Here we explore how 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL), key components of human milk, promote cognitive development by delivering sialic acid to the brain, supporting neural growth, synapse formation, and brain function, with potential benefits extending beyond infancy.
Content Outline
- What are 3’-sialyllactose and 6’-sialyllactose?
- The role of sialic acid in cognitive development
- How 3’-SL and 6’-SL support cognitive health
- Future directions
- Summary
What are 3’-sialyllactose and 6’-sialyllactose?
3’-sialyllactose (3’-SL) and 6’-sialyllactose (6’-SL) are sialylated human milk oligosaccharides. They are known as trisaccharides because they are made up of three monosaccharide molecules:
- Galactose
- Glucose
- N-acetylneuraminic acid (Neu5Ac) – also known as sialic acid
Sialylated or acidic oligosaccharides account for approximately 13% of all the HMOs in human milk[i]. 3’-SL and 6’-SL are the two simplest sialylated HMOs and both exhibit promising prebiotic effects, particularly in modulating the human gut microbiome, supporting Bifidobacteria growth, but they also have numerous health properties, including:
- Antiadhesive antimicrobial properties
- Antiviral activity
- Immune support
- Bone formation and resorption
- Brain development
- Cognitive improvements[ii]
Structure of sialylated HMOs
Unlike fucosylated HMOs such as 2’-fucosyllactose (2’-FL) which have fucose sugars added to it during fucosylation, sialylated HMOs have sialic acid added to the end of the carbohydrate chain (Figure 1).
Figure 1. Lactose can be fucosylated or sialylated to produce HMOs like 2’-FL and 3’-FL or 3’-SL and 6’-SL. In the diagram, fucose sugars are added to the carbohydrate end to produce fucosylated HMOs. Whereas Neu5Ac is added to the carbohydrate ends to produce the sialylated HMOs[iii].
As seen in Figure 1, 3’-SL and 6’-SL are structurally similar. 3’-SL is known as a regioisomer of 6’SL which is just a fancy way of saying they are made up of the same components, they’re just attached at different positions[iv]. In 3’-SL sialic acid attaches to the lactose at the third carbon position, whereas in 6’-SL, it attaches at the sixth position. Although this is just a subtle difference, it can have a big impact on how these molecules function within the body.
These structural differences influence where and how 3’-SL, and 6’-SL are absorbed and how they interact with us. In infants, these HMOs, along with others, help to shape the developing gut microbiome. However, emerging research is uncovering how these sialylated HMOs can support cognitive development.
In this article, we’ll explore how 3’-SL and 6’-SL promote brain health and cognition.
The role of sialic acid in cognitive development
One of the critical components in both 3’-SL and 6’-SL for cognition is sialic acid.
Sialic acids are a class of sugars and are usually found at the ends of glycoproteins, glycolipids, and milk oligosaccharides[v]. Their presence in HMOs is vital for brain development and function, but why?
Sialic acid is essential for the formation of gangliosides, specialised fat cells which are abundant in the brain, particularly in the outer layer of nerve cells (neurons). Gangliosides are important for forming and maintaining the myelin sheaths that protect and increase the signal transmission between neurons. The communication between nerve cells is essential for cognitive processes[vi], including:
- Learning
- Memory
- Reasoning
Research also shows that sialic acid is also critical for synaptogenesis – the development of synapses (the connections between nerve cells) during early brain development. Synapses are developed early in life, achieving maximum density 6 to 12 months after birth[vii].
In general, without sialic acid, neurons would struggle to communicate effectively with one another which could impact cognitive functioning. For example, brain development is linked to an increase in gangliosides and sialoproteins, while brain and memory formation are associated with brain glycoproteins and sialoproteins. Yet, increasing age and other cognitive syndromes, including Parkinson’s Disease, are linked to reduced gangliosides and sialoproteins in the brain[viii].
Clinical trials have demonstrated infants fed formula milk supplemented with gangliosides, not only had an increased ganglioside abundance but increased cognitive development, too[ix].
Although humans can synthesise sialic acid, an infant’s ability is limited because of the immaturity of their liver and other vital organs. So, they need to get it from elsewhere to meet the rapid demands of their growing brain. That’s where human milk and its constituents are valuable because it delivers HMOs, glycoproteins, and glycolipids – rich sources of sialic acid[x].
How 3’-SL and 6’-SL support cognitive health
The sialic acid part of the HMOs, 3’-SL and 6’-SL is the key element that supports cognitive health. Animal studies have shown that these HMOs can help boost cognitive performance through their ability to increase gangliosides in the brain.
Here, we’ll explore some of the research that confirms the benefits 3’-SL and 6’-SL have on brain health and cognition.
Brain development in animal studies
Sialylated HMOs are abundant in breast milk and may be added to infant formula. Previous research has found that fortified infant formula can reduce the development gap between formula-fed and breastfed infants[xi]. With this in mind, Golden et al., (2023) investigated the effect of supplementing 3’-SL and 6’-SL on cognition and brain development at 33 and 61 days after birth in piglets.
