Berberine modulates gut microbiota to attenuate cerebral ferroptosis induced by ischemia-reperfusion in mice

Ferroptosis was reported to be involved in cerebral ischemia-reperfusion injury (CIRI), on which the effects of berberine (BBR) remain unclear. Moreover, based on the critical role of gut microbiota in pleiotropic actions of BBR, we hypothesized that BBR can suppress CIRI-induced ferroptosis by modulating the gut microbiota. In this study, the results showed that BBR obviously attenuated the behavioral deficits of CIRI mice, accompanied with the improved survival rate and neuron damages, as phenocopied by dirty cage experiment. The typical morphological changes in ferroptotic cells and biomarkers of ferroptosis were attenuated in BBR- and its fecal microbiota-treated mice, accompanied by reduced malondialdehyde and reactive oxygen species, and the increased glutathione (GSH). BBR was found to alter the gut microbiota of CIRI mice with decreased abundance of Muribaculaceae, Erysipelotrichaceae, Helicobacteraceae, Streptococcaceae and Tannerellaceae, but elevated Bacteroidaceae and Enterobacteriaceae. KEGG analysis based on the 16S rRNA results indicated that multiple metabolic pathways including ferroptosis and GSH metabolism, were altered by BBR. Oppositely, the antibiotics administration counteracted the protective properties of BBR. Summarily, this study revealed the therapeutic potential of BBR on CIRI via inhibiting neuronal ferroptosis, in which upregulated glutathione peroxidase 1 (GPX1) was possibly involved. Moreover, the BBR-modulated gut microbiota was shown to play the critical role in the underlying mechanism.