Can Prebiotics Improve Cognition?

It’s no longer a secret and hasn’t been for some time, that the gut and brain share an intimate relationship.

The gut houses the enteric nervous system, sometimes referred to as the “second brain”, and we are of course familiar with terms like “butterflies in our stomach” to describe the feeling of anxiety.

Improving the brain with nutrition, however, is difficult. There is plenty of research that shows promising results from nutritional interventions in rodents that fail to translate to larger animals or humans. This is common across all biological domains, not just nutrition.

So, is there credence to the idea that prebiotics can affect our mood or even make us “smarter”? We might not phrase it that way, but we think the answer is yes. The door is wide open for innovation, however. Join us in reviewing the small but growing body of literature demonstrating the potential of prebiotics to change behavior itself.

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Prebiotics and Cognition

Comparatively speaking, there is less data on prebiotics and cognition than other ingredients one might classify as nutraceuticals or nootropics. For many scientists, such terms might even conjure images of pseudoscientific treatments claiming to “boost focus” and “sharpen the brain”. There are a handful of prebiotics, specifically oligosaccharides, that have been studied with a reasonable level of rigor. These are galactooligosaccharide (GOS), fructooligosaccharide (FOS), sialyllactose (SL), and 2’fucosyllactose (2’-FL).

Galactooligosaccharide

Galactose backbone

Linear or branched

Non-digestible and fermentable

See Reference 1

Fructooligosaccharide

Fructose backbone

Linear or branched

Non-digestible and fermentable

See References 2-3

3’- and 6’-Sialyllactose

Sialic Acid - Galactose - Glucose

Non-digestible and fermentable

See Reference 22

2’-Fucosyllactose

Fucose - Galactose - Glucose

Non-digestible and fermentable

See Reference 22

Image

Evidence for GOS and FOS

Galactooligosaccharides reduce stress and anxiety

Some of the earlier data (just from 2012!) demonstrated galactooligosaccharide (2% in drinking water) could delay the disease onset of amyotrophic lateral sclerosis in mouse models4. Since then more sophisticated behavioral work has been conducted identifying benefits of GOS.

Starting with human data, Schmidt et al.,5 found that subjects consuming GOS demonstrated improved outcomes related to stress. In a double-blind randomized placebo-controlled design, male and female participants were instructed to take 5.5 g/day of GOS, FOS, or maltodextrin everyday for 3 weeks. Before and after supplementation participants were tested on a battery of cognitive tests to assess emotional processing and salivary cortisol was collected upon waking to quantify the salivary cortisol waking response. For controls, salivary cortisol peaked 30 minutes after waking and declined thereafter. This held true for all groups but those who consumed GOS demonstrated a less drastic rise and fall in cortisol. After performing a task to assess attention toward emotionally positive or negative words, those fed GOS shifted their attention from negative toward positive stimuli.

Rats fed GOS in drinking water (~6.25 g/L) and injected with lipopolysaccharide (an endotoxin that can induce anxiety-like behavior) demonstrated less anxious behavior than those not fed GOS, and performed closer to controls6.

Rats fed GOS (0.3-0.4 g/mouse/day) were more exploratory, less anxious, more prosocial, and showed less depression-like behavior than controls. They showed these behaviors when fed both GOS and FOS, in addition to rats fed the combination showing greater resilience to chronic social stress7.

The benefits of GOS extend to cognition and are not restricted to emotional states.

Although less documented than their potential anxiolytic effects, GOS may also promote memory related function.

One study looked at the capacity of GOS to reduce neuro-inflammation related cognitive deficits post-surgery8. They found adult rats recovering from surgery displayed improved recognition memory when provided GOS in drinking water (15 g/L), though still not to the level of non-surgery controls.

A later study further investigated the impact of dietary GOS on cognition and found GOS (3% GOS in drinking water) improved attentional set shifting performance in adult male Sprague Dawley rats9.

Galactooligosaccharides reduce stress and anxiety

In mouse models of Alzheimer’s Disease, mice fed FOS (25 or 50 g/kg in chow) were resilient to induced cognitive deficits10. In a water maze they were able to reach performance levels of controls. Though effective here, other research shows that FOS is either just as effective or less-so than GOS.

Burokas and colleagues looked at both GOS and FOS, alone or in combination at 0.3-0.4 g/mouse/day. Across behavioral tasks assessing anxiety, depression, sociability, and cognition they found very little evidence that FOS was as effective as GOS. In most cases, rats fed FOS performed no better than controls, with the exception of a forced swim test designed to assess depression-like behavior.

