Efficacy of Gut Microbiota-Targeted Interventions for Major Depressive Disorder: A Systematic Review and Network...

Evidence associating gut microbiota dysbiosis with the pathophysiology of major depressive disorder (MDD) via the gut-brain axis provides rationale for microbiota-targeted interventions, yet the comparative efficacy of different microbial modulation strategies remains unclear.

The aims for this study was to determine the most effective gut microbiota-targeted intervention for alleviating depressive symptoms in adults with MDD and also to identify the most effective specific modality by conducting a focused network meta-analysis (NMA) on monotherapy interventions to eliminate pharmacological confounding.

The PubMed, Cochrane Library, Web of Science, and PsycINFO databases were searched from inception to November 2025 without language restrictions.

Study screening and risk-of-bias assessment were conducted by 2 independent reviewers, with disagreements resolved by consensus or a third reviewer. A frequentist random-effects NMA was conducted, with comparative ranking evaluated using the surface under the cumulative ranking curve (SUCRA).

A systematic comparison was performed between the outcomes of a meta-analysis of mixed interventions from the initial 38 randomized controlled trials (RCTs) (n = 2338) and those of an NMA of 33 RCTs concentrating on monotherapy treatments (n = 2128). In the SUCRA ranking, microbiota-based therapies exhibited the highest efficacy among all assessed gut microbiota-targeted interventions (SUCRA: monotherapy cohort = 87.4%; mixed cohort = 86.0%). In the monotherapy cohort, significant reductions in depressive symptoms compared with placebo were noted for microbiota-based therapies (standardized mean difference [SMD] = -0.76; 95% CI, -1.18 to -0.34), prebiotics (SMD = -0.55; 95% CI, -0.81 to -0.28), single-strain probiotics (SMD = -0.53; 95% CI, -0.81 to -0.25), multi-strain probiotics (SMD = -0.45; 95% CI, -0.58 to -0.33), and psychobiotics (SMD = -0.36; 95% CI, -0.64 to -0.08). Synbiotics had minimal efficacy as a standalone treatment (SMD = -0.19; 95% CI, -0.60 to 0.21). According to the Grading of Recommendations, Assessment, and Evaluation tool, the certainty of evidence for these outcomes ranged from low to moderate. Acceptability was largely similar for most interventions, whereas dietary patterns demonstrated a markedly increased risk of attrition.

Gut microbiota-targeted interventions are effective for alleviating depressive symptoms in adults with MDD-a finding supported by low-to-moderate certainty of evidence. Although microbiota-based therapies had the most favorable ranking in this network, this finding should be interpreted with caution due to the limited certainty of evidence, and definitive superiority remains unproven. Acceptability was broadly comparable across interventions, supporting these approaches as potential complementary or alternative options.

PROSPERO CRD420251163930.