A systematic review and meta-analysis of the therapeutic role of short-chain fatty acids in modulating depression: bridging the gut-brain axis.

Abstract

Dysregulation of microbiota-gut-brain axis has been implicated in depression, with immune and inflammatory signalling representing potential pathways linking gut microbial alterations to depressive symptoms. Short-chain fatty acids (SCFAs), namely acetate, propionate and butyrate are promising immunomodulating mediators of systemic inflammation and neuroplasticity. However, clinical trials of this pathway have given inconsistent results. The aim of this research was to conduct a synthesis of evidence for the therapeutic role of SCFAs using two approaches, to assess association between SCFA levels and depressive symptom severity, and to assess the efficacy of interventions targeting SCFA-related pathways for depressive symptoms. PubMed, Scopus, PsycINFO, Cochrane Library, and Web of Science were searched from inception till 2 March 2025. Searches were updated on 13 November 2025. For intervention meta-analysis, randomized controlled trials (RCTs) evaluating interventions that have the potential to modulate SCFA production (probiotics, fecal microbiota transplantation (FMT), transcutaneous auricular vagus nerve stimulation (taVNS) and direct SCFA administration were included. For correlation meta-analysis, observational studies correlating the fecal SCFA levels with depression scores and RCT derived dataset were used. Here, correlation coefficients and Standardized Mean Differences (SMD) were pooled using random-effects models. Sensitivity and subgroup analyses were conducted to explore a moderating effect of the intervention type and the metabolic status (BMI). The review included eight randomized controlled trials (N = 430) of which 7 (N = 385) contributed to primary intervention meta-analysis and 7 observational studies (N = 369). Up to 6 datasets contributed to the faecal SCFA correlation meta-analyses. Among non-obese individuals, acetate (p < 0.001) and propionate (p = 0.004) depletion levels were significantly associated with increased severity of depression. SCFA-modulating interventions had a significant beneficial effect on depressive symptoms in comparison to controls (Overall SMD - 0.74, 95% CI - 1.10 to - 0.37; p < 0.0001; I^2 = 64%)), k = 7. Across intervention classes, point estimates were largest for FMT (SMD (-1.45), taVNS (SMD (-1.04), and direct sodium butyrate (SMD (-0.84) although formal subgroup differences were not statistically significant (p = 0.44). Exploratory sensitivity analyses suggested that obesity status may be a potential biological moderator of treatment response, although this finding should be considered hypothesis-generating. This meta-analysis provides preliminary evidence that targeting the immunometabolic gut-brain axis through SCFA-related pathways may represent a promising approach for depressive symptoms, with exploratory findings suggesting a potential role of metabolic phenotype. The findings support further investigation of phenotype-directed SCFA-related interventions, incorporating metabolic and inflammatory characteristics alongside clinical outcomes. Future precision psychiatry trials should be stratified by metabolic status to identify patient subgroups most likely to respond to this form of immunomodulation.