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

Sisi Wang; Du Wu; Fangquan Wu; Hongxia Sun; Xinyu Wang; Hongbing Meng; Qingqing Lin; Keke Jin; Fangyan Wang

doi:10.1186/s12906-023-03946-5

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

BMC Complement Med Ther. 2023 Apr 14;23(1):118. doi: 10.1186/s12906-023-03946-5.

Authors

Sisi Wang^#¹, Du Wu^#², Fangquan Wu¹, Hongxia Sun¹, Xinyu Wang¹, Hongbing Meng¹, Qingqing Lin³, Keke Jin⁴, Fangyan Wang⁵

Affiliations

¹ School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
² Hangzhou Wuyunshan Hospital Hangzhou Health Promotion Institution, Hangzhou, China.
³ Department of Hemodialysis, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China. jinkeke@wmu.edu.cn.
⁵ School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China. fangyan_wang@wmu.edu.cn.

^# Contributed equally.

Abstract

Background: Ethanol-induced gastric mucosal lesions (EGML) is one of the most common digestive disorders for which current therapies have limited outcomes in clinical practice. Prevotella histicola (P. histicola) has shown probiotic efficacy against arthritis, multiple sclerosis and oestrogen deficiency-induced depression in mice; however, its role in EGML remains unclear in spite of its extensive colonisation of the stomach. Ferroptosis, which is characterised by lipid peroxidation, may be involved in EGML. Herein, we aimed to investigate the effects and underlying mechanism of action of P. histicola on EGML in the ferroptosis-dependent pathway.

Methods: P. histicola was intragastrically administered for a week, and deferoxamine (DFO), a ferroptosis inhibitor, was intraperitoneally injected prior to oral ethanol administration. The gastric mucosal lesions and ferroptosis were assessed via histopathological examinations, quantitative real-time PCR, Western blot, immunohistochemistry and immunofluorescence.

Results: P. histicola was originally found to attenuate EGML by reducing histopathological changes and lipid reactive oxygen species (ROS) accumulation. The pro-ferroptotic genes of Transferrin Receptor (TFR1), Solute Carrier Family 39 Member 14 (SLC39A14), Haem 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 up-regulated; the anti-ferroptotic System Xc-/Glutathione Peroxidase 4 (GPX4) axis was inhibited after ethanol administration. However, the changes of histopathology and ferroptosis-related parameters induced by ethanol were 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 the protein level, while activating the System Xc-/GPX4 axis.

Conclusions: We found that P. histicola reduces ferroptosis to attenuate EGML by inhibiting the ACSL4- and VDAC-dependent pro-ferroptotic pathways and activating the anti-ferroptotic System Xc-/GPX4 axis.

Keywords: ACSL4; Ethanol; Ferroptosis; Gastric mucosal lesions; Prevotella histicola; System Xc-/GPX4 axis; VDAC.

MeSH terms

Administration, Oral
Animals
Cation Transport Proteins*
Cyclooxygenase 2
Ethanol
Ferroptosis*
Mice

Substances

Cyclooxygenase 2
Ethanol
SLC39A14 protein, mouse
Cation Transport Proteins

Supplementary concepts

Prevotella histicola