High GABA-producing Lactococcus lactis ZFM559 and its derived GABA alleviate chronic unpredictable mild stress...

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 via the "microbiota-brain" axis remain unclear. Herein, a high GABA-producing strain (L. lactis ZFM559) was optimized via 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 L. lactis 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 Akkermansia and Ligilactobacillus, 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, L. lactis 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 via the microbiota-gut-brain axis.