The Science Behind Breast Milk: Sugars That Program the Immune System
by Mary Ferrari
Human milk oligosaccharides (HMOs) are the third most abundant solid component in human breast milk, following lactose and lipids and they represent one of the most biologically sophisticated elements of early nutrition. Not just simple carbohydrates, HMOs perform a wide range of critical functions that extend far beyond nourishment. They act as powerful prebiotics, selectively stimulating the growth of beneficial gut microbiota such as Bifido bacteria species, which are essential for establishing a healthy intestinal environment in newborns. This early microbial colonization plays a foundational role in shaping immune competence, homeostasis and metabolic health. Later this gives way to a broader population of healthy anaerobic bacteria.
In addition to their prebiotic effects, HMOs exert a protective role against severe neonatal pathologies like necrotizing enterocolitis (NEC), a life-threatening inflammatory condition primarily affecting premature infants. HMOs contribute to this protection by enhancing the integrity of the intestinal barrier and preventing the adhesion of pathogenic bacteria to the gut epithelium. By acting as soluble decoy receptors, they bind harmful microbes and toxins, effectively neutralizing them before they can trigger inflammation or infection.
Even more profound is the ability of HMOs to program the immune system during this critical window of development. Early-life immune education is highly sensitive to environmental inputs, and HMOs guide this process by modulating immune cell responses and promoting tolerance. This immunological programming has long-term effects and is associated with a reduced incidence of allergies and autoimmune diseases later in life. HMOs also play a crucial role in brain development and in the gut barrier’s maturation. Through interactions with gut-associated lymphoid tissue (GALT), HMOs influence the balance between pro-inflammatory and regulatory pathways, fostering a resilient and appropriately calibrated immune system.
HMOs also play a crucial role in brain development. Emerging evidence suggests that these molecules contribute to neurodevelopment. Indirectly, they support the gut-brain axis by shaping the microbiota, which in turn produces metabolites involved in neural signaling and cognitive function. Directly, certain HMOs may be absorbed into systemic circulation and influence brain structure and function, although this remains under active investigation. Along with neurological benefits, HMOs are essential for the maturation of the gut barrier, ensuring proper nutrient absorption while preventing the translocation of toxic substances into the bloodstream.
Breast milk, with its complex and dynamic composition, delivers these benefits in a highly individualized manner. The specific profile of HMOs varies between mothers and across different stages of lactation, reflecting an adaptive system finely tuned to the infant’s needs. This is one of the miracles of human milk: a single class of molecules has such a great impact on the development of the infant.
In this context, the metabolome and metabolomics has emerged as a powerful field of research for advancing our understanding of HMOs and their biological roles. By enabling the comprehensive analysis of metabolites in biological samples, metabolomics provides insights into the functional outcomes of HMO activity. This approach has significant applications in clinical and research settings, allowing for the identification of biomarkers associated with health and disease, as well as the optimization of nutritional interventions.
As research progresses toward a more detailed and comprehensive understanding of HMOs, new opportunities are emerging in the field of neonatal nutrition. One promising direction is the development of targeted supplementation strategies for both breast milk and infant formula. By replicating or enhancing specific HMO profiles, it may become possible to provide each newborn with a more nutritional regimen tailored to their unique physiological needs.
Personalized medicine and personalized nutrition are the keywords driving the application of metabolomics in neonatology for what can be done in the present to protect a newborn particularly in supporting immune development, gut health, and neurodevelopment will affect the future adult as a consequence with profound implications for health outcomes. In this way, HMOs exemplify how early nutritional exposures can shape human health in meaningful and lasting ways.
The Only Food That Shapes a Lifetime
by Mary Ferrari
“Breastfeeding establishes lifelong metabolic protection by helping cells grow in a careful, optimized way rather than overstimulating them.”
How To Establish Immune Tolerance
Breast milk is much more than just simple food for a baby; it is a highly advanced biological signaling system that programs a newborn’s metabolism for the rest of their life.
Unlike infant formulas, human breast milk contains the exact instructions needed to guide early cell development without pushing the baby’s body into a state of metabolic stress. According to scientific research by Bodo C. Melnik and other experts in developmental biology, breastfeeding establishes lifelong metabolic protection by helping cells grow in a careful, optimized way rather than overstimulating them. This natural programming keeps a vital genetic pathway called Wnt/TCF7L2 open and functioning correctly, which acts as a permanent shield against chronic conditions like obesity and diabetes later in life.
