A food-borne probiotic ameliorates depression by modulating tryptophan metabolism along the gut-brain axis

Depression is increasingly conceptualized within a neuroimmune framework, where systemic inflammation originating from a compromised gut barrier can drive neuroinflammation and behavioral deficits. This study investigated whether the probiotic Weizmannia coagulans BC99 exerts antidepressant effects by modulating this gut-immune-brain axis. In a chronic unpredictable mild stress (CUMS) rat model, BC99 supplementation significantly alleviated depressive-like behaviors. Our integrated multi-omics analysis suggests a sequential mechanistic cascade. BC99 first partially restored intestinal barrier integrity, upregulating tight junction proteins (ZO-1, Occludin). This was associated with a marked attenuation of peripheral and hippocampal pro-inflammatory cytokines (IL-23, IFN-γ) and oxidative stress. Concurrently, hippocampal metabolomics showed BC99 shifted tryptophan metabolism from the immune-activated, neurotoxic kynurenine pathway toward the neuroprotective serotonin pathway. Integrated hippocampal transcriptomics and proteomics identified the activation of the BDNF/TrkB/CREB neurotrophic signaling pathway and upregulation of synaptic plasticity proteins (SYN, PSD-95) as central downstream events. These findings outline a potential gut-immune-brain mechanism: BC99-initiated gut barrier repair dampens systemic inflammation, which in turn resolves neuroinflammatory tone and rebalances neurochemistry, ultimately fostering a hippocampal milieu conducive to neuroplasticity and behavioral resilience.