Gut–brain axis and depression: focus on the amino acid and short-chain fatty acid metabolism

Depression, a major psychiatric disorder with profound societal impact, remains incompletely understood in its etiology. Identifying novel pathogenic pathways is therefore essential. The gut microbiota (‘second brain’) critically regulates bidirectional gut–brain axis (GBA) communication with the central nervous system. Dysbiosis correlates strongly with depression, positioning microbiota restoration as a promising therapeutic strategy. Critically, gut microbial metabolic processes – particularly involving amino acids and short-chain fatty acids (SCFAs) – have emerged as key contributors to depression pathogenesis; however, depression-specific alterations in gut microbiota and their metabolic signatures are inadequately characterized, and the molecular mechanisms linking microbial metabolites to depression require further elucidation. This review synthesizes recent advances on GBA-mediated depression pathogenesis, with emphasis on gut dysbiosis-induced disruptions in amino acid and SCFA metabolism, and delineates their mechanistic links to depressive pathophysiology.