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

This study investigated whether dietary poricoic acid A (PAA) alleviates chronic unpredictable stress (CUS)-induced depressive-like behaviors in mice by modulating the gut microbiota-immune axis. Male C57BL/6J mice were subjected to CUS and treated with PAA. Results showed that PAA alleviated depressive- and anxiety-like behaviors, reduced hippocampal neuronal damage, and restored gut microbiota composition by suppressing harmful bacteria like Ligilactobacillus murinus while promoting beneficial taxa such as Akkermansia muciniphila and Lactobacillus reuteri. Hippocampal transcriptomics revealed that PAA modulated immune cell infiltration by reducing M1 and restoring M2 macrophages, with significant correlations between gut microbial taxa and hippocampal immune gene expression. Functional analyses indicated that PAA regulated pathways related to synaptic plasticity and neuroinflammation, which was confirmed by qPCR and Western blot showing restored expression of HSP90B1, RPS6KB2, IGF2BP2, and COL4A5. In conclusion, dietary PAA alleviates depressive-like behaviors in CUS mice by remodeling the gut microbiota and modulating the hippocampal M1/M2 macrophage balance via the gut-brain axis, supporting its potential as a prebiotic-like nutritional agent for major depressive disorder.