Dietary Poricoic acid A alleviates depressive-like behaviors by targeting the gut microbiota-immune axis
Poricoic acid A (PAA) is a bioactive triterpenoid derived from the edible fungus Poria cocos, but its antidepressant-like effects and the involvement of gut microbiota and immune regulation remain unclear. This study aimed to investigate whether dietary PAA alleviates depressive-like behavior in mice exposed to chronic unpredictable stress (CUS) by modulating the gut microbiota-immune axis. Methods: Male C57BL/6J mice were subjected to CUS and treated with PAA. Behavioral tests were performed, and hippocampal damage was evaluated by H&amp;E and TUNEL staining. Gut microbiota composition was analyzed by 16S rRNA sequencing, and hippocampal transcriptomic profiling by RNA-seq, followed by immune cell infiltration, correlation, and functional enrichment analyses. Results: PAA treatment alleviated CUS-induced depressive- and anxiety-like behaviors, reduced hippocampal neuronal damage and apoptosis, and restored gut microbiota composition by suppressing harmful bacteria such as Ligilactobacillus murinus while promoting beneficial taxa including Akkermansia muciniphila and Lactobacillus 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 gene expression. Functional enrichment analyses indicated that PAA regulated pathways related to synaptic plasticity, neuroinflammation, and neuronal development. qPCR and Western blot confirmed that PAA restored hippocampal expression of key molecules involved in neuroinflammation (HSP90B1), synaptic plasticity (RPS6KB2 and IGF2BP2), and blood-brain barrier integrity (COL4A5). Conclusions: Dietary PAA alleviates depressive-like behaviors in CUS mice by remodeling the gut microbiota and modulating hippocampal M1/M2 macrophage balance via the gut-brain axis. These findings support PAA as a potential prebiotic-like nutritional agent for major depressive disorder.