Prevotella histicola suppresses ferroptosis to mitigate ethanol-induced gastric mucosal lesion in mice

Background: Ethanol-inducedgastric mucosal lesion (EGML) is one of the most common digestivedisorderswith the limited outcomes of current therapies in clinic. P. histicola was shown probiotic efficacy against arthritis, multiple sclerosis and estrogen deficiency-induced depression in mice, but the role of P. histicola in ethanol-induced gastric mucosal lesion remains unclear despite of its high colonization in stomach. Ferroptosis characterized by lipids peroxidation may be involved in EGML. Herein, we aimed to investigate the effects and underlying mechanism of P. histicola on EGML in the ferroptosis dependent pathway. Methods: : P. histicola was intragastrically treated for a week and deferoxamine (DFO), a ferroptosis inhibitor, was intraperitoneally injected prior to oral ethanol administration, respectively. The gastric mucosal lesion and ferroptosis were assessed by pathological examination, quantitative real-time PCR, Western blot and immunofluorescence. Results: : P. histicola was originally found to attenuate EGML by the reduced pathological changes and ROS accumulation. The proferroptotic genes of Transferrin Receptor (TFR1), Solute Carrier Family 39 Member 14 (SLC39A14), Heme Oxygenase-1 (HMOX-1), Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4), Cyclooxygenase 2 (COX-2) and mitochondrial Voltage-dependent Anion Channels (VDACs) were upregulated, but the anti-ferroptotic System Xc-/ Glutathione Peroxidase 4 (GPX4)axis was reduced after ethanol administration, which was reversed by DFO. Furthermore, P. histicola treatment significantly downregulated the expression of ACSL4, HMOX-1 and COX-2, as well as TFR1 and SLC39A14 on mRNA or protein level, while activating System Xc-/GPX4 axis. Conclusions: Our study found that P. histicola reduces ferroptosis to attenuate EGML by inhibiting the ACSL4- and VDAC- dependent pro-ferroptotic pathways, and activating anti-ferroptotic System Xc-/GPX4 axis.