Deciphering the Role of Human Milk Oligosaccharides in Brain Health and Cognition Throughout Life

December 16, 2023 8 min read

Deciphering the Role of Human Milk Oligosaccharides in Brain Health and Cognition Throughout Life

Hemisphere. Not a word you come across too often, but when you do, it’s either referring to the planet, or the brain. Both have the capability to blow your socks off when you start to investigate the complexity of their formation and magnificence, and both creations scream out genius. However, this article isn’t interested in the formation of the planet, that’s a whole other science.

In this article, we are going to look at the brain, what makes this multibillion-fibre highway network begin? How does this controller of the body know the right time to execute trillions of commands, the right temperature, when to feed, when to breathe, the optimal heart rate, the right blood pressure, or even how to see? The list is as endless as it is gobsmacking, but there are answers to be had, and some concern scientific research into human milk oligosaccharides (HMOs), glycans provided by human milk, and the results being published are fascinating.

So, prepare to be wowed as we unfold just a little of what makes you tick…

The role of HMOs in early brain development

When we arrive on the planet the brain is formed and prewired, all set up to learn. A myriad of fibres is interwoven ready to carry the trillions and trillions of messages throughout life[i], emphasising the point that the brain is a complex organ.

But this unique control centre for the body doesn’t just develop on its own. Human milk oligosaccharides were originally discovered as a prebiotic, a food for good gut bugs. But over the years research has shown us that they’re more than that, and a review published in 2020 found that HMOs could be relevant for brain health in the developing infant[ii].

Which HMOs influence infant brain development

2’-fucosyllactose (2’-FL) and Lacto-N-neotetraose (LNnT) are the most tested HMOs in humans. A study by Berger et al., (2020) investigated the impact of 2’-FL on infants' cognitive development and found that those who were breastfed more frequently at one month had better cognitive development at two years old[iii]. Further studies have also identified links between some HMOs, including 2’-FL and 6’ siallylactose (6’-SL), and cognition[iv].

 A more recent study in 2022 involving 20 mothers and their infants reported a link between individual HMOS and infant brain development with magnetic resonance imaging (MRI). This is important because many studies that look at the link between HMOs and brain development are conducted in animals, whereas this one occurred in humans. 

 The results of the study found that the HMOs, 2’-FL, 3’-fucosyllactose (3’-FL), and 3’-siallylactose (3’-SL), encourage the grey matter of the brain to mature and promote the development of white matter. Therefore, this research suggests that HMOs are more than just prebiotics and have important roles in supporting the development of the infant brain structure.

 The first 2 years of life are critical for the brain 

In the previous section, the study by Berger et al., (2020) focussed on the first two years of life, leading us to question whether this is relevant. And it is. Although the brain continues to develop into early adulthood[v], it goes through huge transformations from conception up to two years old. 

It’s during this time that the brain can be influenced by environmental factors, like nutrition which, if negative, can have detrimental or lifelong effects. So, this period is particularly important for the brain and the infant, and it’s also the optimum time to feed on HMOs, to support growth and future health. 

HMOs and cognition from childhood to adulthood

The potential for HMOs in the field of cognition and brain health goes beyond infants. For example, the cognitive effects of sialylated HMOs, particularly 3’-SL and 6’-SL, have been under the microscope in recent years. Here, we’ll explore some of the research into HMOs and their impact on the brain from childhood through to adulthood. 

3’-SL and language development

Until recently, the effects of HMOs on language development were limited, not least because language is exclusive to humans. However, a study published in 2021 found that 3’-SL may support language development in children born from mothers with blood type A, and with a specific HMO, Alpha-Tetrasaccharide (A-Tetra)[vi]

In short, the study highlights that 3’-SL has a role in a specific area of cognition, language function, during infancy.  

HMOs in infancy: Their effect into adulthood

Early life can be a key determinator of future health, wellbeing, and even socioeconomic outcomes. 