Breastfeeding has been identified as a critical preventive postnatal condition for both T2DM and obesity.
The Only Food That Shapes a Lifetime
Rashid et al. report that an infant-type Bifidobacterium infantis-HMO synbiotic shapes immune signatures and reduces Th2 bias in formula-fed infants toward a breastfed-like profile. In experimental models, it protects against bronchiolitis and confers lasting immune effects into adulthood, associated with increased 12-HHT, a lipid mediator sufficient to promote disease tolerance.
HMO Permanent Shift
- Mechanism: Fucose residue motifs bind specific C-type lectin receptors, primarily DC-SIGN, on mucosal dendritic cells (DCs).
- Outcome: This interaction instructs immature DCs toward a tolerogenic phenotype, upregulating interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) secretion, which induces naive CD4+ T cells to differentiate into FoxP3+ Tregs.
- Mechanism: Sialic acid residues bind Siglecs (Sialic acid-binding immunoglobulin-like lectins, particularly Siglec-5 and Siglec-9) expressed on antigen-presenting cells and lymphocytes.
- Outcome: Siglec engagement triggers intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs), suppressing pro-inflammatory cascades (such as NF-kB and TNF-alpha) and enhancing immunosuppressive Treg polarization.
- Mechanism: Lacto-N-tetraose backbone configurations serve as ligands for host galectins (e.g., Galectin-1 and Galectin-3).
- Outcome: Galectin activation cross-links cell surface glycans on immune cells, inhibiting effector T-cell activation (Th1/Th17) while promoting Treg survival and expansion.
Can Manufactured HMOs Function Similarly?
Yes. Commercially manufactured HMOs are bio-identical in chemical structure and stereochemistry to those found in human breast milk. Produced via precision microbial fermentation (genetically engineered strains of E. coli or K. lactis), synthetic HMOs like 2′-FL, 3′-SL, and LNT interact with host immune receptors (such as DC-SIGN and Siglecs) and gut bacteria in the exact same manner as native human milk glycans.
Why Nestlé Included Six Specific HMOs
Human breast milk contains over 200 distinct oligosaccharides, but Nestlé selected a specific mix of six HMOs (2′-FL, 3-FL, DFL, LNT, 3′-SL, and 6′-SL) for clinical trial evaluation and commercial formulation for three primary reasons:
1. Representation Across All Three Major Structural Families
Breast milk HMOs fall into three biochemical classes. A blend of six allows formula to cover the entire structural spectrum rather than relying on a single compound:
Neutral Fucosylated (2′-FL, 3-FL, DFL): Provide systemic immune signaling via C-type lectin pathways and prevent pathogen adhesion.
Neutral Core/Non-Fucosylated (LNT): Serve as primary substrates for Bifidobacterium colonization and galectin binding.
Sialylated (3′-SL, 6′-SL): Engage Siglec inhibitory receptors, suppress hyper-inflammatory signaling, and support neurodevelopment.
2. Mimicking Natural Human Milk Proportionality
Rather than an arbitrary ratio, the 6-HMO formulation mirrors the dynamic shift seen in natural lactation across stage 1, stage 2, and stage 3 infant feeds:
Fucosylated HMOs dominate early lactation (up to ~70% of total HMO content).
Sialylated and core HMO proportions shift relative to overall concentration as the infant’s gut mucosa and immune system mature over the first year.
3. Synergistic Synbiotic Action
In trials evaluating this 6-HMO blend (often combined with probiotic strains like Bifidobacterium infantis), the goal is to orchestrate a “synbiotic” environment:
Neutral core and fucosylated structures selectively feed early-life commensals.
Sialylated structures directly regulate host mucosal dendritic cells and systemic interferon response pathways.
Rashid RB, Chung CK, Namubiru P, Ahmed T; CLARA Study Group; Howard DR, Sebina I, Wilkins T, Rana MS, Morrow JP, Creek DJ, Moll JM, Vidal K, Fumero C, Lavalle L, Maes D, Hays NP, Silva-Zolezzi I, Forbes-Blom E, Sprenger N, Picaud JC, Phipps S, Noti M. Early-life immune imprinting by a B. infantis-HMO synbiotic shapes infant immune signatures and protects against experimental respiratory disease. Cell Rep Med. 2026 Aug 18;7(8):102935. doi: 10.1016/j.xcrm.2026.102935.
