Psychobiotics: Examining the Positive Effects of Probiotics on Mood Disorders and Stress

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Human Microbiota

The human microbiota consists of an aggregate of microorganisms that reside on or within a number of tissues and biofluids, including the skin, mammary glands, placenta, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, and gastrointestinal tracts. These microbiota include bacteria, fungi, and archaea. 

For many years it has been estimated that humans have a microbe to human cell ratio of 10:1.  So for every human cell there are 10 microbiota living in or on the human body.  However,  in January 2016 this common knowledge was revisited and new conclusions were made by researchers.  These recent estimates state that the human body contains 39 trillion bacteria and 30 trillion human cells.  1  Even though the estimate has now been lowered to 3.9:1 microbe to human cell ratio, the microbiota play a critical role in human health.

The microbiota in the gastrointestinal tract has the largest numbers of bacteria and the greatest number of species compared to other areas of the body.  2 

Research has demonstrated that the microbiota of the gastrointestinal tract communicates with the central nervous system.  3  This communication is done through neural, endocrine and immune pathways which thereby influences brain function and behavior.

 

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Figure 1.  Diagrammatic representation of the M-G-B axis showing the proposed bidirectional communications.  Gut microbiota can release molecules that can: activate the neuroenteric plexus, stimulate brain production of neuropeptides, as well as increase gut-blood barrier and BBB permeability. The brain releases molecules that stimulate the neuroenteric plexus and gut function. The vagus nerve sends orthodromic and antidromic.  Source: Gut-microbiota-brain axis and effect on neuropsychiatric disorders with suspected immune dysregulation

Emergence of Psychobiotics

The emerging concept of a microbiota-gut-brain axis suggests that modulation of the gut microbiota may be an effective strategy for therapeutics for complex mood disorders and stress.  Psychobiotics is one such therapeutic strategy that has been receiving greater attention from the medical research community.

Psychobiotics are defined as probiotics and prebiotics that are capable of modulating the gut-brain microbiota axis and effect mental health benefits on depression, anxiety, stress and cognition.  4  The research into psychobiotics have always studied the use of probiotics, yet it is only recently that the definition of psychobiotics have included prebiotics which are used to enhance the growth of beneficial gut bacteria.

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Figure 2.  Mechanisms of probiotic effects on the central nervous system.  (Source:  Effect of Probiotics on Central Nervous System Functions in Animals and Humans: A Systematic Review)

Mechanisms of Psychobiotics

Psychobiotics as probiotics have an influence on mood disorders and stress through a number of mechanisms.  

There are three categories of study regarding the neurological and physiological mechanisms of psychobiotics:

  • Regulating the body’s stress response
    • Probiotics affect the hypothalamic-pituitary-adrenal (HPA) axis, by altering corticosteroid (CORT) and/or adrenocorticotropic hormone (ACTH) levels.
  • Neural effects on neurotransmitters and proteins
    • Probiotics can also directly alter central nervous system biochemistry, such as by affecting brain-derived neurotrophic factor (BDNF), c-Fos, gamma-aminobutyric acid (GABA), 5 hydroxytryptamine (5-HT), acetylecholine levels, and dopamine (DA) levels, thus influencing mind and behavior.
  • Regulating the body’s response to inflammation
    • The immune system is influenced by limited pro-inflammatory cytokine production and inflammation, and this, in turn, has effects on the central nervous system.

Regulating the body’s stress response

The stress response mechanism is controlled by the hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis).  The gastrointestinal microbiota is a critical factor in the regulation of the HPA axis. 

Research indicates that if mice that are absent of gut mocrobiota are induced with mild stressors, there is a strong release of stress hormones, compared to mice with a healthly gut microbiota.  5 

The main stress hormone, cortisol, was reduced in human participants when they supplemented with two probiotic strains, namely, Lactobacillus helveticus R0052 and Bifidobacterium longum R0175.  6  

Neural effects on neurotransmitters and proteins

Psychobiotics are capable of producing all 4 main neurotransmitters:

Acetylcholine

Certain species of Lactobacillus are capable of producing acetylcholine.  7

Dopamine

Certain species of Lactobacillus are capable of producing Dopamine.  8

Gamma-aminobutyric acid (GABA)

One Lactobacillus strain and four strains of Bifidobacterium are capable of producing GABA. Lactobacillus brevis DPC6108 was the most efficient of the strains tested, converting up to 90% of MSG to GABA.  9

Serotonin

The gastrointestinal tract contains much of the body’s serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Research has demonstrated that the microbiota plays a critical role in regulating host 5-HT.  10

Regulating the body’s response to inflammation

Psychobiotics are capable of regulating the body’s response to inflammation by reducing the production of cytokines.  11  Chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression.  Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression’s development.

