Poricoic acid A alleviates depressive-like behaviors by targeting the gut microbiota-immune axis

Poricoic acid A (PAA) is a bioactive triterpenoid from the fungus Poria cocos. Nevertheless, whether it exerts antidepressant-like effects and whether the gut microbiota and immune regulation are involved remain unknown.

Male C57BL/6 J mice were subjected to chronic unpredictable stress (CUS) and treated with PAA treatment. Behavioral tests were performed, and hippocampal damage was evaluated by H&E and TUNEL staining. Gut microbiota composition was analyzed using 16S rRNA sequencing, and hippocampal transcriptomic profiling was performed using RNA-seq, followed by immune cell infiltration, correlation, and functional enrichment analyses.

PAA treatment eased CUS-induced depression- and anxiety-like behaviors. It also cut down hippocampal neuron damage and cell death. Besides, PAA fixed gut bacteria balance by lowering harmful germs like L. murinus and boosting good germs like A. muciniphila and L. reuteri. Hippocampal transcriptomic analysis revealed that PAA modulated immune cell infiltration by reducing M1 macrophages and restoring M2 macrophages, with significant correlations between gut microbial taxa and hippocampal immune-related gene expression. Functional enrichment analyses indicated that PAA regulates pathways related to synaptic plasticity, neuroinflammation, and neuronal development. qPCR and western blotting confirmed that PAA restored the hippocampal expression of key molecules involved in neuroinflammation (HSP90B1), synaptic plasticity (RPS6KB2 and IGF2BP2), and blood-brain barrier integrity (COL4A5).

PAA alleviates depression-like Behaviors in CUS mice by remodeling the gut microbiota and modulating the hippocampal M1/M2 macrophage balance via the gut-brain axis. These findings support the potential of PAA as a prebiotic-like nutritional agent for major depressive disorder.