Short-chain fatty acid-producing psychobiotics in mood disorders: mechanistic insights into the microbiota-gut-brain axis.

Abstract

Mood disorders, including major depressive disorder, bipolar disorder, generalized anxiety disorder, and posttraumatic stress disorder, constitute a primary source of global disability, and with conventional monoamine-targeted pharmacotherapy, approximately one-third of patients remain with treatment-resistant disease. Over the past decade, the microbiota-gut-brain axis (MGBA) has emerged as a systems-level pathophysiological framework that explains the chronic neuroinflammation, hypothalamic-pituitary-adrenal axis hyperactivity, and impaired neuroplasticity that characterize treatment-resistant mood disorders. Short-chain fatty acids (SCFAs) are key molecular mediators in MGBA signaling, exerting epigenetic regulation through the inhibition of histone deacetylase, suppression of microglial toll-like receptor 4/nuclear factor-kappa B signaling, reinforcement of intestinal and blood-brain barrier integrity, and rebalancing of tryptophan-kynurenine metabolism. A few small randomized controlled trials and meta-analyses have reported that restoring SCFA output using next-generation psychobiotics (Faecalibacterium prausnitzii, Akkermansia muciniphila, and Clostridium butyricum), prebiotic-rich dietary patterns, defined synbiotics, and direct postbiotic supplementation is associated with symptom improvement, although the evidence base remains preliminary, and have been proposed as candidate prognostic biomarkers. This narrative review synthesizes 2022 to 2026 mechanistic and clinical evidence on SCFA-producing psychobiotics in mood disorders; integrates these findings within a clinical nutrition framework that positions dietary fiber, microbiota-accessible carbohydrates, and targeted psychobiotic supplementation as legitimate adjuncts to conventional psychopharmacology; and discusses the translational challenges of strain specificity, dosing variability, and precision-psychobiotic medicine. Nevertheless, current evidence remains dominated by preclinical models, with human trials constrained by size, duration, and number.