Seventy-five two-day-old piglets were randomly assigned to one of two groups, commercial milk replacer with or without 3’-SL and 6’-SL. Magnetic resonance imaging (MRI) scans were used to assess brain development. Overall, the study found no effects on learning and memory, but the sialylated HMOs may impact temporally-dependent aspects of brain development[xii].
Brain development in human studies
Although there are several studies conducted in animals that suggest HMOs are important for brain development, the research in humans is limited. Berger and colleagues (2022) examined the link between HMOs, including 3’-SL, and tissue microstructure and regional cerebral blood flow in babies.
The results of infant exposure to 3’-SL at one month old are summarised below:
- increased fatty acid values in brain white matter and in cortical gray matter
- reduced mean diffusivity values, associated with lower rates of swelling and inflammation
- increased regional cerebral blood flow in the white matter and cortical gray matter of the frontal lobe
Overall, these results suggest that 3’-SL has an important role in brain development. At just 1 month, HMOs influence the tissue microstructure in the brain by promoting the maturation of gray matter and supporting the development of white matter[xiii].
Language development
Another suggested benefit of sialylated HMOs is their influence on infant language development. Cho and colleagues (2021) enrolled children aged 2 to 25 months in their study who had been at least partially breastfed and were ranked according to their Alpha-Tetrasaccharide (A-tetra), a type of HMO, levels.
The results found that 3’-SL was positively associated with early learning composite (ELC) scores across all age groups. These effects were increased in children over one year compared to those under 12 months[xiv].
Therefore, this research indicates that specific HMOs can influence early cognition, particularly language development. Further research is needed to fully understand how HMOs like 3’-SL exert these benefits.
Memory and gut microbiome modulation
Because 3’-SL and 6’-SL support the abundance of gangliosides and polysialylated neural cell adhesion molecule (NCAM), they may support improved memory development.
Bing et al (2007) found that supplementing milk with a protein-bound source of sialic acid to piglets increased the expression of two genes associated with learning and development.
Furthermore, Jacobi et al (2016) investigated if different isomers of siallylactose enrich the sialic acid in the brain and modulate the gut microbiome of infant piglets. The day-old piglets were randomly assigned to one of the 6 following diets:
- control
- 2G of 3’-SL/L
- 4g of 3’-SL/L
- 2g of 6’-SL/L
- 4g of 6’-SL/L
- 2g of polydextrose/L + 2g of galacto-oligosaccharides (GOS)
The results showed that the pigs who were fed 2g of 3’-SL or 6’-SL had 15% more ganglioside-bound sialic acid in the corpus callosum of their brains compared to control pigs. Equally, piglets fed 4g of 3’-SL had a 10% increase in ganglioside sialic acid in their cerebellum. The piglets fed sialylated HMOs also displayed a more enriched gut microbiome with an increased abundance of beneficial bacteria[xv].
Future directions
This current research into the cognitive benefits of 3’-SL and 6’-SL has led to them, alongside other important HMOs, being added to infant formula milk to enable formula-fed babies to capitalise on the nutritional benefits associated with breast milk.
With sialic acid involved in the development of neurodegenerative diseases, like Alzheimer’s and Parkinson’s Disease, 3’-SL and 6’-SL could have benefits for adult brain health, too.
Oxidative stress is a key contributor to the development of neurodegenerative diseases, so finding substances that can reduce or combat oxidative stress may be important in preventing disease. Researchers screened a library of peptides to find those that mimic 6’-SL, which is known to support brain function. They found that this mimetic peptide could improve the survival and growth of brain and nerve cells when exposed to oxidative stress caused by hydrogen peroxide. Therefore, suggesting that the 6’-SL mimetic peptide could protect nerve cells and offer hope for treating neurodegenerative disease in the future[xvi].
Summary
The early stages of life are a crucial time for brain development, and the nutrients that form the early diet can have long-lasting effects on cognitive health. HMOs like 3’-SL and 6’-SL have a unique and powerful role in the process largely due to their sialic acid component. Sialic acid is important for the normal formation of important neural structures and enhances communication between brain cells.
Sialylated HMOs, like 3’-SL and 6’-SL, have been shown to have benefits in brain development, language development, and memory, but these effects may span further than just infancy. For example, there may be potential for these HMOs to have cognitive benefits in adults and aging populations, especially as neurodegenerative diseases have been associated with impaired sialic acid metabolism[xvii].
Understanding the huge impact 3’-SL and 6’-SL can have on brain health and cognition from infancy through to old age is important, because it can help us to make informed decisions about our health, diet, and lifestyle, such as taking supplements that may support our cognitive function throughout our lifetime.
Written by: Leanne Edermaniger, M.Sc. Leanne is a professional science writer who specializes in human health and enjoys writing about all things related to the gut microbiome.
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