Pediococcus acidilactici attenuates chronic stress-induced depression via generating metabolite indole-3-lactic acid and downregulating neuroinflammation.

BACKGROUND: Depression, a prevalent mental disorder worldwide, is associated with pathological mechanisms including neuroinflammation. Pediococcus acidilactici has shown the potential neuroprotective effects, yet its role in ameliorating depression and the underlying mechanisms remain unclear. METHODS: Eight-week-old male C57BL/6J mice were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks to establish a depression model. Mice were orally administered Pediococcus acidilactici CGMCC 35671 (strain GOLDGUT-EZMind) (1 × 109 CFU/day). Behavioral experiments and biochemical assays were conducted to evaluate its effects on CUMS-induced anxiety and depressive-like behaviors. Serum indole-3-lactic acid (ILA) concentrations and aryl hydrocarbon receptor (AHR) pathway activation in the brain were quantified. To elucidate the potential mechanism by which P. acidilactici CGMCC 35671 ameliorates depression, mice received intraperitoneal injections of the AHR inhibitor CH223191 (100 µL/day, 4 weeks) to block the interaction between ILA and cerebral AHR, thereby assessing its contribution to attenuating neuroinflammation and depression in CUMS mice. RESULTS: Pediococcus acidilactici CGMCC 35671 supplementation significantly ameliorated anxiety-like, depressive-like, and social interaction deficits in CUMS mice. Excessive microglial activation in the hippocampal dentate gyrus and cortex was suppressed, with reduced levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and elevated levels of the anti-inflammatory (IL-22) in the brain. Cortical neurotransmitter levels of serotonin and dopamine were increased, and serum oxidative stress markers were attenuated. Furthermore, P. acidilactici CGMCC 35671 supplementation elevated serum ILA concentrations and upregulated mRNA expression of AHR downstream markers (CYP1A1, CYP1A2, CYP1B1) in the brain. Conversely, AHR inhibitor administration abrogated the ameliorative effects of P. acidilactici CGMCC 35671 on neuroinflammation and depressive symptoms in CUMS mice. CONCLUSION: Pediococcus acidilactici CGMCC 35671 metabolizes tryptophan to produce ILA, which crosses the blood-brain barrier via systemic circulation to activate the AHR pathway, thereby attenuating neuroinflammation and ameliorating depressive symptoms.