Epub 2026 Jul 31. PMID: 42537648; PMCID: PMC13522788.
Declaration of interests
C.K.C., K.V., C.F., L.L., D.M., N.P.H., I.S.-Z., E.F.-B., N.S., and M.N. are employees of Société des Produits Nestlé S.A. (SPN), the sponsor of this trial. J.-C.P. and CLARA Study Group members received a grant from SPN to conduct clinical study. R.B.R., T.A., T.W., M.S.R., P.N., I.S., D.R.H., and S.P. are employees of the QIMR Berghofer MRI, with whom SPN had a collaboration agreement to conduct pre-clinical studies. J.M.M. is an employee of Cmbio, with whom SPN had a service agreement. The investigational products were provided by S.P.N. E.F.B., D.M., and M.N. have filed patent applications related to combinations of HMOs and B. infantis (WO 2024/236049 A1, WO 2024/236050A1, and WO 2022/161865 A1).
The Gut Brain Connection That Doctors Don't Talk About - Repairing the Nervous System
by Mary Ferrari
“Scientists are uncovering a startling reality: the microscopic organisms living in your digestive tract hold immense power over your brain, your immune system, and your overall health.”
The Hidden Control Center Inside Your Body
Have you ever felt like you are doing everything right, yet your body still feels completely out of sync? Millions of people search for answers to unexplained brain fog, persistent fatigue, and unpredictable nerve issues, only to be met with vague explanations. What if the most crucial piece of the puzzle isn’t hidden deep inside your brain, but sitting right inside your digestive system?
Scientists are uncovering a startling reality: the microscopic organisms living in your digestive tract hold immense power over your brain, your immune system, and your overall health. Research by Alicia Sánchez-Sanz and Sergio E. Baranzini highlights how the gut microbiome plays a pivotal role in neurological conditions like multiple sclerosis. The microbes in your gut do not merely digest food. They constantly broadcast biological signals directly to your central nervous system through a high-speed network known as the gut-brain axis.
When your intestinal ecosystem becomes unbalanced, the consequences extend far beyond digestion problems. Harmful shifts in gut bacteria can disrupt critical immune responses, weaken protective biological barriers, and perpetuate chronic inflammation. This systemic inflammatory state can ultimately attack nerve tissue in the brain and spinal cord, driving the onset and progression of multiple sclerosis.
How Gut Microbes Influence Your DNA
The real breakdown happens at the molecular level, driven by what your bacteria produce. Breakthrough research by X. Xu and colleagues reveals that gut bacteria produce special compounds called short-chain fatty acids during the fermentation of dietary fibers. These microbial short-chain fatty acids act as biological switches, known as epigenetic mediators, that fine-tune communication across the gut-brain axis.
Epigenetics refers to changes in gene activity that occur without altering your underlying DNA sequence. In simple terms, while your genetic code remains fixed, the compounds generated by your gut bacteria possess the power to flip specific genetic switches on or off inside your brain cells. When beneficial short-chain fatty acids are abundant, they promote immune tolerance, maintain tight biological barriers, and dampen neuroinflammation. However, when these vital microbial metabolites are lacking, the delicate biochemical balance collapses, leaving the nervous system vulnerable to damage.
Understanding this biological mechanism changes how we view complex health struggles. The connection between gut health and neurological function is not a distant theory, it is an active biological process happening inside you right now and you can influence it.
Rewriting the Future of Brain Health
For years, neurological conditions were viewed as static, irreversible challenges centered purely inside the skull. Today, research proves that your gut microbiome acts as a dynamic control panel that can be influenced, restored, and supported. By targeting the gut-brain axis, supporting beneficial bacteria, and encouraging the production of short-chain fatty acids, science is unlocking revolutionary new pathways for neurological care.
Your biological potential is not entirely locked in your genes; it is heavily shaped by the trillions of microscopic allies living inside your digestive tract. Taking control of your gut environment gives your body the biochemical tools it needs to regulate inflammation, protect nerve tissue, and support long-term brain health from the inside out.
Dendritic Cells: The Lock and Key to Your Immune System
To understand how gut signals govern immune response, we have to look at the gatekeepers of immunity: dendritic cells. Research by L. Xiao and colleagues demonstrates that dendritic cells act as the ultimate lock and key to the immune system. They actively sample compounds in the gut environment and determine whether your body reacts with inflammatory defense or peaceful immune tolerance.