Remember the above study by Schmidt et al.,5 detailing the positive effects on salivary cortisol and attention when human subjects consumed 5.5 g/day of GOS? Unfortunately, those results did not extend to the same dose of FOS.

We ourselves found that oligofructose improved short-term recognition memory in pigs and increased their exploratory behavior, but this did not extend to long-term memory11.

Finally, there have been few studies investigating the role of FOS on cognition, and the results are mixed! This by no means closes the door on FOS as a potentially new and innovative way to alter behavior, it’s simply less researched.

Evidence for Human Milk Oligosaccharides

Just as exciting as GOS and FOS, is emerging research on oligosaccharides present at high levels in human milk. Of those studies, both sialyllactose and 2’-fucosyllactose have seen substantial research. Both these molecules contain residues found in glycoproteins and glycolipids the brain12,13, those being sialic acid and fucose.

Sialyllactose

What makes sialyllactose distinct is its N-acetylneuraminic acid (NeuAc) residue, a type of sialic acid. Sialic acid plays a big role in functions like synaptic transmission, plasticity and neurogenesis14. Oligosaccharides are believed to be critical for proper cognitive function. Sialic acid is commonly found as part of gangliosides in the brain. In human milk nearly 2/3rds of the sialic acid comes from oligosaccharides12!

Sakai15 directly compared forms of sialic acid to sialyllactose to understand if the oligosaccharide as a whole was beneficial, or sialic acid itself. Using two different water mazes to test spatial navigation in adult rats, they fed 1% sialyllactose or two forms of sialic acid in chow for 2 weeks. The authors note that those fed sialyllactose or one of the forms of sialic acid (glycosylated N-acetylneuraminic acid) tended to complete the tasks more quickly, but they were hardly better than controls.

A similar line of research was conducted by Oliveros et al.,16 comparing sialic acid (Neu5Ac) directly to 6’-sialyllactose. Not only did Oliveros et al.,16 control for the form of sialic acid, they controlled the dose as compared to rodent milk. They measured the amount of sialic acid in milk across lactation and provided experimental groups equimolar amounts of sialic acid (Neu5Ac) or 6’-SL. Rat pups were reared by foster mothers whose pups were weaned at 16 days postnatal, such that foster mothers were used at a time that sialic acid in their milk was at its lowest. The experimental groups were still reared by mothers and consumed milk. Rather than give a static dose, the experimenters matched daily sialic acid to their foster mothers' sialic acid content from their last litter. Thus, the daily amount of sialic acid and 6’-SL were calculated based on body weight. Ultimately, animals were given the same concentration and dynamic dose of sialic acid as if they consumed rat milk!

They found no difference in recognition memory at weaning age, however at 1 year of age they observed that both groups provided sialic acid or 6’-sialyllactose performed better than controls in recognition memory tasks. Thus, making the case for the use of longitudinal designs and follow-ups after developmental periods.

Lastly, Tarr et al.,17 investigated the capacity of sialyllactose to prevent stress. They fed 6-8 wk old mice 5% (50 g/kg) 3’- or 6’-SL for 2.5 weeks. In the last week, mice were exposed to a social stressor via the introduction of an aggressive male intruder mouse for 2 hrs per day. Rodents fed both 3’-SL and 6’-SL demonstrated behavior like non-stressed controls, demonstrating a protective effect of sialyllactose.

Sialyllactose containing ingredients

What about lactoferrin, the milk fat globule membrane, casein glycomacropeptide, and oligosaccharide-enriched whey protein? Given the presence of siallylactose in bovine dairy products, these are ingredients sometimes claimed to exert beneficial effects on cognition or brain development, in part due to their oligosaccharide content. Some of them had a big hand in starting the interest in sialyllactose itself18. We purposely did not review these ingredients, even though we have researched some of them ourselves19–21! A discussion on the relevance of these to prebiotics in general muddies the water a bit, and we’ll save a discussion on these for a rainy day.

2’-Fucosyllactose

Last but certainly not least, we come to 2’-fucosyllactose (2’-FL). 2’-FL is perhaps one of the most well researched human milk oligosaccharide of them all. It is maybe a controversial molecule, as not all lactating mothers secrete 2’-FL in their milk22, raising questions about its biological relevance. Regardless, research on its potential to promote cognition has shown impressive results.

Like sialyllactose, 2’-FL contains a residue, fucose, found in the synapse and believed to be important for cognitive function23. Work in the 80’s demonstrated the need for fucosylation of glycoproteins for hippocampal function and performance in behavioral tasks23,24. Yet, these alone do not provide much evidence that dietary 2’-fucosyllactose has a health benefit related to the brain.

