High GABA-producing <i>Lactococcus lactis</i> ZFM559 and its derived GABA alleviate chronic unpredictable mild stress (CUMS)-induced depression <i>via</i> the “microbiota–brain” axis

γ-Aminobutyric acid (GABA) is a crucial inhibitory neurotransmitter with recognized benefits in alleviating depression. However, the ability of exogenous GABA to cross the blood-brain barrier remains debated, and the underlying anti-depression mechanisms <i>via</i> the "microbiota-brain" axis remain unclear. Herein, a high GABA-producing strain (<i>L. lactis</i> ZFM559) was optimized <i>via</i> whole-cell catalysis, and its derived GABA (pGABA, purity of 99.47%) was also prepared, followed by uncovering the underlying anti-depression mechanisms using a chronic unpredictable mild stress (CUMS) model. Results indicated that the administration of both <i>L. lactis</i> ZFM559 and pGABA effectively alleviated depression-like behaviors and physiological disturbances, specifically manifested as suppressed hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, relieved inflammation, and regulated serotonergic (5-HT) metabolism. These effects might be attributed to their ability to reshape the gut microbiota, notably increasing the abundance of <i>Akkermansia</i> and <i>Ligilactobacillus</i>, stimulating enterocytes to release 5-HTP. The circulating 5-HTP entered the brain, enhanced brainstem 5-HT synthesis, and subsequently upregulated the expression of CREB and pCREB while reducing the BDNF level. Notably, <i>L. lactis</i> ZFM559 exhibited stronger effects than pGABA, likely due to its superior impact on tryptophan metabolism (non-kynurenine pathway) and microbial modulation (indole pathway). Our study highlights the potential of GABA-rich probiotics and their derived GABA as psychobiotics, offering a promising strategy for the dietary intervention of depression <i>via</i> the microbiota-gut-brain axis.