Butyrate Is Associated with the Antidepressant Effects of Weizmannia coagulans BC99: Functional Similarity of a Microbial Metabolite in the Microbiota–Gut–Brain Axis

Butyrate, a short-chain fatty acid derived from the gut microbiota, has been linked to depression through correlational studies; however, whether it might act as a sufficient downstream mediator of the antidepressant effects of a probiotic remains poorly understood. To explore this, a chronic unpredictable mild stress (CUMS) rat model was established to evaluate the potential antidepressant effects of Weizmannia coagulans BC99. Behavioral assessments included the sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and open field test (OFT). In addition, 16S rRNA sequencing, serum metabolomics, and short-chain fatty acid (SCFA) profiling were performed. Levels of inflammatory cytokines (IL-1β, IL-6, IL-4, and LPS) and brain-derived neurotrophic factor (BDNF) were measured in serum, hippocampus, and colon by ELISA. An independent sodium butyrate supplementation experiment was conducted to test functional sufficiency, and hippocampal BDNF/TrkB/CREB signaling was assessed by Western blotting. Treatment with BC99 was associated with alleviation of CUMS-induced depressive-like behaviors, increased butyrate levels, reduced neuroinflammation (IL-1β, IL-6, LPS, and IL-4), and restored hippocampal BDNF levels. BC99 also enriched butyrate-producing bacterial taxa (e.g., Lactobacillus, Bifidobacterium, Faecalibaculum) and normalized tryptophan and sphingolipid metabolism. Notably, sodium butyrate alone recapitulated several of the behavioral and anti-inflammatory effects observed with BC99 and, as shown by Western blot, partially restored hippocampal BDNF/TrkB/CREB signaling, which was impaired in CUMS rats. Together, these findings suggest that butyrate may be associated with the antidepressant effects of W. coagulans BC99, potentially acting through suppression of neuroinflammation and activation of the BDNF pathway. Our results support further investigation of butyrate-enhancing strategies as a nutritional approach for depression.