# Dysregulation of Farnesoid X Receptor on Neutrophil Homeostasis Exacerbates Intestinal Inflammation via the mTORC1‐Glycolysis Signaling Pathway

## TL;DR

This study shows that reduced FXR in neutrophils worsens intestinal inflammation in IBD by boosting mTORC1 and glycolysis, suggesting FXR as a potential treatment target.

## Contribution

The novel finding is that FXR regulates neutrophil activity via the mTORC1-glycolysis pathway, linking FXR dysfunction to IBD progression.

## Key findings

- FXR deficiency in neutrophils leads to increased intestinal inflammation and neutrophil extracellular trap formation in IBD.
- Pharmacological activation of FXR with INT-747 reduces mTORC1-glycolysis-driven inflammation in IBD neutrophils.
- FXR suppresses neutrophil pathogenicity in a cell-intrinsic manner, reducing mucosal inflammation.

## Abstract

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.

FXR signaling attenuates neutrophil functions by suppressing mTORC1 activity to ameliorate intestinal mucosal inflammation in IBD. In the inflamed intestinal mucosa, FXR expression is markedly diminished in neutrophils, attenuating its restraint on the mTORC1‐glycolysis axis. This metabolic shift toward elevated glycolysis augments neutrophil migratory capacity, degranulation, and NET formation, contributing to the progression of IBD.