All for one and one for all: Prebiotic blends and anxiety

Forget competition, it’s about cooperation.

We previously wrote about how prebiotics improve memory, reduce anxiety, and can even promote recovery from stroke. That was just about individual prebiotics.

Here, we want to demonstrate that it isn’t necessarily about one prebiotic performing better than another. In fact, the goal of most research has not been to make direct comparisons. Rather, there’s a fair amount of studies that investigated ingredients containing prebiotics, or combinations of prebiotic-like components.

Some of the questions we hear on prebiotics and cognitive performance:

  • Are there synergistic effects?
  • Is one better than another?
  • What is the right dose?

Of course, the answer to the those questions is: it depends.

Let’s take a look at some key studies.

Prebiotic Combinations

Galactooligosaccharide and fructooligosaccharide alleviate social stress and anxiety

“...The combination of GOS and FOS can reduce anxiety and depressive like behavior...and lessen the effects of chronic stress.”

Two representative studies summarize the potential benefit of using galactooligosaccharide (GOS) and fructooligosaccharide (FOS) together1,2. In the first1, rats were fed GOS, FOS, or a combination of the two. A range of techniques designed to assess anxiety and depressive-like behavior were used. Those fed GOS were found to demonstrate less anxiety-like and more pro-social behavior, and this was true for the combination of GOS and FOS. Curiously, FOS did not affect either of these domains, suggesting a strong role for GOS driving this effect in the combination. Conversely, both FOS, GOS, and their combination were found to reduce depressive-like behavior using some methods but not others. Neither of the prebiotics were found to effect recognition memory. All effects observed were specific to sociability and emotion-related outcomes, rather than learning or memory.

The same researchers followed this up with an investigation of the protective effects of GOS and FOS against stress1. Rats were exposed to chronic and unpredictable social stress, and tested on behavioral tasks designed to assess sociability, recognition memory, repetitive behavior, and anxiety. Here, stressed animals displayed worse performance than controls on every test. However, those stressed animals provided a combination of FOS and GOS behaved much closer to non-stressed controls. They had improved sociability and less repetitive behavior, like controls. Though they still underperformed on tests of recognition memory and anxiety, their performance exceeded that of their non-supplemented and stressed counterparts.

In short, Burokas et al.,1 showed that the combination of GOS and FOS can reduce anxiety and depressive like behavior in healthy animals, and importantly lessen the effects of chronic stress.

Galactooligosaccharide and fructooligosaccharide impact the entire lifespan

“…gestational intake of prebiotics had a programming effect…or maternal behavior was altered, producing less anxious offspring.”

The second study showed that the combination of GOS and FOS affects anxiety and social behaviors throughout the entire lifespan2. Rather than focusing on neonatal development or adulthood, they conducted a longitudinal study across the entirety of development on prebiotic supplementation and behavior. Pregnant dams were provided a combination of short chain GOS and long chain FOS, after pups were birthed and then weaned, they too were provided the same combination into adulthood. Across this period mice were subjected to a variety of behavioral tests assessing sociability and anxiety-like behavior.

Notably, pups from supplemented mothers showed less anxiety before weaning, prior to consumption of the prebiotic combination! This suggests that either gestational intake of prebiotics had a programming effect on offspring behavior, or perhaps maternal behavior was altered, producing less anxious offspring. Potentially related to this finding was a reduction in anxiety-like behavior that persisted throughout adolescence, early adulthood, and adulthood. While only tested during adulthood, supplemented mice also showed more prosocial behavior.

This study is the first to investigate a combination of prebiotics across a lengthy developmental period (gestation through adulthood), providing strong evidence of a developmental effect of prebiotic intake.

Prebiotic combinations can affect memory too

These studies were conducted by myself, and it resulted in some of the clearest data I ever produced. Pigs were fed a combination of polydextrose (PDX) and GOS for 4 weeks in early life3. At the end of the trial we tested recognition memory, and every pig performed better than the controls. Not only was recognition memory improved, but the pigs also demonstrated more exploratory behavior. They were simply more active in exploring their environment. Curiously, we did not find any effect of the combination on anxiety, contrary to previous research.

That effect on memory might seem suspicious, but we were able to replicate it two more times. In the second study we added sialyllactose to the mix4, now comparing it to controls who were already fed PDX/GOS. In this follow-up study, both groups performed very well on a recognition memory task, and there was no benefit from the addition of sialyllactose. Now across two studies, three groups showed a benefit to consumption of PDX/GOS. This led to the premature conclusion that sialyllactose does not affect memory. Rather, now we argue that for pigs who were already receiving a benefit from PDX/GOS intake, any additional sialyllactose wasn’t going to make already great performance better.

Prebiotics with dairy bioactives

Should prebiotics be complimented with the addition of a different class of ingredients? That is the line of thought regarding several studies feeding prebiotics with other dairy bioactives such as lactoferrin and the milk fat globule membrane.

Prior to joining, the lab I worked in during graduate school had investigated how a combination of PDX/GOS, lactoferrin, and the milk fat globule membrane affected neurodevelopment in pigs5. What a combination! Surprisingly, this combination did not elicit improvements in spatial memory. Though it did alter the volume of gray and white matter in the brain. Perhaps this combination affects the brain in alternative ways, rather than affecting learning and memory.

