In three systematic reviews [1-3], two of which included meta-analyses [2,3], we have attempted to determine whether and to what degree probiotics may affect central nervous system (CNS) functions, and if so, which probiotic strains, in which groups of patients, and for which functions. At the same time, we have explored whether one such probiotic can affect CNS activity in healthy volunteers [4] under specific stress conditions called “social stress” [5]. We summarise here the results of these attempts in a rather condensed manner.

1. Brain and behavioral effects of microbiota manipulation in animals

Brain effects following manipulating the gut microbiota have first been observed in animal models rather accidentally [1]: Animals raised under sterile conditions developed abnormally with respect to social and stress-related behavioural pattern that normalised with the introduction of commensal gut microbes; experimental elimination of the gut microbiota, e.g, by antibiotics which had detrimental effects of neurocognitive and behavioural functions in otherwise healthy animals. This has led to the exploration of nutritional and equivalent manipulations of the gut microbiota, e.g., by probiotics specifically developed to exert central nervous system functions, sometimes called “psychobiotics” [6]. While transition from animals to humans is successful in some cases [7], occasionally such proof has also failed [8].

It was therefore consequent to explore such CNS effects of gut microbiota manipulation also in humans, even though in this instance, the experimental options are rather limited and do not allow experimental antibiotic elimination of the microbiota, or microbiota transfer in healthy volunteers. In contrast, probiotic provision is easy and usually without major side effects. Therefore, most of respective experimental and clinical trials have been conducted with probiotics that are either on the market already or have been newly developed.

Our respective reviews of the literature [2,3] allow a distinction of three classes of studies that have been performed: i) studies with established probiotics with known effects on the GI tract, e.g. in functional bowel disorders of the type of irritable-bowel-syndrome (IBS), searching for effects of CNS functions; ii) studies in healthy volunteers with established or with novel probiotics selected for specific CNS functions; iii) studies with probiotics on CNS functions is patients with CNS-related (psychiatric, neurologic) disorders.

2. Studies in patients with irritable bowel syndrome with established probiotics

Our systematic review [2] identified 35 randomized, placebo-controlled trials (conducted between 2005 and 2021), of which 11 were available for a meta-analysis. We only evaluated whether the used probiotics elicited responses on standardised measures of depression, anxiety, and quality of life (QoL), the latter as a surrogate marker of overall wellbeing. While QoL moderately improved in following probiotic treatment as compared to placebo, neither depression nor anxiety measures were different. For the 11 trials (including nearly 2000 patients) entered into the meta-analysis, heterogeneity was (too) high to allow a consistent outcome, and variability between the used probiotics was high: most were multi-strain probiotics of different composition. Only one study tested direct effects of the probiotic (B longum) on brain functions (using functional MRI). In summary we concluded that while there may be an effect of probiotics on global well-being (QoL), it cannot be excluded that this occurred secondary to improvement of gastrointestinal functions; however, the missions overall effects on measures of anxiety and depression let us to believe, that there is no global effect of probiotics in general on measures of mood and wellbeing, and that probiotics developed for gastrointestinal functions are unlikely to also affect brain functions to the same degree.

3. Studies with healthy volunteers, with variable probiotics and different brain measures.

In our second meta-analysis [3], we identified 54 trials. Of these 54 studies, 41 presented data from healthy volunteers, and 30 of these were meta-analysed.

Study outcomes at qualitative level for the studies included in the meta-analysis are displayed in the figure. For most studies and for most measures applied no difference between the probiotic and the placebo groups were observed (indicated as ↔). Only few studies reported superiority of probiotics over the placebo group (indicated as ↑) (taken from [3], Figure 3).

Six studies recorded EEG, and 5 used imaging technology (fMRI, MEG), including our own [4]; the remaining used behavioural measures and psychometric tests. Four of the EEG studies and five of the imaging studies reported changed brain activation under probiotics in comparison to placebo, but they differed substantially with respect to the investigational paradigm, even when the umbrella term “stress” was applied (cold pressor, Stroop test, face recognition with social enforcement, ostracism), and with different probiotics. Three EEG studies evaluated effects on sleep, two the effects on memory function, and another few on memory formation and other neurocognitive functions. Overall, the studies imply that selected probiotics may alter several brain functions in healthy controls but do not allow to draw a valid conclusion whether this would be of clinical relevance in patients with respective disorders.

4. Studies in psychiatric/neurological patients with different probiotics

The range of patients with different psychiatric disorders is wide among the 13 patient studies [3] going beyond healthy volunteers and includes depression and major depressive disorders (4 studies), schizophrenia (4 studies), and general anxiety disorders, chronic fatigue syndrome, fibromyalgia, insomnia, and mild cognitive impairment (1 study each). Half of the 4 studies in depressed patients, and 3 of the 4 studies in schizophrenia found no difference between probiotic and placebo. This indicates at this stage no clear clinical benefit of probiotics in the treatment of patients with psychiatric or neurologic disorders exists, beyond the fact that quite different probiotics were used in these trials, and that clinical inclusion and exclusion criteria were not harmonized between trials. Also, for other neurological conditions such as multiple sclerosis (3 trials) [9], autism spectrum disorder (2 trial) [10], and Alzheimer dementia (3 trials) [11] the current evidence in meta-analyses is rather low, partially based on poor methodology and a high risk of bias. For other diseases such as Parkinson´s Disease, only study protocols exist [12], and many areas such as pain beyond IBS are still completely uninvestigated. Whether or not probiotics, and especially psychobiotics developed for acting on brain functions, neither is clinical efficacy established, nor is it known, which mechanisms of action may account for such effects.  Much more research is needed, and especially research that uses strong pharmacological rational rather than “quick and dirty” study methodology.

Summary

While quite a collection of probiotics exists that claim or have shown putative beneficial effects on brain functions in preclinical models, some have extended and translated this evidence into humans, but mostly in healthy volunteers with different experimental models for sleep, stress, mood, and some neurocognitive functions, yet no clear picture has emerged which probiotic may be beneficial for with central function in which patient group.

References

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