Glucocorticoid signaling mitigates colitis-associated visceral hypersensitivity by suppressing 5-HT release in enterochromaffin cells via a GR-PI3K-SGK1 axis

  • Int Immunopharmacol. 2026 Mar 1:172:116207. doi: 10.1016/j.intimp.2026.116207.
Dongping Lyu  1 ,  Xia Wang  1 ,  Jinghui Zhang  1 ,  Shichen Fu  1 ,  Lixiang Li  1 ,  Shiyang Li  2 ,  Yanqing Li  3 ,  Xiuli Zuo  4
Affiliations
  • 1. Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China; Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for digestive disease, Qilu Hospital, Shandong University, Jinan 250012, China.
  • 2. Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for digestive disease, Qilu Hospital, Shandong University, Jinan 250012, China; Advanced Medical Research Institute, Shandong University, Jinan 250012, China.
  • 3. Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China; Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for digestive disease, Qilu Hospital, Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of Gastrointestinal Tumor, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 4. Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China; Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for digestive disease, Qilu Hospital, Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of Gastrointestinal Tumor, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: [email protected].
PMID: 41554225 DOI: 10.1016/j.intimp.2026.116207
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 hypersensitivity. Our findings revealed a non-classical mechanism for glucocorticoids and highlighting their potential use in managing IBS-like symptoms in IBD patients.

Keywords
5-HT; Enterochromaffin cell; Glucocorticoids; Inflammatory bowel disease; Irritable bowel syndrome; Visceral hypersensitivity.
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