More evidence that prebiotics are protective against stress

Thompson et al.,6 used the same combination and investigated sleep patterns in stressed and non-stressed rats. Non-stressed rats showed increased non-rapid eye movement (NREM) sleep at various times in adulthood. When stressed, rats fed the prebiotic and milk bioactive combination showed better rebound in rapid eye movemeny (REM) sleep. This group later used the same combination to investigate anxiety behavior. Juvenile rats were fed the prebiotic blend and milk bioactives and four weeks later showed less anxiety-like behavior7. When this group looked into stress behavior using only PDX/GOS and/or lactoferrin (no milk fat globule membrane), only the group fed the combo of prebiotics and lactoferrin demonstrated reduced depressive-like behavior8.

A separate group performed two similar studies, investigating the role of prebiotics in protecting against stress.

In the first, Neufeld et al.9 used a combination of PDX/GOS and/or Lactobacillus rhamnosus GG to protect against stress from maternal separation in rats. Either the pre- or probiotic improved exploratory behavior, but only the combination reduced anxiety-like behavior in stressed rats. Although rats fed the prebiotic showed almost identical cognitive performance to those fed the combination, only the combination was shown to improve spatial memory in stressed rats.

The second study used PDX/GOS and/or the milk fat globule membrane in a rat model of maternal separation10. Rats not exposed to stress showed no benefit to intake of the prebiotics or milk bioactive with respect to learning or reference memory. For stressed rats, those fed the prebiotics, bioactives, or combination all had improved reference memory! Here, it seems there was not a synergistic effect, and any of the components promoted cognition.

Bringing it back

The overwhelming theme across all research is that anxiety and depressive-like behavior can be eliminated or reduced by the intake of prebiotics. This appears to be true whether they are provided throughout the lifespan or during discrete periods.

Now that we’ve reviewed some key studies (by no means all of them), let’s review the questions at the beginning of the article.

  • Are there synergistic effects?
    • Sometimes
  • Is one better than another?
    • Not conclusively
  • What is the right dose?
    • Unknown

We take an optimistic view towards these unanswered questions: look at the opportunities!

But how do they work? Why would something nondigestible affect the brain? Stay tuned for a look at the molecular mechanisms behind the cognitive promoting effects of prebiotics.

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.

References

1.  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.

2.  Szklany, K., Wopereis, H., de Waard, C., van Wageningen, T., An, R., van Limpt, K., Knol, J., Garssen, J., Knippels, L. M. J., Belzer, C. & Kraneveld, A. D. Supplementation of dietary non-digestible oligosaccharides from birth onwards improve social and reduce anxiety-like behaviour in male BALB/c mice. Nutr. Neurosci. (2019) doi:10.1080/1028415X.2019.1576362.

3.  Fleming, S. A., Monaikul, S., Patsavas, A. J., Waworuntu, R. V., Berg, B. M. & Dilger, R. N. Dietary polydextrose and galactooligosaccharide increase exploratory behavior, improve recognition memory, and alter neurochemistry in the young pig. Nutr. Neurosci. 22, 499–512 (2017) doi:10.1080/1028415X.2017.1415280.

4.  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.

5.  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.

6.  Thompson, R. S., Roller, R., Mika, A., Greenwood, B. N., Knight, R., Chichlowski, M., Berg, B. M. & Fleshner, M. Dietary Prebiotics and Bioactive Milk Fractions Improve NREM Sleep, Enhance REM Sleep Rebound and Attenuate the Stress-Induced Decrease in Diurnal Temperature and Gut Microbial Alpha Diversity. Front. Behav. Neurosci. 10, 240 (2017) doi:10.3389/fnbeh.2016.00240.

7.  Mika, A., Gaffney, M., Roller, R., Hills, A., Bouchet, C. A., Hulen, K. A., Thompson, R. S., Chichlowski, M., Berg, B. M. & Fleshner, M. Feeding the developing brain: Juvenile rats fed diet rich in prebiotics and bioactive milk fractions exhibit reduced anxiety-related behavior and modified gene expression in emotion circuits. Neurosci. Lett. 677, 103–109 (2018) doi:10.1016/j.neulet.2018.01.052.

8.  Mika, A., Day, H. E. W., Martinez, A., Rumian, N. L., Greenwood, B. N., Chichlowski, M., Berg, B. M. & Fleshner, M. Early life diets with prebiotics and bioactive milk fractions attenuate the impact of stress on learned helplessness behaviours and alter gene expression within neural circuits important for stress resistance. Eur. J. Neurosci. 45, 342–357 (2017) doi:10.1111/ejn.13444.

9.  Neufeld, K. M., Kang, N., Bienenstock, J. & Foster, J. A. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–265 (2011) doi:10.1111/j.1365-2982.2010.01620.x.

10.  O’Mahony, S. M., McVey Neufeld, K. A., Waworuntu, R. V., Pusceddu, M. M., Manurung, S., Murphy, K., Strain, C., Laguna, M. C., Peterson, V. L., Stanton, C., Berg, B. M., Dinan, T. G. & Cryan, J. F. The enduring effects of early-life stress on the microbiota–gut–brain axis are buffered by dietary supplementation with milk fat globule membrane and a prebiotic blend. Eur. J. Neurosci. 51, 1042–1058 (2020) doi:10.1111/ejn.14514.

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