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How Do Human Milk Oligosaccharides (HMOs) Promote Brain Health?

August 10, 2022 5 min read

How Do Human Milk Oligosaccharides (HMOs) Promote Brain Health? A Look at How 2'-FL, 3'-SL, and 6'-SL Impact Cognition

When you think about maintaining or improving your brain health, your thoughts probably don’t first go to the gut. However, researchers have recently recognized gut health as affecting much more than just digestion. One group of compounds intimately related to brain function and cognitive health are HMOs, or human milk oligosaccharides. 

Three of the most studied HMOs are 2’FL, 3’SL, and 6’SL — let’s take a closer look at how these molecules impact our brain and what the research is telling us about HMOs and cognition.

HMOs 101: What Are 2'-FL, 3'-SL, and 6'-SL?

HMOs are a type of carbohydrate abundant in human breast milk. Known as prebiotics, HMOs are non-digestible chains of carbohydrates called oligosaccharides that travel to the large intestine and can benefit gut, immune, and cognitive health. Although HMOs are only naturally present in breast milk, they can also be created through a scientific process involving enzymes and fermentation. 

Two families of HMOs include the fucosylated HMOs—called 2′-Fucosyllactose (2’FL)—and sialylated HMOs, known as 3′Sialyllactose (3-SL) and 6′-Sialyllactose (6’SL). 

The difference between these two types involves alterations in their chemical structures. For example, fucosylation is adding fucose sugar units to a molecule, while sialylation adds sialic acid to the end of a carbohydrate chain. 

2’-FL is the most abundant HMO found in human milk and was the first HMO to be added to infant formula. Therefore, 2’FL is most strongly linked to immune health, brain development, and fighting inflammation. 

The ​​sialylated HMOs—3’SL and 6’SL—also are known to benefit brain health, as sialic acid is an essential nutrient to form compounds critical to cognitive function.

How Do HMOs Impact Brain Health?

Although about 200 distinct HMOs have been identified, three are thought to be most closely linked to brain health: 2’FL, 3’SL, and 6’SL. As these HMOs have different properties and molecular structures, researchers believe that each HMO has varying effects on cognitive function. 

Two of the most prominent HMOs found in breastmilk—2'-FL and 6'-SL—are vital for developing an infant’s brain. Fucosylated HMOs like 2’-FL are present in the brain’s hippocampus, where they play a crucial role in memory and learning. 

The sialylated HMOs—3’SL and 6’SL—provide sialic acid, which is essential to form compounds called gangliosides. Briefly, gangliosides are a type of lipid (fat) highly abundant in the brain, enriching cell membranes and facilitating neuronal communication. People without proper ganglioside function exhibit symptoms of severe neurodegenerative diseases, highlighting the importance of these sialic acid-carrying fats. 

HMOs may also benefit cognitive function because they lead to the production of short-chain fatty acids (SCFAs). When we consume HMO prebiotics, the indigestible carbohydrate portion of the HMO is metabolized by our gut bacteria. These SCFA metabolites—butyrate, propionate, and acetate—are beneficial compounds that support cognitive, digestive, and immune health. 

These mechanisms behind HMOs and cognitive function are a prime example of the gut-brain axis, a bidirectional communication pathway between our intestinal microbiota and central nervous system. This axis means that gut microbiota—and their metabolites—can directly or indirectly impact brain cells and cognitive function, and vice versa.

[[READ: the team of registered dietitians at Go Wellness review PureHMO®]]

Research on HMOs and Cognition

Now that we know the basics of how HMOs can impact our brains, let’s take a closer look at the available research on HMOs and cognition. 

In studies dating back to the 1990s, researchers found that 2’FL supplementation increased rats’ long-term potentiation—a process of strengthening synaptic connections between neurons. They also found that another form of HMO, 3’FL, had no beneficial effect on the brain, underlying the differences between varying HMO structures. 

In more recent years, animal research has found that HMOs benefit the brain by strengthening synapses between neurons, which improves memory and learning abilities. In a study with rats, those receiving 2’FL supplementation exhibited enhanced learning, memory, and brain function. 

The cognitive effects of sialylated HMOs have also been investigated. Research published in 2018 found that 6’SL supplementation improved memory and long-term potentiation in rats. Similarly, young piglets fed sialylated HMOs had increased ganglioside-bound sialic acid in the brain, suggesting benefits to cognitive function. 

3’SL has also produced some beneficial brain-related benefits. In a trial with stressed-out mice, those who took either 3’SL or 6’SL showed reductions in anxiety and maintenance of normal neuron count. 

