J Food Bioact

Journal of Food Bioactives, ISSN 2637-8752 print, 2637-8779 online

Journal website www.isnff-jfb.com

Review

Volume 12, December 2020, pages 3-8

The use of probiotics in depression

**Table 1.** Experimental findings supporting a role of the gut microbiome in the modulation of depressive symptoms
Development of depressive-like behaviors in germ-free mice inoculated with fecal samples of individuals with depression (Zheng et al., 2016)
Different composition of the intestinal microbiota of individuals with major depressive disorder compared to controls (Bravo et al., 2011; Jiang et al., 2015; Zheng et al., 2016)
Altered counts of both gram-positive and gram-negative bacteria in individuals with depression (Jiang et al., 2015; Naseribafrouei et al., 2014)
Link between alterations in the microbiome (e.g. Faecalibacterium) of individuals with depression and severity of depression (Jiang et al., 2015)

Table 1. Experimental findings supporting a role of the gut microbiome in the modulation of depressive symptoms

Development of depressive-like behaviors in germ-free mice inoculated with fecal samples of individuals with depression (Zheng et al., 2016)

Different composition of the intestinal microbiota of individuals with major depressive disorder compared to controls (Bravo et al., 2011; Jiang et al., 2015; Zheng et al., 2016)

Altered counts of both gram-positive and gram-negative bacteria in individuals with depression (Jiang et al., 2015; Naseribafrouei et al., 2014)

Link between alterations in the microbiome (e.g. Faecalibacterium) of individuals with depression and severity of depression (Jiang et al., 2015)

**Table 2.** Potential mechanisms involved in probiotic effects on the brain
Increases in the diversity of intestinal microbiota and the composition of beneficial bacteria (Kwok et al., 2014; Smith et al., 2014; Wang et al., 2015)
Changes in food metabolites, such as short-chain fatty acids and tryptophan, due to “improvements” in intestinal microbiota (Desbonnet et al., 2008; Hsiao et al., 2013)
Effects on gut-brain interaction through the vagus and enteric nerves (Bercik et al., 2011b; Bravo et al., 2011)
Biochemical changes in the brain, including concentrations of brain-derived neurotrophic factor (O’Sullivan et al., 2011) and neurotransmitters, such as monoamines (Liu et al., 2016a, Liu et al., 2016b) and γ-aminobutyric acid (Bravo et al., 2011)
Reduced corticosteroid levels due to attenuation of the stress response mediated by the hypothalamic-pituitary-adrenal axis (Ait-Belgnaoui et al., 2012)
Effects on the immune system by decreasing the production of pro-inflammatory cytokines and inflammation (Desbonnet et al., 2008; Desbonnet et al., 2010)

Table 2. Potential mechanisms involved in probiotic effects on the brain

Increases in the diversity of intestinal microbiota and the composition of beneficial bacteria (Kwok et al., 2014; Smith et al., 2014; Wang et al., 2015)

Changes in food metabolites, such as short-chain fatty acids and tryptophan, due to “improvements” in intestinal microbiota (Desbonnet et al., 2008; Hsiao et al., 2013)

Effects on gut-brain interaction through the vagus and enteric nerves (Bercik et al., 2011b; Bravo et al., 2011)

Biochemical changes in the brain, including concentrations of brain-derived neurotrophic factor (O’Sullivan et al., 2011) and neurotransmitters, such as monoamines (Liu et al., 2016a, Liu et al., 2016b) and γ-aminobutyric acid (Bravo et al., 2011)

Reduced corticosteroid levels due to attenuation of the stress response mediated by the hypothalamic-pituitary-adrenal axis (Ait-Belgnaoui et al., 2012)

Effects on the immune system by decreasing the production of pro-inflammatory cytokines and inflammation (Desbonnet et al., 2008; Desbonnet et al., 2010)

**Table 3.** Systematic reviews and meta-analyses of the effects of probiotics on depression in humans
Authors	Type of study	Conclusions
Huang et al., 2016	Meta-analysis of randomized controlled trials	Oral probiotic use showed a significant reduction in depression scale score in both individuals with major depressive disorder and healthy people. Beneficial effects were found in people aged 60 and below, but not in those aged 65 and older.
Pirbaglou et al., 2016	Systematic review of 10 randomized controlled trials (4 in clinically diagnosed and 6 in non-clinical samples)	Limited support for positive impact of some probiotics on reducing depressive symptoms.
Wallace and Milev, 2017	Systematic review of 10 studies assessing symptoms of depression (mood, anxiety, cognition)	The majority of studies found positive effects on measures of depressive symptoms.
Ng et al., 2018	Meta-analysis of the use of probiotics in alleviating depressive symptoms (10 clinical trials with 1349 participants)	No significant effects of probiotic supplementation on mood compared to placebo. Subgroup analysis found significant mood improvements in individuals with mild-to-moderate depressive symptoms and non-significant effects in healthy people.
Goh et al., 2019	Meta-analysis of 19 double-blind, randomized, placebo-controlled trials (1901 participants)	Treatment with probiotics significantly improved depressive symptoms compared to placebo. Significant beneficial effect of probiotics on depressive symptoms in people with major depressive disorder, but not in other clinical conditions and in the general population.
Liu et al., 2019	Random-effects meta-analysis of 34 controlled clinical trials investigating the effects of prebiotics and probiotics on depression	No significant difference between prebiotics and placebo; small but significant effects for probiotics, with larger effect in clinical/medical samples than community ones.
Nikolova et al., 2019	Systematic review and meta-analysis of 3 randomized controlled trials of probiotics (2 studies of probiotics in addition to antidepressants and 1 study on probiotics as sole treatment) in clinical depression (229 participants)	Possible beneficial effects of probiotics on depressive symptoms when used as supplement to antidepressants.
Chao et al., 2020	Meta-analysis of randomized controlled trials evaluating the effectiveness of probiotics on depressive symptomatology in participants with a depressive disorder diagnosis	Significant alleviation of depressive symptoms in individuals with depression following administration of probiotics compared to placebo.
Noonan et al., 2020	Systematic review of probiotics as treatment for clinically diagnosed depression	Significant improvements following probiotics in one or more outcome measures compared to placebo/no treatment or to baseline measurements.

