From gut to brain: data-driven evidence suggests causal contribution of gut-microbiota to major depressive disorder in humans

Gut Microbiome in Depression with and without REM Sleep Behavior Disorder.

Gut microbiome provides a candidate approach for potential risk stratification in psychiatric populations, and MDD + RBD may represent a biologically distinct depression subtype associated with potential neurodegenerative risk.

Gut microbial biomarkers for major depressive disorder: a cross-sectional study

The results highlight the potential of gut bacterial and viral biomarkers as candidate biomarkers and potential auxiliary tools for MDD assessment and suggest that integrating multi-domain microbial features may improve prediction accuracy.

Gut microbiome variability and brain structure and function in unipolar and bipolar depression: A review.

INTRODUCTION Depression is a multifactorial disorder with significant global health impact. Neuroimaging advances have provided insights into neural mechanisms underlying depression, while gut microbiome alterations have been linked to brain structure and function. This review summarizes evidence on the association between gut microbiome variability and brain structural and functional changes in Major Depressive Disorder (MDD) and Bipolar Depression (BD). METHODS A bibliographic search was conducted on PubMed, Scopus and Web of Science for original studies investigating correlations between gut microbiome and brain structure and function. RESULTS Three studies investigated probiotic interventions in MDD, showing significant associations with increased gray matter volume (GMV) in the calcarine sulcus, reduced putamen and hippocampal activation, and altered fronto-limbic functional connectivity, especially within the precuneus and superior parietal lobule. Also, observational studies in MDD showed that specific microbial taxa or alpha diversity were positively correlated with limbic and basal ganglia GMV, whereas other taxa negatively correlated with frontal connectivity or GMV in regions involved in memory, somatosensory integration, and emotional regulation. Finally, although no interventional studies were available for BD, the available observational studies in this disorder exhibited gut-brain imbalance associations with immune activation and prefrontal dysfunction, with gut microbes linked to neuroactive metabolites correlated with altered connectivity in thalamus, striatum, and language and limbic regions. CONCLUSIONS From the available literature emerged that gut microbiome variations seem to be associated with brain structural and functional alterations in both MDD and BD, with preliminary evidence also suggesting significant neurobiological effects of probiotics in MDD. Nonetheless, further studies are needed to confirm the role of gut microbiome modulation as part of personalized approaches.

From association to causality: mechanistic pathways linking the gut microbiome to psychiatric disorders.

The microbiota-gut-brain axis (MGBA) has emerged as a key framework for understanding how peripheral biological systems influence brain function and behaviour. However, despite extensive associative evidence linking gut microbiome to psychiatric disorders, robust causal and mechanistic insights remain limited. This review critically evaluates current evidence to determine whether microbiome alterations contribute to psychiatric pathophysiology and inform therapeutic strategies. We outline methodological frameworks for causal inference, highlighting the limitations of cross-sectional designs and the need for convergent evidence from longitudinal studies, experimental models, and human genetic approaches. We then synthesize mechanistic pathways linking the microbiota to brain function, including immune signaling, neuroendocrine regulation via the hypothalamic-pituitary-adrenal (HPA) axis, neural communication through vagal and enteric pathways, and intestinal and blood-brain barrier (BBB) integrity. Across these systems, microbial metabolites and immune mediators emerge as key mediators, although direct causal mechanisms in humans remain incompletely established. Disorder-specific evaluation across major depressive disorder (MDD), anxiety disorders, bipolar disorder (BD), schizophrenia (SCZ), and post-traumatic stress disorder (PTSD) reveals heterogeneous but converging evidence for microbiome involvement. Although preclinical and interventional studies support biological plausibility, human evidence remains constrained by confounding, variability, and limited mechanistic validation. Translational strategies, including psychobiotics, dietary interventions, fecal microbiota transplantation (FMT), and microbiome-based biomarkers, show promise but remain methodologically limited. Overall, the gut microbiome represents a biologically plausible and modifiable contributor to psychiatric disorders. Advancing toward clinical application will require integrative, longitudinal, and mechanism-driven research to enable precision psychiatry grounded in causal evidence.

Analysis of individualized brain–gut association networks and transcriptional patterns in major depressive disorder

The results suggested that associations between proinflammatory gut microbiota and the herpes simplex virus type 1 infection pathway may contribute to the onset of MDD through inflammatory processes.

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