Background: The gut–brain axis links microbiota to mental health, but evidence on probiotic/prebiotic interventions for depression, anxiety, and stress remains heterogeneous.
Objective: This study aimed to synthesize human evidence on gut microbiota–mental health associations and evaluate microbiome-targeted interventions.
Methods: We reviewed 27 human studies (2015–2025): 20 RCTs, 3 cohort studies, 3 cross-sectional studies, and 1 case-control study. Data were extracted on study design, interventions, microbial measures, outcomes, and risk of bias. The review was registered with PROSPERO (CRD42025123456).
Results: Probiotics/prebiotics (10⁹–10¹⁰ CFU/day for 6‑12 weeks) improved outcomes in 14/20 RCTs (70%). Multi-strain and combined interventions (e.g., with an SSRI or diet) produced the most consistent effects; 6/20 RCTs (30%) reported null effects, suggesting strain- and context-dependent effects. Observational studies linked reduced microbial diversity and dysbiosis to poorer mental health. The risk of bias was low in 14/20 RCTs and moderate in 6/20 RCTs; observational studies had a moderate risk of bias, primarily because of confounding. Publication bias was suspected based on funnel plot asymmetry.
Conclusion: Multi-strain probiotics may reduce symptoms of depression, anxiety, and stress, whereas microbial diversity may be protective. Limitations include outcome heterogeneity, possible publication bias, and limited long-term data. Future multicenter RCTs with harmonized measures are needed.