New Insights on the Science of HMOs Part 2: How HMOs Benefit Brain Development and Health

Early life nutrition has implications for future health: experts weigh in  

• Human milk oligosaccharides (HMOs) are an important bioactive component of human breastmilk and may be a key component of the cognitive benefits associated with breastfeeding.¹  
  
• The first 1000 days are a critical window for brain development.² Emerging preclinical evidence suggests that HMOs may exert both direct and indirect influence on both brain development and health.^{3, 4}  
  
• In this article, Dr. Louise Kristine Vigsnæs, Head of Biology, and Dr. Stine Dam Jepsen, Scientist at dsm-firmenich, provide insights on how HMOs may influence brain development and health.
  

HMOs are a bioactive component of breastmilk that appear to positively impact the brain

Research over the last several decades reveals that certain aspects of cognitive development  are superior in breastfed infants as compared to those that are formula-fed.^5, 6 A review published in 2020 by Al-Khafaji et al. assessing the potential impact of human milk oligosaccharides (HMOs) on the gut-brain axis suggests that the cognitive benefits of breastfeeding may be due, in part, to HMOs found in breastmilk.¹ The potential link between the HMOs in breastmilk and coginitive development is supported in other literature as well.^3,4  

Until recently, the presence of HMOs in infant formula was very limited and a key differentiating factor between breastmilk and infant formula composition, which may help explain why breastfed infants experience a number of unique, positive health outcomes.^7, 8 HMOs are the third largest solid component of human breastmilk. While milk oligosaccharides are present in cow’s milk, they are much more abundant and structurally diverse in human milk.⁹  

The function of individual HMOs is linked to their structure and high abundance in breast milk, and the potential impact of certain HMOs on brain health is likely dependent on both the structure of the HMO and the amount provided.¹ Emerging data from preclinical models and an infant observational study suggest a role of HMOs in brain development and cognition,^10-15 with some preclinical data indicating that the impact on brain might be influenced by the gut microbiota,^11,12 illustrating the functionality of the gut-brain axis.  

Dr. Louise Vigsnæs, Head of HMO Biology, and Dr. Stine Dam Jepsen, Scientist at dsm-firmenich, answer questions on the role of HMOs and brain health 

Why are the first 1000 days so important for brain development? 

The brain is a complex and unique organ that develops and changes throughout life. In the early years – ranging from conception throughout the first two years of life – the brain goes through the biggest transformation.² While the development of the brain is a lengthy process that continues into adulthood, growth acceleration and its ability to grow are highest within the first 1,000 days.¹⁶ Different parts of the brain and different cognitive functions develop along different timelines, and in these periods, the brain is particularly susceptible to environmental stimuli. During phases of rapid brain development, suboptimal nutrition, malnutrition or damage from external factors can have irreversible and lifelong consequences.^2,16,17  

How does gut health affect brain health generally, even beyond infants?  

We understand a great deal about this based on both animal models and human associational data. The gut-brain axis is a well-described bidirectional communication pathway.¹⁸  Recently, the gut immune system was recognized as a contributor to this communication system.¹⁹ In this sense, the health status of the gut contributes to the interaction between the immune system and the brain, which has implications for brain health.¹⁹ 

A favourable balance of beneficial bacteria in the GI tract is desirable for overall health.^20,21 Emerging data in animal models suggest that, in the gut, a balanced immune response supports pathogen resistance and helps reduce unnecessary inflammation.22 When the balance of microbiota in the gut is disturbed, brain health can be affected.^23,24 As an example, inflammation in the gut releases immunity-related molecules such as cytokines, which can enter the systemic circulation, travel to the brain, and potentially impact brain health.²⁵ In addition, the gut microbiota produces neurotransmitters that can cross talk with the nervous system.²⁶ However, if the gut microbiota is not in balance, the production of neurotransmitters change and can impact brain health.²⁶ Dysbiosis and inflammation in the gut may be linked to certain neurologic conditions.^27-30 These associations suggest an interplay between the gut and neurologic regulation, which upon further investigation may provide evidence of the importance of the gut in brain health. 

To sum up, the health status in the gut appears to be tightly linked to the health status of the brain. 

The role of HMOs in brain development and health 

Recent studies suggest certain HMOs may have direct or indirect influence on brain development and health. 2’FL is the most commonly used HMO in infant formula and preclinical studies show potential positive outcomes in brain health and function.^11,31  Sialylated HMOs, including the most commonly studied 3’SL and 6’SL, may have the potential to affect brain health based on preclinical^3,12,13,32 and observational studies.³³ Drs. Vigsnæs and Jepsen provided additional insight into how HMOs might exert their influence on the brain.  

How do HMOs affect the developing brain? Do all HMOs have a similar impact? 

While the science continues to evolve in this area, the exact mechanisms through which HMOs affect brain health are emerging. Individual HMOs have unique properties, and we could therefore speculate that different HMOs would also have varying effects on brain health. An observational study found that breastfed infants have higher amounts of sialic acids in their brain tissue compared to formula-fed infants.³³ In addition, a preclinical study has shown that animals fed with HMOs containing sialic acid had higher amounts of sialic acid in their brain tissue compared to the control group.¹² This could indicate that sialylated HMOs are utilized as building blocks for the brain.  

Fucosylated HMOs may also impact brain development, as they have been shown to be broken down by the gut bacteria to short chain fatty acids (SCFAs), which are metabolites that may indirectly affect brain health.^1,34,35 An association infant study by Berger et al. found that infants receiving higher concentrations of the fucosylated HMO 2’FL in breast milk at one month of age have improved cognitive development at 2 years of age, linking early HMO ingestion to cognitive development.15  Preclinical studies in animals have found that feeding fucosylated HMOs impact memory and cognition and improve learning and long term potentiation.^4,10,11 These studies suggest an emerging role for HMOs in the field of brain health and development. 

The gut-brain-immune axis

New research indicates we should add an immune component to the gut-brain axis, creating the gut-brain-immune axis.^{1, 36} Drs. Vigsnæs and Jepsen explain how the brain, through cross-talk, may influence the gut and immune systems.  

As before, animal models give us insights here. The brain can affect the gut, its microbiota, and the gut immune system through regulation of gut motility, secretions in the gut (e.g. gastric acid or mucus) and gut permeability.^18,37 For example, brain health can affect the integrity of the gut barrier, seen in data illustrating that chronic psychological stress can result in increased intestinal permeability; this in turn can trigger the immune system to initiate an inflammatory response.38 In addition, the brain regulates the release of bioactive molecules into the gut, affecting the microbiota as well as the gut immune cells.³⁷ 

HMOs may have the potential to positively impact the gut-brain-immune axis in a variety of ways. While the body of evidence in these areas continues to grow and evolve, the review by Al-Khafaji et al. provides an excellent overview of the evidence to-date. Next-generation HMOs are part of our exciting innovation roadmap, with four new HMOs becoming available this year for innovation trials to further catalyze the already fast-growing HMO market.