Abstract
Background: Women are disproportionately affected by depression and generalized anxiety disorder compared to men throughout their lives. Hormonal changes during the menstrual cycle, pregnancy, postpartum, and menopause are often associated with mood disturbances. Evidence suggests that modulating the gut microbiome through gut-targeted interventions may offer a novel therapeutic approach for various mental health conditions. Objective: This systematic review and meta-analysis aimed to synthesize evidence from randomized controlled trials (RCTs) on the efficacy of gut microbiome-targeted interventions in improving mental health symptoms in women during key hormonal transitions. Methods: A systematic search was conducted from inception to August 2025 across Embase, MEDLINE (PubMed), Web of Science, PsycINFO, CINAHL, Scopus, FSTA, CENTRAL, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov. Two reviewers independently screened, extracted data, and assessed study quality. Methodological quality was evaluated using Cochrane's risk-of-bias tool (RoB 2.0). Statistical analyses were performed with Comprehensive Meta-Analysis software (version 4). Results: Eleven RCTs were included, of which eight were used in the meta-analyses. Gut microbiome-targeted interventions significantly reduced depressive symptoms (Standardized Mean Difference (SMD) = -0.848; 95% Confidence Interval (CI): -1.470 to -0.226; p = 0.008) and anxiety symptoms (SMD = -0.997; 95% CI: -1.684 to -0.311; p = 0.004) versus controls. Heterogeneity was high (depression: Cochran's Q = 87.1, I(2) = 92%, τ(2) = 0.729; anxiety: Q = 35.3, I(2) = 89%, τ(2) = 0.535), but sensitivity analyses confirmed robustness. Meta-regressions indicated that treatment duration was not a significant moderator (depression: p = 0.12; anxiety: p = 0.28). Conclusions: Gut-targeted interventions significantly reduced symptoms of both depression and anxiety, highlighting their potential as complementary therapeutic strategies for managing mood disorders in women across hormonal life stages. However, high heterogeneity limits the ability to determine optimal standardized clinical recommendations, highlighting the need for further research to guide clinical applications and inform individualized approaches to treatment.