When specialized compounds like milk oligosaccharides directly interact with human dendritic cells, they turn the key toward immune tolerance. Instead of sounding a false alarm that leads to autoimmune attacks, properly signaled dendritic cells instruct the immune system to remain calm, calming systemic inflammation before it can target your central nervous system.
In this landmark August 2026 clinical trial published in Cell Reports Medicine, researchers discovered that supplementing with a blend of six manufactured, structurally diverse HMOs successfully re-programs the body’s immune pathways and B. infantis plus B. lactis. The study details how early-life supplementation with a six-HMO and B. infantis synbiotic blend expands immuno-regulatory plasmacytoid dendritic cells (pDCs). This process activates a protective pDC–Treg immune axis that increases 12-HHT and suppresses runaway Th2-biased tissue inflammation. The study details how early-life supplementation with a six-HMO and B. infantis synbiotic blend expands immuno-regulatory plasmacytoid dendritic cells (pDCs). This process activates a protective pDC–Treg immune axis that increases 12-HHT and suppresses runaway Th2-biased tissue inflammation. The study also demonstrated that this exact combination altered the gut environment and attenuated the systemic Th2 bias in formula-fed infants, effectively imprinting a balanced immune cell network that closely resembled the natural tracking observed in exclusively breastfed infants. Infants were enrolled and randomized at 14 days of age. The infants were fed the experimental formula containing the six manufactured HMOs and the Bifidobacterium synbiotic blend continuously from that baseline up to 4 months of age.
“We demonstrate that supplementation with this infant-type synbiotic changes systemic immune cell networks and reduces a Th2 bias in formula fed infants, to more closely follow the pattern observed in exclusively breastfed infants enrolled as a non-randomized reference group. To gain further mechanistic insight, we evaluated the impact of early-life synbiotic supplementation on preclinical models of respiratory infection and allergic airway inflammation. We find that synbiotic supplementation improves disease tolerance toward an sLRI associated with aberrant Th2 responses in early life and reduces susceptibility to experimental asthma later in life. The improved infection and allergy outcomes following synbiotic supplementation associate with significant changes in the levels of systemic metabolites and the expansion of immunoregulatory plasmacytoid dendritic cells (pDCs) and regulatory T cell (Treg) responses. Together, these findings support the concept that during a critical developmental window in early life an infant-type synbiotic has the capacity to shape immune system imprinting and prevent the development of a severe infection and subsequent asthma via the promotion of disease tolerance.“
How Gut Microbes and Antibodies Drive Brain Repair
The biological dialogue continues at the molecular level through microbial metabolites and targeted immunoglobulins. Research by X. Xu and colleagues reveals that gut bacteria produce short-chain fatty acids during fiber fermentation. These short-chain fatty acids act as epigenetic mediators, turning gene switches on or off across the gut-brain axis to protect barrier integrity and suppress neuroinflammation without altering underlying DNA.
Beyond preventing damage, your body can actively rebuild damaged nerve shielding. Research by Y. Li and colleagues demonstrates that immunoglobulins directly enhance the differentiation of oligodendrocyte-precursor cells—the specialized cells responsible for generating new myelin—and actively promote remyelination. Because natural sources like bovine colostrum are packed with immunoglobulins (IgG), this opens up exciting possibilities for how targeted immune factors can support active tissue repair in conditions like multiple sclerosis.
What You Can Do
Understanding this complex biological network raises an actionable question: what can you do to support these mechanisms every day?
- Nurture your microbiome: Consume prebiotics and fibers that fuel gut bacteria, driving the production of short-chain fatty acids that signal your brain cells.
- Support immune tolerance: Provide your digestive system with bioavailable immune-modulating nutrients (HMO’s) that interact with dendritic cells to promote anti-inflammatory signaling.
- Promote myelin repair: Incorporate nutrient-dense immunoglobulins, such as those naturally found in bovine colostrum, to provide your body with the biological tools that support cellular repair and remyelination.
Your biological potential is not locked in place. By taking targeted control of your gut environment and immune inputs, you give your body the exact tools it needs to regulate inflammation, protect nerve tissue, and restore long-term brain health from the inside out.
Source:
2026
Sánchez-Sanz, Alicia, and Sergio E. Baranzini. 2026. “The Gut Microbiome in Multiple Sclerosis.” Neurology: Neuroimmunology & Neuroinflammation 13 (6): e200638. https://doi.org/10.1212/NXI.0000000000200638.
