacteria and maintaining gut microbiota balance. Research indicates that HMOs may reduce the risk of infant illnesses, possibly due to their inhibitory effects on pathogenic microorganisms. Additionally, HMOs demonstrate significant value in the health of preterm infants. They contribute not only to building a healthy gut microbiota but also to enhancing immune function and reducing the risk of infections.

"The Gold Standard for Nutrition: A Review of Human Milk Oligosaccharide and its Effects on Infant Gut Microbiota" points out that HMOs, as the gold standard of maternal milk nutrition, attribute much of their nutritional value. HMOs rank as the third-largest component in human breast milk after lactose and lipids, exhibiting unique structural diversity that infants cannot digest and absorb. Serving as prebiotics, HMOs offer multiple benefits by directly or indirectly interacting with the gut microbiota, promoting the growth of beneficial bacteria, exerting anti-pathogen effects, and regulating gut epithelial cell responses. Recent studies highlight HMOs' promotion of infant health and reduction of disease risks, showcasing their potential as food additives and therapeutic agents. This paper discusses the impact of HMOs on infant gut microbiota, with a focus on the molecular mechanisms underlying the benefits of HMOs.

"Human Milk Oligosaccharide DSLNT and Gut Microbiome in Preterm Infants Predicts Necrotizing Enterocolitis" explores the interaction between HMOs and infant gut microbiota, as well as their association with necrotizing enterocolitis (NEC) in infants. The study reveals that the concentration of a specific HMO (disialyllacto-N-tetraose, DSLNT) significantly decreases in infants with NEC. Furthermore, the intake of HMOs is associated differently with bacterial communities in oral and fecal samples of infants, possibly influencing the development of their microbiota. These findings shed light on the vital role of HMOs and gut microbiota in the health and disease of premature infants, paving the way for risk stratification of diseases and biomarker development.

"The Role of Human Milk Oligosaccharide Metabolizing Bacteria in the Development of Atopic Dermatitis/Eczema" focuses on the potential of HMOs in preventing atopic dermatitis. Research suggests that human milk oligosaccharides play a significant role in establishing infant gut microbiota and regulating the immune system, potentially offering protection against atopic dermatitis. Through an in-depth exploration of the role and metabolites of HMO-metabolizing bacteria, mechanisms underlying the protective effects of HMOs can be revealed, providing theoretical support for the development of new eczema prevention methods.

"Exclusively Breastfed Infant Microbiota Develops over Time and Is Associated with Human Milk Oligosaccharide Intakes" examines the bacterial dynamics of maternal and infant microbiota during exclusive breastfeeding and explores the correlation between the intake of human milk oligosaccharides (HMOs) and bacterial communities in infant oral and fecal samples. The study finds that HMO concentrations and intake change over time, and the association between HMO intake and bacterial communities differs in infant oral and fecal samples. This association may impact the development of infant gut microbiota and subsequently influence short-term and long-term infant health.