Abstract

The phenomenon of inflammatory bowel disease (IBD) patients experiencing irritable bowel syndrome (IBS)-like symptoms, particularly during periods of endoscopic remission, is a significant and well-documented clinical challenge. Increased 5-hydroxytryptamine (5-HT) availability from enterochromaffin (EC) cells is implicated in visceral hypersensitivity, a hallmark of IBS. While glucocorticoids are effective in IBD, their potential to alleviate IBS symptoms and their interaction with gut 5-HT system remain unexplored. A murine model of colitis-associated visceral hypersensitivity was established in epithelium-specific Tph1 knockout mice. After dexamethasone treatment, visceral hypersensitivity was assessed by both behavioral test and electromyography. 5-HT synthesis was analyzed via flow cytometry, ELISA, immunohistochemistry, and qPCR. In vitro mechanistic studies were performed in QGP-1 cells using RNA sequencing, western blot, and pharmacological inhibitors. In the murine model of colitis-associated visceral hypersensitivity, dexamethasone effectively alleviated visceral hypersensitivity, which was abolished by the epithelium-specific knockout of Tph1. Dexamethasone treatment significantly downregulated peripheral 5-HT biosynthesis by reducing Tph1 expression in EC cells. Abundant GR expression in EC cells was confirmed by single-cell transcriptomic analysis and immunofluorescence. In QGP-1 cells, dexamethasone dose-dependently suppressed TPH1 and 5-HT production in a GR-dependent manner. Mechanistically, transcriptomic profiling revealed dexamethasone-induced activation of the PI3K signaling pathway, and subsequent pharmacological inhibition experiments established that dexamethasone represses TPH1 through a GR-PI3K-SGK1 signaling axis. This study identified a novel GR-PI3K-SGK1 signaling axis in EC cells that downregulates 5-HT synthesis and alleviates visceral hy