A healthy, balanced gut microbiome, for example, from infancy provides a solid foundation to establish an abundant and diverse microbial ecosystem. HMOs have a significant role to play here because they predominantly feed the health-promoting Bifidobacteriaspecies residing in the gut. These also go on to feed other species, produce bioactive compounds such as vitamins and short-chain fatty acids, and generally support a healthy gut[vii]

These mechanisms, such as the production of acetate and butyrate and their roles within the immune system and strengthening the integrity of the gut barrier, means Bifidobacteria, supported by HMOs, are fundamental in both infancy and adulthood. 

6’-SL and cognition

That’s not all. A balanced microbiome supports many other areas of our cognitive health and development. 

In a mouse study by Hauser et al., (2021), mice deprived of lactational 6’-SL during infancy were found to have altered cognitive functioning in memory, perseveration, and attention in adulthood, suggesting 6’-SL has a profound benefit for cognitive development[viii].

Could HMOs help with depression?

According to the World Health Organisation, 280 million people across the world have depression[ix], confirming that this is a burden for both individuals and health services. But, as we know, HMOs can influence the composition of your gut microbiome, including the abundance and activity of Bifidobacteria. Could this be key to supporting depression?

Bifidobacteriais known to increase the production of important metabolites, particularly butyrate, through its ability to cross-feed butyrate-producing species such as Faecalibacterium prausnitzii.Valles-Colomer et al., (2019) found that an increase in butyrate-producing bacteria was associated with a better quality of life for depressed individuals[x]

So, HMOs, through their ability to modulate the adult gut microbiome may have a positive effect on mood and quality of life in depressed patients. 

The future: HMOs and their potential role in adult brain function

There is no way of saying HMOs can halt or reverse brain diseases or impairments like Alzheimer's disease (AD) and dementia at the moment. There is, however, some promising research that has been conducted, showing how an imbalanced gut is common in those living with these conditions compared to those who are not.

As we age it is not a foregone conclusion that we are in for it with regards to dementia and beyond. There are many other factors that play a role in the onset of conditions such as:

In all these areas, dysbiosis has been identified as a contributor to the cause. This is also the case for dementia and AD.

HMOs and their role in maintaining the gut microbiota and its effect on Alzheimer’s Disease
 

In 2020, a study headed by Liu et al researched the gut microbiota and dysbiosis in Alzheimer's disease. The study observed the communication of the microbiota-gut-brain axis and its role in the maintenance of brain homeostasis, and how the bioactive components via the endocrine, immune, metabolic, and neural pathways delivered this. 

The study showed that dysbiosis promoted a series of processes, neuroinflammation, oxidative stress, amyloid-beta aggregation, and insulin resistance. Dysbiosis was the contributing factor leading to this series of interruptions of brain homeostasis[xvi].

Another study carried out by Naomi et al (2022), researched the role of prebiotics, synbiotics, and probiotics in the diet and a balanced gut microbiota was seen to slow the progression of Alzheimer's disease[xvii].

With HMOs being prebiotic with additional capabilities, although they are not directly involved in the slowing of AD, they have been proven to initiate, feed, and bolster the gut microbiota. They have also been shown to teach certain processes like teaching the immune system to protect.      

Summary

HMOs play a critical role in the development of the human brain from infancy through adulthood. Emerging research shows specific HMOs aid the structural development of the brain, while others can improve cognitive outcomes.

As research progresses, who knows what these tiny, innate molecules could be capable of? Future studies will no doubt investigate their potential role in chronic neurodevelopmental diseases as well as conditions that directly affect our mood and cognition, such as depression. 

Written byLeanne 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. 

Sources

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[iii] Berger PK, Plows JF, Jones RB, Alderete TL, Yonemitsu C, Poulsen M, et al. Human milk oligosaccharide 2’-fucosyllactose links feedings at 1 month to cognitive development at 24 months in infants of normal and overweight mothers. PLOS ONE. 2020;15(2). doi: 10.1371/journal.pone.0228323  

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Positively Associated with Infant Neurodevelopment and are Not Impacted by Maternal BMI or Diabetic Status. J Nutr Food Sci 4: 024. 

