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

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.