New Insights on the Science of HMOs Part 3: The potential Benefits of HMOs on Immunity

Early Life Nutrition has Implications for Future Health: Experts Weigh In

• In this third article for the 3-part series on the impact of human milk oligosaccharides (HMOs) on human health, we explore the potential role of HMOs in the development and functioning of the immune system. Additionally, the evolving science around how HMOs might influence the gut-brain-immune axis is discussed. 
• HMOs, the third largest component of breastmilk (excluding water) after fat and lactose, have demonstrated their potential to modulate neonatal immunity in preclinical research studies.^1-5 Additionally, clinical data around possible immune benefits for infants are emerging.^6,7 Scientists are eager to uncover more details around how HMOs might positively influence immunity and contribute to human health.^8,9 
• In this article, Dr. Louise Kristine Vigsnæs, Head of Biology at dsm-firmenich, and Stine Dam Jepsen, Scientist at dsm-firmenich, provide an overview of what’s known about how HMOs may influence immunity and explain how we should interpret the evidence available to date. 

Scientists explore the potential impact of HMOs on immunity

With HMOs comprising a large proportion of the composition of human milk and being a clear differentiator between human milk and cow’s milk,^1,2 scientists have been intrigued to understand the role they play in human development. Further, breastfed infants experience a number of unique, positive health outcomes which may potentially be attributed to HMOs, as compared to formula-fed infants who generally do not ingest HMOs.¹⁰ Of the many bioactive molecules in human milk, HMOs are the most abundant, adding to the curiosity around how they benefit the human body.^11,12  

The evidence around HMOs and their impact on the immune system is emerging, and much of it is from preclinical work. The data suggest HMOs may impact the immune system via a number of proposed mechanisms: through modification of the intestinal microbiota,^1,13,14 through their potential to deflect undesirable organisms from adhering to cell walls, ^5,15,16 and by supporting the immune response.^1,17,18 Further research and additional clinical data are needed before a clear understanding of how HMOs impact the immune system can be reached, but emerging data are promising.^8,9

Early Life is a critical time for immune system development

Louise Vigsnaes, Head of Biology at dsm-firmenich, and Stine Dam Jepsen, Scientist at dsm-firmenich, contribute to our understanding of HMOs and immunity via the following Q&A. To begin, an exploration of the development of the immune immune system in early life is discussed: 

Q: Describe how typical immune development progresses in a healthy, full-term infant. Also, when is the functionality of the immune system considered to “mature”?

The immune system is dynamic and will change and adapt throughout the lifecycle. During birth, an infant transitions from a near-sterile environment to one full of antigens, many of which are related to the beneficial intestinal microbiota but some of which may be associated with pathogens.  This shift forces the infant’s immune system to begin discriminating between non-threatening and threatening antigens, and responding appropriately to those that represent danger.^19,21  However, both the innate and adaptive immune systems of the newborn are immature compared to that of older children and adults, leaving the infant susceptible to infections. Early life is a critical time that shapes the immune system, and multiple factors contribute to its development including mode of delivery (i.e. vaginal versus cesarean), gestational age at birth, feeding type (e.g. breast milk, formula, or both), and even environmental influences such as  geography.^19,40 As the  immune system matures during the first few years of life, it develops to become a more effective first line of defense against pathogenic bacteria or viruses.¹⁹

Maturation of the immune system is a dynamic and complex process, but its functionality is thought to be at its peak when we reach adolescence and young adulthood. In older adulthood, the functionality of the immune system declines and becomes less effective.^21,23

Q: Approximately 70% of the immune system’s cells reside in the gut, illustrating the significant role the GI tract plays in immunity. Describe how the gut is central to the function of our immune system.

The gut is an impressive organ, and comprises the largest compartment of the immune system.  The gut wall has the critical role of nutrient absorption while also preventing entry of undesirable microorganisms into the bloodstream. In fact, the gut is the largest surface area of the body to which foreign substances and microbes are exposed.²⁴ In addition, the gut creates a home for an endless number of microorganisms, most of which are non-harmful and can actually provide benefits to the host, such as helping to educate the immune system and support a proper immune response.²⁵ However, the gut can also host infectious agents and problematic foreign material. 