The Gut Microbiome in Multiple Sclerosis
2026
Xu X, Cheng Y, Liu X, Ding W, Zhu Z, Wu L, Ling Z, Gao Y, Yue J. Microbial SCFAs as epigenetic mediators: fine-tuning the gut-brain axis in neurodegenerative disorders. Curr Res Microb Sci. 2026 Feb 23;10:100574. doi: 10.1016/j.crmicr.2026.100574. PMID: 41798063; PMCID: PMC12966653.
2019
Xiao L, van De Worp WR, Stassen R, van Maastrigt C, Kettelarij N, Stahl B, Blijenberg B, Overbeek SA, Folkerts G, Garssen J, Van’t Land B. Human milk oligosaccharides promote immune tolerance via direct interactions with human dendritic cells. Eur J Immunol. 2019 Jul;49(7):1001-1014. doi: 10.1002/eji.201847971. Epub 2019 Apr 4. PMID: 30900752; PMCID: PMC6619030.
2023
Li Y, Noto D, Hoshino Y, Mizuno M, Yoshikawa S, Miyake S. Immunoglobulin directly enhances differentiation of oligodendrocyte-precursor cells and remyelination. Sci Rep. 2023 Jun 9;13(1):9394. doi: 10.1038/s41598-023-36532-3. Erratum in: Sci Rep. 2023 Aug 10;13(1):12995. doi: 10.1038/s41598-023-40118-4. PMID: 37296298; PMCID: PMC10256778.
2026
Rashid RB, Chung CK, Namubiru P, Ahmed T; CLARA Study Group; Howard DR, Sebina I, Wilkins T, Rana MS, Morrow JP, Creek DJ, Moll JM, Vidal K, Fumero C, Lavalle L, Maes D, Hays NP, Silva-Zolezzi I, Forbes-Blom E, Sprenger N, Picaud JC, Phipps S, Noti M. Early-life immune imprinting by a B. infantis-HMO synbiotic shapes infant immune signatures and protects against experimental respiratory disease. Cell Rep Med. 2026 Aug 18;7(8):102935. doi: 10.1016/j.xcrm.2026.102935. Epub 2026 Jul 31. PMID: 42537648; PMCID: PMC13522788.
About galactose, an essential sugar….
Galactose is a vital monosaccharide that acts as a primary building block for cell-surface sugars (glycans). Without galactose, proper glycosylation cannot occur, meaning the immune system fails to produce the surface markers needed to recognize self-tissue, leading to a loss of immune tolerance and an inability to dampen autoimmune responses.
Why Galactose is Critical for Immune Tolerance
To understand immune tolerance, it helps to look at how the immune system “sees” the body.
Glycosylation: Galactose is an essential structural component required to build the complex sugar chains that attach to proteins and lipids (glycoproteins and glycolipids).
Self-Recognition: Immune cells use these galactose-containing glycoproteins (like specific antibodies and cell receptors) as passports. Without galactose to complete these chains, the immune system cannot properly read these “self” markers. Receptor Interaction: Immune tolerance often relies on anti-inflammatory receptors called galectins, which specifically bind to galactose-containing glycans on the surface of immune cells. When these receptors recognize the right galactose structures, they send signals that suppress overactive inflammation and induce tolerance.
How Galactose Forms Human Milk Oligosaccharides (HMOs)
Human milk oligosaccharides (HMOs) are complex, non-digestible sugars found in breast milk that act as prebiotics and immune modulators.
Galactose is the foundational building block for all HMOs.
The Lactose Core: Every HMO is built on a foundation of lactose, which is a disaccharide made of one glucose molecule and one galactose molecule.
Elongation: Specific enzymes in the mammary gland (glycosyltransferases) add additional sugar units—including more galactose and \(N\)-acetylglucosamine (GlcNAc)—to this lactose core.
Branching & Decoration: To create the vast diversity of HMO structures, these elongating chains can be further decorated with fucose and sialic acid molecules, both of which utilize galactose to anchor onto the growing sugar structure.
The Missing Probiotic Your Gut Was Designed For
Human milk is widely recognized as the first functional food encountered in human life due to its rich composition of nutrients and bioactive compounds. Among these, human milk oligosaccharides (HMOs) stand out as one of the most biologically significant components. HMOs are complex carbohydrates that play a critical role in shaping early immune development, gut microbiota, and overall health outcomes. Their multifunctional properties explain many of the long-term protective effects associated with breastfeeding.
