# Western Diet Inhibits FUT7‐Mediated Treg Intestinal Homing to Disrupt the Homeostasis of Intestinal Epithelial Cells in Crohn's Disease

## TL;DR

A Western diet disrupts gut cell balance in Crohn's disease by reducing Treg cell function, and a new nanoparticle treatment may help restore gut health.

## Contribution

The study reveals a novel mechanism linking Western diet to Crohn's disease via FUT7 and proposes a targeted nanoparticle therapy to restore intestinal homeostasis.

## Key findings

- Western diet downregulates FUT7 in Tregs, impairing their intestinal homing and communication with gut cells.
- Treg-specific FUT7 knockout worsens colitis and gut barrier disruption in a mouse model of Crohn's disease.
- A CD4-targeted nanoparticle upregulates FUT7 in Tregs, improving gut barrier function and reducing inflammation.

## Abstract

The Western diet (WD) is a potential risk factor for developing Crohn's disease (CD), characterized by disordered homeostasis of intestinal epithelial cells (IECs). However, how WD disrupts the IEC homeostasis remains unclear. Here, it is shown that WD disrupts the IEC homeostasis through inhibiting Fut7‐mediated Treg intestinal homing to weaken Treg and IEC signaling crosstalk. In this study, it is found that WD disrupted the IEC barrier, downregulated Fut7 expression in Tregs, and decreased colonic Tregs. The combined analyses of single‐cell RNA‐sequencing and spatial transcriptomics revealed that WD weakened the intestinal homing ability of Tregs and the signaling crosstalk between Tregs and IECs. Furthermore, Treg‐specific Fut7 knockout decreased colonic Tregs and aggravated the severity of colitis and IEC barrier disruption in the 2,4,6‐trinitrobenzenesulfonic acid‐induced mouse CD model, while upregulation of Fut7 in Tregs alleviated their severity. On top of this model, transfer of Tregs in vivo ameliorated colitis and IEC barrier disruption in the naive CD4+ T cell transfer model, but Fut7‐knockdown Tregs cannot do so. In addition, it is found that FUT7 expression in Tregs is downregulated in patients with active CD. Thus, these findings offer a novel insight into the pathogenesis of CD.

In this study, we constructed a nanoparticle that was CD4 antibody‐mediated targeted, Fut7‐expressing plasmid‐loaded cationic liposome, namely CD4‐LDP‐Fut7. Upregulation of Fut7 expression in Tregs by using CD4‐LDP‐Fut7 can increase Treg homing to the intestine, thereby facilitating repair of the intestinal epithelial barrier and inhibiting inflammation in the intestine.