The gut is able to mitigate the nearly endless number of possible threats to our health with some of the body’s greatest defense mechanisms. These include the gut wall – which functionas as physical barrier – as well as commensal bacteria. These are bacteria that help to create an unfavorable environment for pathogens, preventing their ability to invade and colonize the GI tract, and support the optimal functioning of the host’s immune system.^26,27 Besides these protective factors, different immune cell types perform tasks critical to overall immune function. These include 1) “phagocytic” innate immune cells that provide the first line of defense by ingesting and removing foreign material and undesirable microorganisms, and 2) the antigen-specific lymphocytic immune cells that combat the intrusion of foreign invaders when the innate immune system is breached.²⁸ However, a balanced immune response is key! If the body’s defense mechanisms fail to eliminate intruders, infections can occur. On the other hand, if the body mounts an immune reaction against innocuous antigens, it can cause persistent inflammation or autoimmunity (attack on your own cells).²⁹

Preclinical and clinical studies uncover how HMOs support the immune system

Q: There are some interesting cell and animal studies suggesting that HMOs might influence immunity. Can you describe the reasons why this might be the case?

Emerging data from preclinical studies have shown that HMOs can impact the immune system in different ways, such as by hindering the undesirable agent itself, by supporting the microbiome and creating a favorable environment in the gut for the growth of helpful micro-organisms, or by modulating the immune cells themselves. In-vitro studies have shown that HMOs can deflect the adhesion of undesirable microorganisms to intestinal cells^5,30,31 and inhibit the growth and production of biofilm from Streptococcus group B.^4,3  In-vitro studies have also shown that when HMOs are utilized by specific gut bacteria, biomolecules like short chain fatty acids (SCFAs) are produced. These biomolecules help create an ecological niche that may resist colonization by undesirable microorganisms.³³

The ability of HMOs to interact with or activate immune cells is currently being investigated, and more research is needed to fully understand this mechanism. The early research in this area includes a study that reported – in an in-vitro model – acidic HMOs like 3’SL decreased markers of inflammation.³⁴ In a piglet model, the HMOs 2’FL, LNnT, and 6’SL were found to reduce the duration of diarrhea,³⁵and in combination with 3’SL, alter both systemic and gastrointestinal immune cells in infected animals.³⁶

From the preclinical studies mentioned above, we see that different HMOs may affect the immune system in different ways, and thus have come to understand that HMO structure impacts functionality. Fucosylated HMOs have shown to be degraded into short chain fatty acids (SCFAs), creating a community of healthy microbes in the GI tract and supporting immune health..³³ However, further investigation in this area is required before we fully understand how the different structures of HMOs impact immune-regulating properties.

Q: Regarding the evidence associated with HMOs and immunity in early life, what does the current science tell us about the role of  HMOs in the  development and/or functionality of the immune system of infants? 

Clinical trial evidence suggests HMOs may help support immunity during infancy. Puccio and coworkers reported that supplementing a standard infant formula with 2’FL and LNnT led to reductions in the parent-reported incidence of bronchitis, lower respiratory tract infections, and usage of antifever medication and antibiotics.6 It is important to note that, while the infants were fed the HMO-supplemented formula for the first six months of life, several of these beneficial immune effects were observed through 12 months of age.  Interestingly, a second publication from the same study reported that supplementation of 2’FL and LNnT led to an increase in bifidobacteria in infant fecal microbiota, which is closer to that of breast-fed infants. In addition, the infants with higher amounts of bifidobacteria had significantly lower parent-reported antibiotic usage throughout the first year of life.⁷

Another clinical study reported that supplementing a standard infant formula with 2’FL resulted in a reduced incidence of “infectious” events compared to the control formula³⁷ and a further post-hoc analysis revealed a significant decrease in respiratory tract infections.³⁸ Another publication from the same study found that cytokine expression in infants fed formula supplemented with 2’FL was closer to that of the breast-fed group vs. infants fed the control formula without 2’FL.³⁹ From the clinical evidence available at present, it seems that 2’FL and LNnT might play a role in impacting development and/or functionality of the immune system in infants, however, it will be interesting in the future to examine the impact of other HMO-structures on immunity.

dsm-firmenich: A leader in innovative solutions for Early Life Nutrition

DSM is a leading global solutions provider to the Early Life Nutrition and Dietary Supplement industries with a unique portfolio including nutritional lipids, vitamins and custom nutrient premixes. With the integration of HMOs into its portfolio, dsm-firmenich furthers its leadership in providing meaningful solutions to help set infants on a path to a long, healthy life, which is part of our promise to help keep the world’s growing population healthy. Next-generation HMOs are part of dsm-firmenich’s exciting innovation roadmap, poised to further catalyze the already fast-growing HMO market.

dsm-firmenich is a reliable, end-to-end, innovative, purpose-led partner powered by expert services to deliver science-backed nutrition and health products and quality customized solutions.