HMOs are the third most abundant solid component in human milk, following lactose and lipids, with concentrations typically ranging from 5 to 15 grams per liter in mature milk and even higher in colostrum. These molecules are structurally complex, composed of five primary monosaccharides—glucose, galactose, N-acetylglucosamine, fucose, and sialic acid—which combine in numerous ways to create over 100 distinct HMO structures. This structural diversity allows HMOs to perform a wide range of biological functions making them far more than simple carbohydrates.
One of the defining features of HMOs is that they are not digested by the host. Instead, they pass through the upper gastrointestinal tract intact and reach the colon, where they serve as selective substrates for beneficial gut bacteria. This characteristic places HMOs in the category of prebiotics. By promoting the growth of specific microbial populations—particularly Bifidobacterium species—HMOs help establish a first stage healthy gut microbiome. In breastfed infants, these bacteria can make up as much as 50–90% of the gut microbiota, a dominance mostly attributed to the presence of HMOs.
Beyond their prebiotic role, HMOs contribute to immune defense. They act as decoy receptors, preventing pathogens from binding to intestinal cells, thereby reducing the risk of infections. Additionally, HMOs influence immune cell activity, modulate inflammatory responses, and support the maturation of the intestinal barrier. These combined effects help explain why breastfed infants have lower risks of gastrointestinal infections, allergies, and chronic diseases later in life.
Another important aspect of HMOs is their systemic impact. Although only a small fraction—approximately 1%—is absorbed into circulation, this amount is sufficient to interact with immune cells throughout the body. This suggests that HMOs may influence not only gut health but also broader immune and metabolic pathways. Emerging research also points to potential roles in cognitive development and neurological function.
The composition of HMOs varies widely among individuals and is influenced by factors such as genetics, stage of lactation, and environmental conditions.
HMOs are essential for establishing a balanced gut microbiota, strengthening the intestinal barrier, and guiding immune system development. Their ability to selectively nourish beneficial bacteria while inhibiting pathogens makes them uniquely effective as compared to other prebiotics.
Application to Adults: The Role of HMO Supplementation
Although HMOs are naturally associated with infant nutrition, their biological functions are not limited to early life. The same mechanisms that benefit infants—modulation of the gut microbiome, immune regulation, and anti-inflammatory activity—are highly relevant to adult health as well.
In adults, gut dysbiosis is increasingly linked to conditions such as metabolic disorders, autoimmune diseases, and chronic inflammation. HMO supplementation offers a targeted way to reshape the microbiome by selectively feeding beneficial bacteria like Bifidobacteria, which are often depleted in modern adult populations. Unlike generic prebiotics, HMOs provide a more precise ecological signal potential leading to more predictable and beneficial microbial shifts.
HMOs help strengthen the intestinal barrier and reduce low-grade inflammation, which is a primary driver of many chronic diseases. Their ability to act as decoy receptors support immune resilience.
Most importantly HMOs represent a bridge between early-life programming and adult health. By reintroducing these significant mammalian molecules into the adult diet, supplementation may help restore aspects of immune tolerance and microbial balance that were originally established during infancy but later disrupted or never established at all.
In this regard, HMO supplements are not simply another prebiotic—they are a biologically recognized tool with the potential to rebuild foundational aspects of gut and immune function, extending the benefits of human milk far beyond infancy.
A Landmark Discovery: HMOs Directly Regulate Human Immune Cells
by Mary Ferrari
“In the present study, we show for the first time that HMOs modulate human moDCs in a microbiota-independent way.”
