OP31 High fat diet exacerbates colitis through microbial metabolite deoxycholic acids induced-ferroptosis

Abstract Background High-fat diet (HFD) is closely related to the occurrence and development of IBD, which increases level deoxycholic acid (DCA). DCA-treated mice showed pro-inflammatory cell infiltration colonic inflammation. Ferroptosis, a newly recognized form death characterized by iron overload generation reactive oxygen species (ROS) has recently been observed in colitis. Whether DCA affects ferroptosis whether it contributes colitis not explored. Methods Twenty-four Female C57BL/6 were randomly divided into 4 groups: control group, DSS plus group. Real-time PCR Western blotting used detect transcription protein expression ferroptosis-related genes. RNA sequencing was analyze changes differential genes intestinal tissue treated with DCA. Transmission electron microscope employed epithelial morphology intracellular mitochondria. Finally, binding force between HIF-2α calculated molecular dynamics explore structural biological basis interaction HIF-2α, screen innovative drugs. Results We found that exacerbated disease activity index, histological damage In vivo, KEGG pathway enriched tissues. treatment significantly induced DSS-induced mice, as evidenced overload, ROS MDA production, accompanied decreased GPX4 increased ACSL4. microscopy also confirmed vitro, IEC-6 cells Caco-2 under combined Lipopolysaccharide (LPS). Interestingly, revealed levels apical divalent metal transporter-1 (DMT1) upregulated treated-mice DMT1 direct target gene hypoxia inducible factor (HIF)-2α. could increase lines. Pharmacological inhibition inhibited blocked promotion These data provide mechanistic for widely reported link risk. Conclusion Taken together, these findings suggest aggravates through induction HIF2α-DMT1 signaling provides new perspective UC prevention future.