Short-chain fatty acids (SCFAs) are essential metabolites in the interaction between gut microbiota and the host. Recently, they have been implicated in the development of major depressive disorder (MDD). However, the alterations of SCFAs in the blood and feces of individuals with depression are still debated. Additionally, it is uncertain whether interventions targeting gut microbiota can reverse these changes. This research aims to investigate the variations of SCFAs in depression and assess the effects of probiotic and prebiotic interventions on SCFA levels and clinical symptoms. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We conducted a comprehensive search across databases including PubMed, Cochrane Library, Web of Science, Embase, PsycINFO, Wanfang Data, CNKI, VIP, and SinoMed. The search encompassed all published articles from their inception to March 13, 2026. This study synthesized evidence from 16 case-control studies and 6 randomized controlled trials (RCTs) through a systematic review and meta-analysis. The case-control analysis found significantly lower plasma levels of acetate (SMD = -0.51, 95% CI -0.86, -0.15), propionate (SMD = -0.65, 95% CI -1.06, -0.25), butyrate (SMD = -0.43, 95% CI -0.72, -0.15), and valerate(SMD = -1.09, 95% CI -2.02, -0.17) in individuals with depression compared to healthy controls. In fecal samples, no significant differences were found in the three main SCFAs, but fecal valerate was decreased and isobutyrate was increased. The RCT analysis showed that probiotic and prebiotic interventions, compared to placebo, significantly increased fecal levels of acetate (SMD = 0.58, 95% CI 0.07, 1.08), propionate (SMD = 0.55, 95% CI 0.19, 0.91), butyrate (SMD = 0.47, 95% CI 0.10, 0.85) and isobutyrate(SMD = 0.64, 95% CI 0.41, 0.87), and SCFA elevation was associated with improved depressive symptoms. MDD patients have significantly lower circulating levels of the main SCFAs (acetate, propionate, butyrate) and valerate, with distinct fecal changes (decreased valerate, increased isobutyrate). The results indicated that depression primarily associated with reduced circulating levels of SCFAs. However, intestinal microecological interventions partially regulated fecal SCFAs. This study offered preliminary evidence suggesting SCFAs as potential exploratory biomarkers for depression and their possible association with the gut microbiota-mood axis. Further validation through larger, standardized research is necessary. PROSPERO, TRN: CRD420251251955.
J et al. (Wed,) studied this question.