SAHA Alleviates Diarrhea-Predominant Irritable Bowel Syndrome Through Regulation of the p-STAT3/SERT/5-HT Signaling Pathway

Jian Shen; Bimeng Zhang; Jianjie Chen; Jiazheng Cheng; Jiali Wang; Xianhui Zheng; Yu Lan; Xiaowen Zhang

doi:10.2147/JIR.S331303

SAHA Alleviates Diarrhea-Predominant Irritable Bowel Syndrome Through Regulation of the p-STAT3/SERT/5-HT Signaling Pathway

J Inflamm Res. 2022 Mar 10:15:1745-1756. doi: 10.2147/JIR.S331303. eCollection 2022.

Authors

Jian Shen¹, Bimeng Zhang², Jianjie Chen³, Jiazheng Cheng¹, Jiali Wang¹, Xianhui Zheng¹, Yu Lan¹, Xiaowen Zhang¹

Affiliations

¹ Department of Pediatrics, Shuguang Hospital Affiliated to Shanghai Traditional Chinese Medical University, Shanghai, 201203, People's Republic of China.
² Department of Acupuncture and Moxibustion, Shanghai General Hospital (The First People's Hospital Affiliated to Shanghai Jiaotong University), Shanghai, 200080, People's Republic of China.
³ Department of Internal Medicine, Shuguang Hospital Affiliated to Shanghai Traditional Chinese Medical University, Shanghai, 201203, People's Republic of China.

Abstract

Objective: Irritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and stool irregularity. However, its pathophysiological mechanisms, which trigger intestinal motility disorders and diarrhea leading to diarrhea-predominant IBS (D-IBS), remain largely unknown.

Methods: In the present study, we established a D-IBS rat model by mother-infant separation combined with restraint stress. Then we exposed the modelled rats to suberoylanilide hydroxamic acid (SAHA) treatment, followed by determination of their visceral sensitivity. Toluidine blue staining served to reveal the effects of SAHA treatment on mast cells of D-IBS model rats. Then we measured the expression of serotonin (5-hydroxytryptamine; 5-HT) and its receptors by ELISA.

Results: Construction of short hairpin RNA (sh)-serotonin transporter (SERT) lentivirus vectors verified the regulation of the 5-HT signaling pathway by phosphorylated (p)-STAT/SERT. SAHA treatment of D-IBS model rats reduced the fecal water content, electromyography integral change rate, abdominal withdrawal reflex score, and number of mast cells, as well as the expression of 5-HT type 3A (5-HT3AR), 3B receptor (5-HT3BR), and 4 receptor (5-HT4R) receptors. The treatment also elevated the expression of signal transducer and activator for transcription 3 (STAT3) and SERT. Activation of p-STAT3 may reverse the inhibitory effect of SAHA on the elevated visceral sensitivity of D-IBS model rats. Moreover, SAHA promoted the transcription of SERT through repression of the p-STAT3/5-HT signaling, thereby inhibiting the visceral sensitivity of D-IBS model rats.

Conclusion: This study highlights that SAHA treatment can alleviate D-IBS through regulation of the p-STAT3/SERT/5-HT signaling pathway.

Keywords: 5-HT; SAHA; SERT; diarrhea type irritable bowel syndrome; p-STAT3.