Recently in early 2020 some of the only known clinical data relating 2’-FL to infant cognition was published25. Both the number of feedings per day and concentration of 2’-FL in milk were positively related to infant cognitive development at 24 months of age, as measured by the Bayley Scales of Infant Development III. Curiously, there was no association found at 6 months of age, again suggesting the importance of longitudinal study designs and follow-ups.

This finding is well supported by a few but well-designed studies in rodents. In the first, both young adult mice and rats were provided oral gavages of either 0.312% or 0.625% 2’-FL for 5 or 12 weeks to provide ~350 mg/kg body weight per day26. Supplemented mice performed better on not just one test, but place learning, associative learning, and working memory tasks!

A follow-up study by the same group provided critical evidence linking potential mechanisms to the cognition-promoting effects of dietary 2’-FL27. The authors investigated the role of the vagus nerve in 2’-FL's cognitive-promoting effects. The study was conducted using a 2x2 design wherein rats were vagotomized (or not) and fed 2’-FL (or not) and tested on a 1:1 ratio lever pressing task. The goal was to test the ability of the rat to learn the association between pressing a lever once to receive a food reward. All rats were able to learn this task, but not better than those fed 2’-FL with an intact vagus nerve. Essentially, to maximally reap the benefit of consuming 2’-FL, the vagus nerve is a necessary component. This gave critical evidence to the hypothesis that prebiotics might have a direct effect on the brain, rather than indirect, through the production and circulation of microbial metabolites. Why the vagus nerve is required, we still don’t know.

HMO are not just for babies

Why care about human milk oligosaccharides (HMO) if you’re not a parent or an infant? There is more to these oligosaccharides than meets the eye, and their potential to shape even adult brain function is beginning to emerge. Consider work done by Wu et al.,28 on 2’-FL and neurodegeneration, for example. In a rodent model of stroke, they found that oral post-treatment of 2'FL was able to improve locomotor activity. 2’-FL supplemented rats still performed worse than controls, but their performance was markedly better than those stroke-model rodents who did not receive supplementation.

This is one example of what is likely to come: more research on the potential of prebiotics to improve cognition in healthy, injured, and diseased conditions.

Is there an optimal dose?

Probably, but we aren’t aware of any studies that conducted a proper dose-response trial to find out. Furthermore, this dose is likely different for each form of oligosaccharide, and even for each product. One manufacturer’s product may be quite different from another’s in terms of purity and other compounds present, like protein.

Is there an optimal dose?

  • Several prebiotics improve cognition
  • Dose response studies haven’t been conducted
  • One prebiotic is not necessarily better than another
  • Experimental clinical research with longitudinal designs are desperately needed

If you’re an optimist, you might be ready to jump on the bandwagon and get involved in a hot area of research. If you’re a skeptic, you might want to weigh and consider future work done to identify the right doses, structures, and compositions to support the results seen in preclinical models.

References

About the author: Stephen Fleming is President and Co-founder of Traverse Science. He believes science doesn’t have to be hard and should accelerate business, not slow it down. He has a background in neuroscience and nutrition from the University of Illinois at Urbana-Champaign where he studied oligosaccharide intake and brain development for his PhD. If you want to learn more, follow him and Traverse Science on LinkedIn, and connect with us at engage@traversescience.com.

About the company: Traverse Science is a nutrition consulting firm working with ingredient suppliers and consumer packaged goods companies in the human and animal nutrition space. We work with clients to get science done, whether that means organizing and conducting a study, analyzing new or long-forgotten data, or writing a manuscript for peer review or guidance document for internal use. As teams change, time runs short, or projects pivot, we provide the muscle and the know-how to finish your nutrition science and get your projects out the door – whatever that means for you. We believe that science doesn’t have to be hard, and we’re here to make it easy.

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  2. Huazano-García, A. & López, M. G. Enzymatic Hydrolysis of Agavins to Generate Branched Fructooligosaccharides (a-FOS). Appl. Biochem. Biotechnol. 184, 25–34 (2018) doi:10.1007/s12010-017-2526-0.

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  6. Savignac, H. M., Couch, Y., Stratford, M., Bannerman, D. M., Tzortzis, G., Anthony, D. C. & Burnet, P. W. J. Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-β levels in male mice. Brain. Behav. Immun. 52, 120–131 (2016) doi:10.1016/j.bbi.2015.10.007.

