Reproducible Gut Microbiome Alterations in Major Depressive Disorder: A Systematic Review of Taxonomic and Functional Findings

Abstract

Background/Objectives: Major depressive disorder (MDD) has been increasingly associated with alterations of the gut microbiome through the microbiota–gut–brain axis. However, published findings remain highly heterogeneous, limiting identification of reproducible microbial signatures associated with depression. This systematic review aimed to evaluate reproducible taxonomic and functional gut microbiome alterations in patients with MDD compared with healthy controls. Methods: A systematic literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science Core Collection, and the Cochrane Library for studies published between January 2016 and December 2025. Observational human studies evaluating gut microbiome composition in adults with clinically diagnosed MDD and healthy control groups were included. Methodological quality was assessed using the Newcastle-Ottawa Scale. Due to substantial methodological heterogeneity, findings were synthesized using structured qualitative narrative analysis. Results: Sixteen observational studies were included in the qualitative synthesis. Findings related to alpha diversity were inconsistent across studies, whereas beta diversity alterations demonstrated greater reproducibility across independent cohorts. The most recurrent microbiome pattern involved depletion of short-chain fatty acid (SCFA)-producing bacteria, particularly Faecalibacterium and Roseburia, together with recurrent alterations affecting members of the Ruminococcaceae, Lachnospiraceae, and Clostridia groups. Functional microbiome alterations demonstrated greater consistency than higher-level taxonomic findings and included reduced butyrate synthesis pathways, dysregulated amino acid and tryptophan metabolism, increased lipopolysaccharide biosynthesis, and enrichment of pro-inflammatory microbial signatures. Antidepressant-naïve cohorts generally demonstrated more homogeneous dysbiosis patterns than mixed-treated populations. Conclusions: Current evidence suggests that functional gut microbiome dysregulation may represent a more reproducible biological feature of MDD than isolated taxonomic alterations alone. However, substantial heterogeneity in study design, participant characteristics, sequencing methodologies, and analytical approaches continues to limit clinical translation. Large-scale longitudinal multi-omics studies using standardized methodologies are required to clarify the role of the gut microbiome in depressive disorders and to evaluate the potential utility of microbiome-based biomarkers and interventions in mental health and public health practice.