Mechanisms By Which Probiotics Act On The Human Brain Still Elude Us, But We’re Getting Closer

By definition, anything that’s called a probiotic must produce a scientifically demonstrated health effect. And in theory, this could be a brain health effect. We know that bidirectional communication occurs between the gut and brain — and furthermore, that the commensal gut microbiota may play a role in modulating this “gut-brain axis,” likely through pathways that involve the immune, endocrine, and neural systems (1).

Logically, this has led to the idea that modulating the gut microbiota could be a way to change central nervous system (CNS) function and affect human behavior — especially when people are facing challenges like stress, mood and anxiety disorders, or impaired memory and neurocognitive functions. So scientists have set out to answer whether probiotics can benefit the human brain. And, if so, how?

Credit: Wikimedia Commons

Probiotic promise

Many pre-clinical (that is, animal) studies have shown that probiotics, acting via the gut-brain axis, can affect behavior and the brain (2). However, moving from animal models into human work with healthy volunteers (or eventually, patients) has proven challenging. Some probiotics just don’t translate: for instance, a promising strain of Lactobacillus that successfully modulated stress responses in animals failed to exert the same effects in humans (3).

Stymied by lack of standardization

One big problem in the field is standardization. The novel molecular techniques (‘omics technologies) that scientists use for assessing gut microbiota composition in health and disease have been widely used for at least the past decade. But because methods vary drastically, comparison of results across different papers, laboratories, and journals remains challenging (4). This same “methodological diversity” exists even when it comes to measuring what the brain is doing in conditions of health and disease: during rest; following exposure to stressors or other stimuli; and with different technologies such as electroencephalography (EEG), functional magnetic resonance imaging (fMRI), positron-emission tomography (PET), or magnetoencephalography (MEG). Each method has its advantages and pitfalls (5), so scientists lack agreement on what should serve as the norm.

Initial human studies on probiotics & behavior

Despite the heterogeneity of methods at both the gut end and the brain end, several initial clinical studies have been published that used neuroimaging to provide insights into brain function when people consume probiotics. Studies have focused on modulations of CNS functions in healthy volunteers (6, 7) and in individuals with irritable bowel syndrome (IBS) (8): 4 to 6 weeks of consuming a multi-strain (6,7) or single strain probiotic (8) altered brain activation in emotion-associated brain areas and their inter-connections — and in the case of those with IBS, this was associated with improved depression scores (but left intestinal symptoms mostly unaltered).

The right task for the task

Notably, all three of the existing studies used a visual task (viewing and scoring of faces with different emotional expressions) during brain tracking. Such a task is well-suited to the brain imaging situation: lying completely still in a brain scanner while using one or two fingers to press buttons in response to predefined questions and tasks. Whether this truly mirrors the stressful and/or emotional tasks used for animal models (2) remains questionable. Furthermore, both of the existing studies that looked at healthy volunteers used a multi-strain probiotic, raising the question of whether one of the strains was uniquely responsible for the observed effects. Further investigations need to use targeted approaches and different stress paradigms.

It may be possible to construct better tasks for humans, showing more realistically how they act under conditions of real-life stress and how gut microbiota manipulation might change this. A previous study (9) discussed here showed that in humans we can more adequately mimic the animal stress models used in pre-clinical studies — for example, the effects of animals’ social stressors such maternal separation or subordinate colony housing (10).

For this human study, the task was called Cyberball Game (CBG) (11); it made use of social exclusion (or ostracism) in a computerized ball game between three participants: one is the person in the brain scanner, while the other two are programmed players visible on a computer screen. In the task, the three participants exchange the ball fairly for a period of time, and then the two virtual players start playing amongst themselves, leaving the person in the scanner isolated. Even knowing (or assuming) that the two counter-players are programmed does not prevent us from experiencing ostracism. From an evolutionary perspective, humans are highly sensitive to social exclusion and have sensitive monitoring systems to detect subtle cues (12) in this respect — an important survival strategy, since social isolation is seen as a threat (13). In this study, manipulating the microbiota by a locally acting antibiotic (rifaximin) changed the processing of stress signals during the CBG and had a stress-reducing effect on healthy volunteers (9).

A probiotic for mice and men

In a new study (14), the same group investigated a novel probiotic, Bifidobacterium longum 1714, which has been shown to reduce stress-related behaviors in pre-clinical studies in animals (15, 16), and improve stress responses and cognitive function in healthy volunteers (17). They hypothesized that the probiotic strain would alter resting state brain activity and neurophysiological responses to CBG-induced social stress following a 4-week double-blinded placebo-controlled intervention in 40 healthy male and female volunteers. This MEG study confirmed that the probiotic altered resting brain activity associated with psychometrically assessed “Energy/Vitality,” and it also reduced mental fatigue.

