Microbial metabolites in the gut-brain axis: their impact on depression pathophysiology and treatment

Gut microbiota influences major depressive disorder (MDD) via the microbiota-gut-brain axis through various metabolites, but a systematic understanding of their neuroregulatory mechanisms is lacking. This review categorizes gut microbial metabolites according to their metabolic origin and physiological function, clarifies their roles in depression-related neurobiological processes, and explores their therapeutic potential. Following PRISMA-ScR guidelines, a scoping review screened 1,249 records from five databases (2020-2025), including 23 studies on tryptophan metabolism, short-chain fatty acids (SCFAs), gamma-aminobutyric acid (GABA), and other metabolites that regulate depression-related neurobiological pathways; tryptophan metabolism affects serotonin/kynurenine pathways, causing neuroinflammation and neurotransmitter imbalance; SCFAs(primarily butyrate, less so propionate) modulate gene expression, neuroinflammation, and microglial function as histone deacetylase (HDAC) inhibitors; GABA-producing bacteria influence synaptic plasticity and suppress hypothalamic-pituitary-adrenal (HPA) axis hyperactivity; and other metabolites (e.g., homovanillic acid and β-hydroxybutyrate) have neuroprotective effects and affect neurotransmitter dynamics. Notably, this review advances the field via an integrative cross-pathway perspective, a critical appraisal of evidence strength across animal/human studies, and translational implications. Microbiome-modifying interventions (like probiotics, prebiotics, and dietary changes), are promising in animal models for correcting metabolite dysregulation and alleviating depressive symptoms.