Depression is a prevalent mental disorder with current treatments often exhibiting delayed effects or insufficient efficacy, highlighting the need for novel therapeutic approaches. A growing body of research suggests a link between gut microbiota and mental health, specifically depression. Differences in gut microbiota composition have been observed between healthy individuals and those with depression, prompting investigation into probiotic therapy as a potential intervention. This review aims to systematically analyze existing research on the molecular mechanisms connecting probiotics and depression, focusing on randomized controlled trials (RCTs) to provide robust evidence for the potential benefits and efficacy of probiotic therapy.

The authors conducted a comprehensive literature review to identify relevant studies exploring the molecular mechanisms of action of probiotics in depression. Existing research indicated a correlation between gut microbiota and depression, but the specific mechanisms linking the gut and the central nervous system (CNS) remained unclear. Previous studies have investigated the role of inflammatory markers, neurotrophic factors, and neurotransmitters in the gut-brain axis (GBA), suggesting potential pathways through which probiotics might exert their therapeutic effects. However, inconsistencies in study design, probiotic strains, and outcome measures hampered a clear understanding of the efficacy of probiotics in treating depression.

This systematic review followed PRISMA guidelines. A comprehensive literature search across multiple databases yielded 5819 initial citations. After screening for relevance and quality, 20 RCTs met the inclusion criteria. The studies included patients with depressive symptoms, major depressive disorder (MDD), or MDD with comorbid somatic illnesses. Interventions involved probiotic administration alone or as an add-on treatment, compared to placebo. The primary outcome was the evaluated molecular mechanism of action for probiotics. The meta-analysis utilized Review Manager (RevMan) version 5.3 to calculate the standardized mean difference (SMD) with 95% confidence intervals (CI). Risk of bias was assessed using the RoB 2 and ROBINS-I tools. Only parameters assessed in at least two good-quality studies were included in the meta-analysis.

The meta-analysis of 20 RCTs (comprising 1461 participants) revealed significant findings: Probiotic administration was associated with a significant increase in BDNF levels compared to placebo (SMD = 0.37, 95% CI [0.07, 0.68], p = 0.02) in depressed patients with and without somatic comorbidities. In depressed patients with somatic comorbidities, CRP levels were significantly lower (SMD = −0.47, 95% CI [−0.75, −0.19], p = 0.001), and nitric oxide levels significantly higher (SMD = 0.97, 95% CI [0.58, 1.36], p < 0.0001) in the probiotic group. No significant differences were observed in IL-1β, IL-6, IL-10, TNF-α, and cortisol levels between the probiotic and placebo groups. The efficacy of probiotics in healthy individuals with subclinical depressive or anxiety symptoms was inconclusive due to contradictory results across the limited number of relevant studies.

The findings suggest a potential therapeutic role for probiotics in depression, particularly in patients with co-morbid somatic conditions. The observed increase in BDNF levels aligns with the known role of BDNF in neurogenesis and synaptic plasticity, crucial for mood regulation. The reduction in CRP and increased nitric oxide in patients with somatic comorbidities points towards a potential anti-inflammatory effect of probiotics, which is relevant given the established link between inflammation and depression. The lack of significant changes in other inflammatory markers requires further investigation. The inconsistencies in findings for healthy individuals with subclinical symptoms underscore the need for more research in this population. The varying efficacy across studies may be attributed to differences in probiotic strains, duration of treatment, and co-morbidities, highlighting the importance of future studies to standardize these parameters.

This systematic review and meta-analysis provides evidence supporting the use of probiotics as a potential add-on therapy for depression, particularly in individuals with co-morbid somatic illnesses. The increased BDNF levels and modulation of inflammatory markers in some subgroups suggest promising mechanisms of action. Future research should focus on larger, well-designed RCTs with standardized protocols to investigate the optimal probiotic strains, doses, and durations for various patient populations. Investigating the long-term effects of probiotics and exploring their use in combination with other antidepressant treatments are essential for establishing the clinical relevance of this therapeutic approach.

The relatively small number of included studies and the heterogeneity in study designs and outcome measures limit the generalizability of the findings. Many studies had a moderate or high risk of bias, particularly those focusing on patients with MDD without somatic co-morbidities. The lack of subgroup analyses due to insufficient data further restricts the interpretation of the results. The inclusion of English-language publications only may have introduced publication bias. Finally, the duration of probiotic treatment varied across studies, potentially influencing the observed outcomes.