Dysregulation of Farnesoid X Receptor on Neutrophil Homeostasis Exacerbates Intestinal Inflammation via the...

Neutrophils significantly accumulate within the inflamed intestinal mucosa of patients with inflammatory bowel disease (IBD), where the farnesoid X receptor (FXR) is typically downregulated. However, the mechanisms by which FXR modulates neutrophil-mediated mucosal inflammation in IBD remain elusive. Here, we demonstrated that FXR expression is markedly decreased in neutrophils from patients with active IBD. Fxr ^-/- mice exhibited exacerbated colitis following DSS insults or Citrobacter rodentium infection, evidenced by heightened neutrophil-driven immune responses including increased neutrophil infiltration and neutrophil extracellular trap (NET) formation. Adoptive transfer of Fxr ^-/- neutrophils into WT recipients exacerbated DSS-induced intestinal inflammation, indicating that FXR suppresses the pathogenic activity of neutrophils in a neutrophil-intrinsic manner. An ex vivo functional assay revealed that Fxr ^-/- neutrophils display elevated ROS production, NET formation, and migratory capacity upon inflammatory challenge. Mechanistically, RNA-sequencing and functional assays revealed enhanced mTORC1 signaling and glycolysis in Fxr ^-/- neutrophils. Consistently, pharmacological activation of FXR with INT-747 significantly restrained the mTORC1-glycolysis-mediated proinflammatory responses in neutrophils from IBD patients. Our findings identify FXR as a critical regulator of neutrophil-mediated mucosal inflammation via the mTORC1-glycolysis pathway, highlighting its therapeutic potential in IBD.