  7. Burokas, A., Arboleya, S., Moloney, R. D., Peterson, V. L., Murphy, K., Clarke, G., Stanton, C., Dinan, T. G. & Cryan, J. F. Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice. Biol. Psychiatry 82, 472–487 (2017) doi:10.1016/j.biopsych.2016.12.031.

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  10. Yen, C.-H., Wang, C.-H., Wu, W.-T. & Chen, H.-L. Fructo-oligosaccharide improved brain β-amyloid, β-secretase, cognitive function, and plasma antioxidant levels in D-galactose-treated Balb/cJ mice. Nutr. Neurosci. 20, 228–237 (2017) doi:10.1080/1028415X.2015.1110952.

  11. Fleming, S. A., Mudd, A. T., Hauser, J., Yan, J., Metairon, S., Steiner, P., Donovan, S. M. & Dilger, R. N. Dietary Oligofructose Alone or in Combination with 2′-Fucosyllactose Differentially Improves Recognition Memory and Hippocampal mRNA Expression. Nutrients 12, 2131 (2020) doi:10.3390/nu12072131.

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  15. Sakai, F., Ikeuchi, Y., Urashima, T., Fujihara, M., Ohtsuki, K. & Yanahira, S. Effects of Feeding Sialyllactose and Galactosylated N-Acetylneuraminic Acid on Swimming Learning Ability and Brain Lipid Composition in Adult Rats. J. Appl. Glycosci. 53, 249–254 (2006) doi:10.5458/jag.53.249.

  16. Oliveros, E., Vázquez, E., Barranco, A., Ramírez, M., Gruart, A., Delgado-García, J. M., Buck, R., Rueda, R. & Martín, M. J. Sialic acid and sialylated oligosaccharide supplementation during lactation improves learning and memory in rats. Nutrients 10, (2018) doi:10.3390/nu10101519.

  17. Tarr, A. J., Galley, J. D., Fisher, S. E., Chichlowski, M., Berg, B. M. & Bailey, M. T. 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. 50, 166–177 (2015) doi:10.1016/j.bbi.2015.06.025.

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  19. Mudd, A. T., Alexander, L. S., Berding, K., Waworuntu, R. V., Berg, B. M., Donovan, S. M. & Dilger, R. N. Dietary prebiotics, milk fat globule membrane, and lactoferrin affects structural neurodevelopment in the young piglet. Front. Pediatr. 4, 1–10 (2016) doi:10.3389/fped.2016.00004.

  20. Fleming, S. A., Chichlowski, M., Berg, B. M., Donovan, S. M. & Dilger, R. N. Dietary Sialyllactose Does Not Influence Measures of Recognition Memory or Diurnal Activity in the Young Pig. Nutrients 10, 395 (2018) doi:10.3390/nu10040395.

  21. Fil, J. E., Fleming, S. A., Chichlowski, M., Gross, G., Berg, B. M. & Dilger, R. N. Evaluation of Dietary Bovine Milk Fat Globule Membrane Supplementation on Growth, Serum Cholesterol and Lipoproteins, and Neurodevelopment in the Young Pig. Front. Pediatr. 7, 417 (2019) doi:10.3389/fped.2019.00417.

  22. Bode, L. Human milk oligosaccharides: Every baby needs a sugar mama. Glycobiology 22, 1147–1162 (2012) doi:10.1093/glycob/cws074.

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  24. Jork, R., Grecksch, G. & Matthies, H. Impairment of glycoprotein fucosylation in rat hippocampus and the consequences on memory formation. Pharmacol. Biochem. Behav. 25, 1137–1144 (1986) doi:10.1016/0091-3057(86)90100-0.

  25. Berger, P. K., Plows, J. F., Jones, R. B., Alderete, T. L., Yonemitsu, C., Poulsen, M., Ryoo, J. H., Peterson, B. S., Bode, L. & Goran, M. I. 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 15, e0228323 (2020) doi:10.1371/journal.pone.0228323.

  26. Vázquez, E., Barranco, A., Ramírez, M., Gruart, A., Delgado-García, J. M., Martínez-Lara, E., Blanco, S., Martín, M. J., Castanys, E., Buck, R., Prieto, P. & Rueda, R. Effects of a human milk oligosaccharide, 2′-fucosyllactose, on hippocampal long-term potentiation and learning capabilities in rodents. J. Nutr. Biochem. 26, 455–465 (2015) doi:10.1016/j.jnutbio.2014.11.016.

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For more like this, check out our post on prebiotic blends on cognition

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