Table 3. Systematic reviews and meta-analyses of the effects of probiotics on depression in humans

Authors

Type of study

Conclusions

Huang et al., 2016

Meta-analysis of randomized controlled trials

Oral probiotic use showed a significant reduction in depression scale score in both individuals with major depressive disorder and healthy people. Beneficial effects were found in people aged 60 and below, but not in those aged 65 and older.

Pirbaglou et al., 2016

Systematic review of 10 randomized controlled trials (4 in clinically diagnosed and 6 in non-clinical samples)

Limited support for positive impact of some probiotics on reducing depressive symptoms.

Wallace and Milev, 2017

Systematic review of 10 studies assessing symptoms of depression (mood, anxiety, cognition)

The majority of studies found positive effects on measures of depressive symptoms.

Ng et al., 2018

Meta-analysis of the use of probiotics in alleviating depressive symptoms (10 clinical trials with 1349 participants)

No significant effects of probiotic supplementation on mood compared to placebo. Subgroup analysis found significant mood improvements in individuals with mild-to-moderate depressive symptoms and non-significant effects in healthy people.

Goh et al., 2019

Meta-analysis of 19 double-blind, randomized, placebo-controlled trials (1901 participants)

Treatment with probiotics significantly improved depressive symptoms compared to placebo. Significant beneficial effect of probiotics on depressive symptoms in people with major depressive disorder, but not in other clinical conditions and in the general population.

Liu et al., 2019

Random-effects meta-analysis of 34 controlled clinical trials investigating the effects of prebiotics and probiotics on depression

No significant difference between prebiotics and placebo; small but significant effects for probiotics, with larger effect in clinical/medical samples than community ones.

Nikolova et al., 2019

Systematic review and meta-analysis of 3 randomized controlled trials of probiotics (2 studies of probiotics in addition to antidepressants and 1 study on probiotics as sole treatment) in clinical depression (229 participants)

Possible beneficial effects of probiotics on depressive symptoms when used as supplement to antidepressants.

Chao et al., 2020

Meta-analysis of randomized controlled trials evaluating the effectiveness of probiotics on depressive symptomatology in participants with a depressive disorder diagnosis

Significant alleviation of depressive symptoms in individuals with depression following administration of probiotics compared to placebo.

Noonan et al., 2020

Systematic review of probiotics as treatment for clinically diagnosed depression

Significant improvements following probiotics in one or more outcome measures compared to placebo/no treatment or to baseline measurements.

**Table 4.** Limitations and problems of the available findings in respect to the use of probiotics in depression
Self-report of depressive symptoms versus clinically confirmed diagnosis of major depressive disorder.
Threshold of depression severity for inclusion (mild versus moderate).
Small sample sizes in studies of individuals with major depressive disorder.
Wide variety of composition of the single-strain and multiple-strain probiotics used.
Dose and duration of probiotic supplementation.
Use of probiotics as supplementation to pharmacological therapy or as sole treatment.
Degree of improved symptomatology: symptom rating scales versus remission of depression.
Different antidepressive effects of probiotics in different age groups.
Unclear long-term efficacy of probiotics during supplementation and following discontinuation.

Table 4. Limitations and problems of the available findings in respect to the use of probiotics in depression

Self-report of depressive symptoms versus clinically confirmed diagnosis of major depressive disorder.

Threshold of depression severity for inclusion (mild versus moderate).

Small sample sizes in studies of individuals with major depressive disorder.

Wide variety of composition of the single-strain and multiple-strain probiotics used.

Dose and duration of probiotic supplementation.

Use of probiotics as supplementation to pharmacological therapy or as sole treatment.

Degree of improved symptomatology: symptom rating scales versus remission of depression.

Different antidepressive effects of probiotics in different age groups.

Unclear long-term efficacy of probiotics during supplementation and following discontinuation.