Interleukin 10 (IL-10) is an anti-inflammatory cytokine and its function is as an essential immunoregulator in the intestinal tract.  12   The effects of anti-depressive agents (pharmaceuticals) is through the increase in production of IL-10.  Certain psychobiotics can stimulate the release of IL-10.   In vitro stimulation with Lactobacillus GG resulted in significantly enhanced release of IL-10 and IFN-gamma, compared with cytokine release in unstimulated controls.  13

Strains of Probiotics Used as Psychobiotics

The psychobiotics that have been used in animal and human clinical studies include specific strains of the Bifidobacterium and Lactobacillus genera, including, but not limited to:

Bifidobacterium

  • B. longum
  • B. breve
  • B. infantis

Lactobacillus

  • L. helveticus
  • L. rhamnosus
  • L. plantarum
  • L. casei

Prebiotics Used as Psychobiotics

Prebiotics are known to induce the growth of beneficial gastrointestinal microflora.

Prebiotics have significant neurobiological effects in rats, but their action in humans has not been reported.  A study from 2015 explored the effects of two prebiotics on the secretion of the stress hormone, cortisol, and emotional processing in healthy volunteers.  14

Another study from 2009 found that irritable bowel syndrome (IBS) patients that took 7 grams per day of trans-galacto-oligosaccharide prebiotic for 12 weeks showed improvements in subjective global assessment (SGA), anxiety and depression and QOL scores.  These scores are indicators of anxiety and depression.  15  

Research Studies on Psychobiotics

There are a number of research studies  designed to systematically review the effects of psychobiotics (probiotics) on mood disorders and stress in animals and humans.  Specifically, the psychobiotics used in these studies showed efficacy in improving psychiatric disorder-related behaviors including:

  • Depression
  • Stress
  • Anxiety

All of the examined studies were on rodents (mice or rats), and some on humans.

Table 1 contains a list of studies of the effects of psychobiotics on the mood disorders of depression and anxiety as well as stress:

Table 1: Psychobiotics and Their Effect on Depression, anxiety and Stress

Neurological ConditionAbstractReference
Depression
For a 3-week period, either a probiotic containing milk drink, or a placebo, were consumed daily. Mood and cognition were measured at baseline, and after 10 and 20 days of consumption.   The consumption of a probiotic-containing yoghurt improved the mood of those whose mood was initially poor.1
R esults indicate an anti-depressant effect of L. helveticus NS8 in rats subjected to chronic restraint stress depression and that this effect could be due to the microbiota-gut-brain axis. They also suggest the therapeutic potential of L. helveticus NS8 in stress-related and possibly other kinds of depression.2
Probiotic administration in patients with major depressive disorder (MDD) for 8 wk had beneficial effects on Beck Depression Inventory, insulin, homeostasis model assessment of insulin resistance, hs-CRP concentrations, and glutathione concentrations, but did not influence fasting plasma glucose, homeostatic model assessment of beta cell function, quantitative insulin sensitivity check index, lipid profiles, and total antioxidant capacity levels. Probiotic capsule consisted of three viable and freeze-dried strains: Lactobacillus acidophilus (2 × 10(9) CFU/g), Lactobacillus casei (2 × 10(9) CFU/g), and Bifidobacterium bifidum (2 × 10(9) CFU/g).3
To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex.4
In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P 5
We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naïve adult mice. Behavioral tests revealed that chronic ingestion of PS128 increased the locomotor activities in both ELS and naïve adult mice in the open field test. In the elevated plus maze, PS128 significantly reduced the anxiety-like behaviors in naïve adult mice but not in the ELS mice; whereas the depression-like behaviors were reduced in ELS mice but not in naïve mice in forced swimming test and sucrose preference test.6
L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior.7
L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.8
H ealthy male and female participants (n = 40) consumed either a placebo product or a mixture of several probiotics (Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis W19 and W58) over a period of 4 weeks. Relative to placebo, probiotic-treated participants exhibited substantially reduced reactivity to sad mood (assessed by the Leiden Index of Depression Sensitivity Scale), an effect that was specifically attributable to reduced rumination and aggressive cognition.9
In this study, we conducted a randomized, double-blind, placebo-controlled clinical trial to evaluate the immunopotentiation and fatigue-alleviation effects of Lactobacillus gasseri OLL2809 (LG2809) and α-lactalbumin (αLA) in university-student athletes after strenuous exercise. LG2809 ingestion was effective in preventing reduced natural killer cell activity due to strenuous exercise and elevating mood from a depressed state.10
Stress
A combination of L. rhamnosus and L. helveticus reversed stress-induced memory dysfunction in Citrobacter rodentium -infected mice11
This study aims to assess the potential benefits of the probiotic Bifidobacterium infantis in the rat maternal separation (MS) model, a paradigm that has proven to be of value in the study of stress-related GI and mood disorders. Cytokine concentrations in stimulated whole blood samples, monoamine levels in the brain, and central and peripheral hypothalamic-pituitary-adrenal (HPA) axis measures were also analysed. MS reduced swim behavior and increased immobility in the FST, decreased noradrenaline (NA) content in the brain, and enhanced peripheral interleukin (IL)-6 release and amygdala corticotrophin-releasing factor mRNA levels. Probiotic treatment resulted in normalization of the immune response, reversal of behavioral deficits, and restoration of basal NA concentrations in the brainstem.12
Fermented milk containing Lactobacillus casei strain Shirota prevents the onset of physical symptoms in medical students under academic examination stress.13
In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). A probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort.14
L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.15
We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naïve adult mice. These results suggest that chronic ingestion of PS128 could ameliorate anxiety- and depression-like behaviors and modulate neurochemicals related to affective disorders. Thus PS128 shows psychotropic properties and has great potential for improving stress-related symptoms.16
Anxiety
Innately anxious BALB/c mice received daily Bifidobacterium longum (B.) 1714, B. breve 1205, the antidepressant escitalopram or vehicle treatment for 6 weeks. Behavior was assessed in stress-induced hyperthermia test, marble burying, elevated plus maze, open field, tail suspension test, and forced swim test. Physiological responses to acute stress were also assessed. These data show that these two Bifidobacteria strains reduced anxiety in an anxious mouse strain.17
The use of Bifidobacterium infantis has shown evidence of relieving anxiety and depression associated with IBS18
Lactobacillus helveticus ROO52 has also been shown to reduce anxiety-like behavior and alleviate memory dysfunction19
Lactobacillus rhamnosus JB-1 reduced anxiety- and depression-related behaviors in the elevated plus maze and forced swim test20
L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior.21
The probiotic Bifidobacterium longum NCC3001 normalizes anxiety-like behavior and hippocampal brain derived neurotrophic factor (BDNF) in mice with infectious colitis.22
In this pilot study, 39 CFS patients were randomized to receive either 24 billion colony forming units of Lactobacillus casei strain Shirota (LcS) or a placebo daily for two months. Patients provided stool samples and completed the Beck Depression and Beck Anxiety Inventories before and after the intervention. We found a significant rise in both Lactobacillus and Bifidobacteria in those taking the LcS, and there was also a significant decrease in anxiety symptoms among those taking the probiotic vs controls (p = 0.01).23
L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.24
Lactobacillus fermentum strain NS9 normalised the composition of gut microbiota and alleviated the ampicillin-induced inflammation in the colon. The levels of the mineralocorticoid and N-methyl-D-aspartate receptors were also elevated in the hippocampus of the ampillicin+NS9 treated group. NS9 administration also reduced the anxiety-like behaviour and alleviated the ampicillin-induced impairment in memory retention.25

The various strains of psychobiotics used for mood disorders and stress are listed in Table 2:

Table 2: Psychobiotics Strains

Neurolgical ConditionStrain of Psychobiotic
Depression
Bifidobacteria infantis
Bifidobacterium bifidum
Bifidobacterium bifidum W23
Bifidobacterium lactis W52
Bifidobacterium longum R0175
Lactobacillus acidophilus
Lactobacillus acidophilus W37
Lactobacillus brevis W63
Lactobacillus casei
Lactobacillus casei Shirota
Lactobacillus casei W56
Lactobacillus gasseri OLL2809
Lactobacillus helveticus NS8
Lactobacillus helveticus R0052
Lactobacillus plantarum PS128
Lactobacillus rhamnosus (JB-1)
Lactobacillus salivarius W24
Lactococcus lactis W19
Lactococcus lactis W58
Stress
Bifidobacterium infantis
Bifidobacterium longum R0175
Lactobacillus casei Shirota
Lactobacillus helveticus
Lactobacillus helveticus R0052
Lactobacillus plantarum PS128
Lactobacillus rhamnosus
Anxiety
Bifidobacterium breve 1205
Bifidobacterium infantis
Bifidobacterium longum 1714
Bifidobacterium longum NCC3001
Bifidobacterium longum R0175
Lactobacillus casei Shirota
Lactobacillus fermentum NS9
Lactobacillus helveticus ROO52
Lactobacillus rhamnosus JB-1
Based on referenced studies from Table 1

Table 3 lists the two mood disorders and stress and the psychobiotics that have a multiple effect on these disorders:

Table 3: Psychobiotic Strains with Multiple Effects on Mood Disorders and Stress

Strain of PsychobioticDepressionStressAnxiety#
Bifidobacterium bifidumX1
Bifidobacterium bifidum W23X1
Bifidobacterium breve 1205X1
Bifidobacterium infantisXXX3
Bifidobacterium lactis W52X1
Bifidobacterium longum 1714X1
Bifidobacterium longum NCC3001X1
Bifidobacterium longum R0175XXX3
Lactobacillus acidophilusX1
Lactobacillus acidophilus W37X1
Lactobacillus brevis W63X1
Lactobacillus caseiX1
Lactobacillus casei ShirotaXXX3
Lactobacillus casei W56X1
Lactobacillus fermentum NS9X1
Lactobacillus gasseri OLL2809 (LG2809)X1
Lactobacillus helveticusX1
Lactobacillus helveticus NS8X1
Lactobacillus helveticus R0052 XXX3
Lactobacillus plantarum PS128XX2
Lactobacillus rhamnosusX1
Lactobacillus rhamnosus JB-1XX2
Lactobacillus salivarius W24X1
Lactococcus lactis W19X1
Lactococcus lactis W58X1
Based on referenced studies from Table 1

Videos on Psychobiotics

  • Microbiome, Brain and Behavior - Ted Dinan

    Microbiome, Brain and Behavior - Ted Dinan

  • Psychobiotics as novel psychotropics Ted Dinan (UK)

    Psychobiotics as novel psychotropics Ted Dinan (UK)

  • A Gut Feeling - Professor Ted Dinan, University College Cork

    A Gut Feeling - Professor Ted Dinan, University College Cork

  • Psychobiotics, Bacteria for your brain? - Wegdan Rashad

    Psychobiotics, Bacteria for your brain? - Wegdan Rashad

  • Mind-altering microbes: Elaine Hsiao at TEDxCaltech

    Mind-altering microbes: Elaine Hsiao at TEDxCaltech

  • Heribert Watzke: The brain in your gut

    Heribert Watzke: The brain in your gut

  • Food for thought: How gut microbes change your mind

    Food for thought: How gut microbes change your mind

  • Rob Knight: How our microbes make us who we are

    Rob Knight: How our microbes make us who we are

Resources:

Bifidobacterium bifidum

Bifidobacterium bifidum W23

Bifidobacterium breve 1205

Bifidobacterium infantis

Bifidobacterium lactis W52

Bifidobacterium longum BB536® (1714 not commercially available)

Bifidobacterium longum BB536® (NCC3001 not commercially available)

Bifidobacterium longum R175

Lactobacillus acidophilus

Lactobacillus acidophilus W37

Lactobacillus brevis W63

Lactobacillus casei

Lactobacillus casei Shirota

Lactobacillus casei W56

Lactobacillus fermentum (NS9 not commercially available)

Lactobacillus gasseri (OLL2809 not commercially available)

Lactobacillus helveticus

Lactobacillus helveticus (NS8 not commercially available)

Lactobacillus helveticus R0052

Lactobacillus plantarum (PS128 not commercially available)

Lactobacillus rhamnosus

Lactobacillus rhamnosus (JB-1 not commercially available)

Lactobacillus salivarius (W24 not commercially available)

Lactococcus lactis W19

Lactococcus lactis W58

Galactooligosaccharide  (Prebiotic)

Note to reader:  If you know of any credible products with the above probiotic strains, other than the ones referenced, please contact the Editor