Although both placebo and probiotic recipients reported higher subjective distress, the changes in neural activity after the stressor were seen only when they had consumed B. longum 1714 and not placebo. Also, the correlation between changes in subjective distress and neural activities was significant for B. longum 1714 only. These data support the notion that this probiotic plays a role in managing stress via modulation of the underlying neural processes — going beyond the previous behavioral data in animals and humans. Taking this further, the authors suggest that in contrast to placebo, B. longum 1714 reduced participants’ stress response and enabled them to manage the increased distress level by upregulating processes for appraising stressful events and downregulating negative emotions.

Next steps with B. longum 1714

The probiotic seems promising — but to fully understand its effects on brain function and human behavior, it’s necessary to explore the effects of the strain on other central nervous system functions such as pain sensitivity, mood, sleep, and memory — in both healthy controls and eventually also in patients with psychiatric disorders (depression, anxiety), neurologic (neurodegenerative) conditions, and gastrointestinal disorders such as IBS. And if it does not work in these patient groups, it may be suitable in “subclinical” populations, e.g. not in anxiety and depression but in “mood disturbances” in otherwise healthy volunteers.

Furthermore, comparison of these effects to those of other probiotics is needed to explore the sensitivity and specificity of the findings. And correlating the brain data with relevant findings at the microbiota level (18) (8,19) using contemporary ‘omics technologies is just a first step toward finding the pathways by which these changes may have occurred. Other options include manipulations on the metabolic, immunologic, and neural levels that are accessible for human research.

A stress-busting probiotic? Not quite yet. But with more research on the mechanisms by which certain probiotics influence the human brain, scientists might be able to zero in on the right strain for alleviating real-life anguish.

This is part 3 of a series covering “microbiota” provided by Paul Enck from the Tübingen University Hospital and science writer Kristina Campbell. Continuous updates on microbiota research can be found at www.gutmicrobiotaforhealth.com.

References:

  1. Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. The Journal of neuroscience. 2014;34(46):15490-6.
  2. Wang H, Lee IS, Braun C, Enck P. Effect of probiotics on central nervous system functions in animals and humans – a systematic review. Journal of neurogastroenterology and motility. 2016;22(4):589-605.
  3. Kelly JR, Allen AP, Temko A, Hutch W, Kennedy PJ, Farid N, et al. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain, behavior, and immunity. 2017;61:50-9.
  4. Thomas V, Clark J, Dore J. Fecal microbiota analysis: an overview of sample collection methods and sequencing strategies. Future microbiology. 2015;10(9):1485-504.
  5. Bastos AM, Schoffelen JM. A Tutorial Review of Functional Connectivity Analysis Methods and Their Interpretational Pitfalls. Frontiers in systems neuroscience. 2015;9:175.
  6. Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144(7):1394-401, 401 e1-4.
  7. Bagga D, Aigner CS, Reichert JL, Cecchetto C, Fischmeister FPS, Holzer P, et al. Influence of 4-week multi-strain probiotic administration on resting-state functional connectivity in healthy volunteers. European journal of nutrition. 2018; doi: 10.1007/s00394-018-1732-z. [Epub ahead of print]
  8. Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, et al. Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome. Gastroenterology. 2017;153(2):448-459.
  9. Wang H, Braun C, Enck P. Effects of Rifaximin on Central Responses to Social Stress-a Pilot Experiment. Neurotherapeutics. 2018;  doi: 10.1007/s13311-018-0627-2. [Epub ahead of print]
  10. Reber SO, Slattery DA. Editorial: Using Stress-Based Animal Models to Understand the Mechanisms Underlying Psychiatric and Somatic Disorders. Frontiers in psychiatry. 2016;7:192.
  11. Wang H, Braun C, Enck P. How the brain reacts to social stress (exclusion)-a scoping review. Neuroscience and biobehavioral reviews. 2017;80:80-8.
  12. Macdonald G, Leary MR. Why does social exclusion hurt? The relationship between social and physical pain. Psychological bulletin. 2005;131(2):202-23.
  13. Silk JB, Alberts SC, Altmann J. Social bonds of female baboons enhance infant survival. Science. 2003;302(5648):1231-4.
  14. Wang V, Braun C, Murphy E, Enck P. Bifidobacterium longum 1714TM strain modulates brain activity of healthy volunteers during social stress. 2018 (under review)
  15. Savignac HM, Kiely B, Dinan TG, Cryan JF. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterology and motility. 2014;26(11):1615-27.
  16. Savignac HM, Tramullas M, Kiely B, Dinan TG, Cryan JF. Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behavioural brain research. 2015;287:59-72.
  17. Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A, Boylan G, et al. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Translational psychiatry. 2016;6(11):e939.
  18. Tillisch K, Mayer E, Gupta A, Gill Z, Brazeilles R, Le Neve B, et al. Brain structure and response to emotional stimuli as related to gut microbial profiles in healthy women. Psychosomatic medicine. 2017;79(8):905-13
  19. Bagga D, Reichert JL, Koschutnig K, Aigner CS, Holzer P, Koskinen K, et al. Probiotics drive gut microbiome triggering emotional brain signatures. Gut microbes. 2018:1-11.
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