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[vi] Cho S, Zhu Z, Li T, Baluyot K, Howell BR, Hazlett HC, Elison JT, Hauser J, Sprenger N, Wu D, Lin W. Human milk 3'-Sialyllactose is positively associated with language development during infancy. Am J Clin Nutr. 2021 Aug 2;114(2):588-597. doi: 10.1093/ajcn/nqab103. PMID: 34020453; PMCID: PMC8326052.

[vii] Stuivenberg GA, Burton JP, Bron PA, Reid G. Why Are Bifidobacteria Important for Infants? Microorganisms. 2022 Jan 25;10(2):278. doi: 10.3390/microorganisms10020278. PMID: 35208736; PMCID: PMC8880231. 

[viii] Hauser J, Pisa E, Arias Vásquez A, Tomasi F, Traversa A, Chiodi V, Martin FP, Sprenger N, Lukjancenko O, Zollinger A, Metairon S, Schneider N, Steiner P, Martire A, Caputo V, Macrì S. Sialylated human milk oligosaccharides program cognitive development through a non-genomic transmission mode. Mol Psychiatry. 2021 Jul;26(7):2854-2871. doi: 10.1038/s41380-021-01054-9. Epub 2021 Mar 4. PMID: 33664475; PMCID: PMC8505264.

[ix] Depressive disorder (depression) [Internet]. World Health Organization; [cited 2023 Nov 19]. Available from: https://www.who.int/news-room/fact-sheets/detail/depression#:~:text=An%20estimated%203.8%25%20of%20the,world%20have%20depression%20(1).

[x] Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, Schiweck C, Kurilshikov A, Joossens M, Wijmenga C, Claes S, Van Oudenhove L, Zhernakova A, Vieira-Silva S, Raes J. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol. 2019 Apr;4(4):623-632. doi: 10.1038/s41564-018-0337-x. Epub 2019 Feb 4. PMID: 30718848.

[xi] Justin BN, Turek M, Hakim AM. Heart disease as a risk factor for dementia. Clin Epidemiol. 2013 Apr 26; 5:135-45. doi: 10.2147/CLEP.S30621. PMID: 23658499; PMCID: PMC3641811. 

[xii] Cholerton B, Baker LD, Montine TJ, Craft S. Type 2 Diabetes, Cognition, and Dementia in Older Adults: Toward a Precision Health Approach. Diabetes Spectr. 2016 Nov;29(4):210-219. doi: 10.2337/ds16-0041. PMID: 27899872; PMCID: PMC5111529.

[xiii] Singh-Manoux A, Dugravot A, Shipley M, Brunner EJ, Elbaz A, Sabia S, Kivimaki M. Obesity trajectories and risk of dementia: 28 years of follow-up in the Whitehall II Study. Alzheimers Dement. 2018 Feb;14(2):178-186. doi: 10.1016/j.jalz.2017.06.2637. Epub 2017 Sep 21. PMID: 28943197; PMCID: PMC5805839.

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[xv] Anang JB, Gagnon JF, Bertrand JA, Romenets SR, Latreille V, Panisset M, Montplaisir J, Postuma RB. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology. 2014 Sep 30;83(14):1253-60. doi: 10.1212/WNL.0000000000000842. Epub 2014 Aug 29. PMID: 25171928; PMCID: PMC4180482.

[xvi] Liu S, Gao J, Zhu M, Liu K, Zhang HL. Gut Microbiota and Dysbiosis in Alzheimer's Disease: Implications for Pathogenesis and Treatment. Mol Neurobiol. 2020 Dec;57(12):5026-5043. doi: 10.1007/s12035-020-02073-3. Epub 2020 Aug 23. PMID: 32829453; PMCID: PMC7541367.

[xvii] Naomi R, Embong H, Othman F, Ghazi HF, Maruthey N, Bahari H. Probiotics for Alzheimer's Disease: A Systematic Review. Nutrients. 2021 Dec 22;14(1):20. doi: 10.3390/nu14010020. PMID: 35010895; PMCID: PMC8746506.


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