Gut microbiota-driven metabolites modulate the development of stress-related mental disorders

Stress-related mental disorders, including depression, anxiety, and post-traumatic stress disorder, represent a major global health burden, yet their underlying biological mechanisms and effective therapeutic strategies remain incompletely understood. Growing evidence from both preclinical and clinical studies indicates that alterations in gut microbiota composition and function are closely associated with the onset and progression of these disorders. A central role of the gut microbiota is the biotransformation of dietary and host-derived substrates into diverse metabolites that enter systemic circulation and influence host physiology. In this review, we highlight gut microbiota-driven metabolites. short-chain fatty acids, amino acid-related metabolites, bile acids, and monoamine-related metabolites, as key mediators of gut-brain communication that influence neural, immune, epigenetic, and endocrine processes involved in stress-related mental disorders. We summarize emerging microbial and metabolic signatures identified in animal models and human studies. Furthermore, we discuss microbiome-targeted strategies for the prevention and treatment. However, the complexity of the gut microbiota and pronounced inter-individual variability limit causal inference from current clinical studies. Consequently, translating these findings into clinical practice will require standardized study designs, longitudinal clinical investigations, and the integration of multi-omics approaches to advance precision microbiome-based interventions for psychiatric disorders.