7-Ketodeoxycholic Acid Promotes Colonic Mucosal Healing by Inducing Calcium Release from Endoplasmic Reticulum via the TGR5-IP3R Pathway.

Abstract

Defective healing of injured mucosa is a hallmark of many pathological conditions, such as ulcerative colitis (UC). Wound healing is a pivotal process that is essential for the reconstruction of epithelial homeostasis following damage to mucous membrane. However, the endogenous metabolites capable of expediting intestinal mucosal healing remain largely undefined. The aim of this study is to identify a pro-repair metabolite to accelerate colonic wound healing. The investigation reveals that the serum levels of 7-ketodeoxycholic acid (7-KDCA), deoxycholic acid (DCA), and lithocholic acid (LCA) are depleted in patients with UC and colitic mice relative to controls. Among the three bile acids, 7-KDCA exhibits the most conspicuous, which is correlated with disease severity. 7-KDCA treatment exerts the strongest promotion of mucosal healing in mice with dextran sulfate sodium-induced mucosal damage or biopsy-induced colonic wounding injury. Mechanistically, 7-KDCA functions by driving intestinal epithelial cell migration through induction of calcium release from the endoplasmic reticulum via targeting the TGR5-IP3R axis. Amidst the array of endogenous metabolites potentially active in progression of UC, 7-KDCA stands out as the preeminent facilitator in the healing of colonic mucosa. This finding may hold clinical significance for treating mucosal defect-related diseases, including UC.