In a May 2021 observational study, researchers looked at mother-child pairs in which the infants were partially or fully breastfed. They found a positive association between 3’SL consumption and infant cognition, especially with language development and function. 

Lastly, in an indirect route of benefiting the brain, studies have also found that butyrate—one of the short-chain fatty acids produced after HMO consumption—stimulates the production of brain-derived neurotrophic factor (BDNF). BDNF is a protein that prompts new neuron growth in the adult brain. This increase in brain cell growth, known as neurogenesis, is linked to the preservation of cognition with age, better memory, and reduced risk of neurodegenerative diseases.

Do HMOs Reduce the Risk of Alzheimer’s Disease?

Although we can’t say for sure if HMOs prevent Alzheimer’s disease, we do know that HMO prebiotics are beneficial for brain health and cognition. 

Some reasons why HMOs may help with Alzheimer’s disease are because they promote healthier gut bacterial diversity and stimulate the production of neuroactive molecules, including neurotransmitters like gamma-aminobutyric acid (GABA) and serotonin. 

Studies with animals have also found that HMOs help modulate behavior, learning, memory, and other forms of cognition, which may translate to better human brain health. However, we don’t know yet know for sure if supplementing with HMOs could reduce the risk of Alzheimer’s disease because there haven’t been any long-term human clinical trials on this topic—not yet, at least.

Key Takeaways:

  • HMOs are non-digestible carbohydrates known as prebiotics that can benefit cognitive, digestive, and immune health.
  • Three of the most studied HMOs regarding brain health include 2’FL, 3’SL, and 6’SL.
  • 2’-FL HMOs are present in the brain’s hippocampus, where they play an essential role in memory and learning.
  • The sialylated HMOs—3’SL and 6’SL—provide sialic acid, which is essential to forming brain-boosting compounds called gangliosides.
  • HMOs may also benefit cognitive function because they lead to the production of short-chain fatty acids like butyrate, which supports the growth of new neurons.
  • Although many studies with animals show the benefits of HMOs on brain health, there hasn’t yet been extensive research on human HMO consumption and cognitive function. 

 

Written By: 

Cambria Glosz, Registered Dietitian 

 

References: 

Al-Khafajia AH, Stine DJ, Christensen KR, et al. The potential of human milk oligosaccharides to impact the microbiota-gut-brain axis through modulation of the gut microbiota. Journal of Functional Foods. 2020;74:104176. https://doi.org/10.1016/j.jff.2020.104176. 

Cho S, Zhu Z, Li T, et al. Human milk 3'-Sialyllactose is positively associated with language development during infancy. Am J Clin Nutr. 2021;114(2):588-597. doi:10.1093/ajcn/nqab103 

Docq S, Spoelder M, Wang W, Homberg JR. The Protective and Long-Lasting Effects of Human Milk Oligosaccharides on Cognition in Mammals. Nutrients. 2020;12(11):3572. Published 2020 Nov 21. doi:10.3390/nu12113572 

Heyck M, Ibarra A. Microbiota and memory: A symbiotic therapy to counter cognitive decline?. Brain Circ. 2019;5(3):124-129. Published 2019 Sep 30. doi:10.4103/bc.bc_34_19 

Jacobi SK, Yatsunenko T, Li D, et al. Dietary Isomers of Sialyllactose Increase Ganglioside Sialic Acid Concentrations in the Corpus Callosum and Cerebellum and Modulate the Colonic Microbiota of Formula-Fed Piglets. J Nutr.2016;146(2):200-208. doi:10.3945/jn.115.220152 

Krug M, Wagner M, Staak S, Smalla KH. Fucose and fucose-containing sugar epitopes enhance hippocampal long-term potentiation in the freely moving rat. Brain Res.1994;643(1-2):130-135. doi:10.1016/0006-8993(94)90018-3 

Oliveros E, Ramirez M, Vazquez E, et al. Oral supplementation of 2'-fucosyllactose during lactation improves memory and learning in rats. J Nutr Biochem. 2016;31:20-27. doi:10.1016/j.jnutbio.2015.12.014 

Tarr AJ, Galley JD, Fisher SE, Chichlowski M, Berg BM, Bailey MT. The prebiotics 3'Sialyllactose and 6'Sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: Evidence for effects on the gut-brain axis. Brain Behav Immun. 2015;50:166-177. doi:10.1016/j.bbi.2015.06.025 

Vázquez E, Barranco A, Ramírez M, et al. Effects of a human milk oligosaccharide, 2'-fucosyllactose, on hippocampal long-term potentiation and learning capabilities in rodents. J Nutr Biochem. 2015;26(5):455-465. doi:10.1016/j.jnutbio.2014.11.016


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