In the past decades, there has been a growing appreciation that breast milk beneficially supports the innate immune system and modulates microbiota composition during the first months of life. Breastfeeding is known to reduce the risk of inflammatory diseases, infectious diseases, asthma and allergic disease, as well as autoimmune diseases. The developing immune system must learn one of its most important lessons: how to distinguish harmless substances from genuine threats. This process, known as immune tolerance, is essential for preventing excessive inflammation, allergies, and autoimmune disease throughout life. For a long time, protection against pathogens was attributed to secretory IgA, which could capture pathogens from the gastrointestinal system of the child and later milk components were identified as possible immune modulators. Today among the various bioactive components in breast milk, human milk oligosaccharides (HMOS) have been suggested to play a key role. HMOS are a diverse mixture of over 1000 individual oligosaccharides that belong to different core structures consisting of short chain and long chain oligosaccharides typically present in a 9:1 ratio. In this paper the term “HMOS” is used as term for the complete mixture of HMOS, when individual compounds are referred to, they are labelled with their specific name. Among the most abundant oligosaccharides present in the majority of human milk samples, are 2’‐fucosyllactose (2’FL), 3’‐sialyllactose (3’SL), 6’‐sialyllactose (6’SL), and Lacto‐N‐Fucopentaose I (LNFP‐I), with a disaccharide lactose backbone at the reducing end, consisting of glucose, galactose, N‐acetyl‐glucosamine, fucose and sialic acid. While human milk oligosaccharides (HMOs) are widely recognized for their ability to nourish beneficial bacteria such as Bifidobacterium infantis, growing evidence shows that these remarkable carbohydrates also communicate directly with the immune system. It is known that HMOS are sampled by the lamina propria residing dendritic cells (DCs). In addition, some structures have been detected in systemic circulation, suggesting absorption in the small intestine. These findings indicate possibilities of direct interaction between HMOS and human dendritic cells.
A landmark study published in 2019 demonstrated for the first time that HMOs can regulate human immune cells independently of the gut microbiota, revealing an entirely new mechanism by which breastfeeding helps shape lifelong immune health……
A Landmark Discovery: HMOs Directly Regulate Human Immune Cells
Human milk oligosaccharides as prebiotics
Based on its richness in immune-related components such as human milk, human milk oligosaccharides (HMOs), milk proteins, and lipids, breast milk can be considered the first functional food that humans encounter in their lifetime. According to WHO recommendations breast milk has to be the only food in an infant’s diet in the first six months of age which is then continued up to two years of age with the suitable complementary foods. Regarding breast milk balanced composition, it is considered as the best food of infants thus many studies have been carried out to determine the benefits of breast milk. Based on numerous studies breast milk have a tendency to reduce the risk of type 2 diabetes, obesity, allergies, celiac disease, necrotizing enterocolitis (NEC), gastrointestinal tract infections and some type of cancers. The benefits of breast milk can be explained by its special combination which includes; macronutrients, micronutrients and bioactive components such as immunoglobulins, hormones, growth factors and oligosaccharides. One of the essential bioactive compounds of breast milk is known as human milk oligosaccharides (HMOs). HMOs are unique, bioactive carbohydrates which are identified as the most significant components of breast milk. Since they have structural complexity and multifunctional properties, they are one of the most wondered components of breast milk. HMOs promote the development of the neonatal intestinal immune, and nervous systems. This article briefly describes the history, complex structure and different functions of HMOs and highlight the importance of maternal diet for HMO biosynthesis.
Human milk oligosaccharides promote immune tolerance via direct interactions with human dendritic cells
During the first months of life, breastfeeding plays an essential role in programming the immune system, in part by modulation of the microbiota composition. The developing and rapidly changing microbial community will constantly interact with the immune system. More importantly, breastfeeding also directly influences the immune system by providing the infants with immune modulatory compounds such as HMOS. Several HMOS structures have been documented not to be digested by GI enzymes but to be absorbed into the systemic circulation in both breastfed infants and rats orally administrated with HMOS 15, suggesting that immune cells such as DCs are likely to be exposed to HMOS throughout the body. The immune modulatory effects of prebiotic oligosaccharides mixture, as well as specific HMOS 3’FL and 6’SL 24 on human moDCs have been described by previous studies. However, the effects of the authentic (i.e. complete) HMOS mixture on the human DC phenotype and function have not been reported before. In the present study, we show for the first time that HMOS modulate human moDCs in a microbiota‐independent way. The unique mixture of HMOS, isolated from mature human milk, induces a semi‐maturation state and suppresses LPS‐induced immune activation of human moDCs. These HMOS‐conditioned DCs are then able to modulate T‐cell responses in which both TLR4 as well as DC‐SIGN seem to play a role, suggesting a key role of HMOS in early life immune development.
Xiao L, van De Worp WR, Stassen R, van Maastrigt C, Kettelarij N, Stahl B, Blijenberg B, Overbeek SA, Folkerts G, Garssen J, Van’t Land B. Human milk oligosaccharides promote immune tolerance via direct interactions with human dendritic cells. Eur J Immunol. 2019 Jul;49(7):1001-1014. doi: 10.1002/eji.201847971. Epub 2019 Apr 4. PMID: 30900752; PMCID: PMC6619030.