Shen Jian, Zhang Bimeng, Chen Jianjie, Cheng Jiazheng, Wang Jiali, Zheng Xianhui, Lan Yu, Zhang Xiaowen
Department of Pediatrics, Shuguang Hospital Affiliated to Shanghai Traditional Chinese Medical University, Shanghai, 201203, People's Republic of China.
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.
J Inflamm Res. 2022 Mar 10;15:1745-1756. doi: 10.2147/JIR.S331303. eCollection 2022.
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.
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.
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.
This study highlights that SAHA treatment can alleviate D-IBS through regulation of the p-STAT3/SERT/5-HT signaling pathway.
肠易激综合征（IBS）的特征为腹痛、腹胀和大便不规律。然而，其触发肠道运动障碍和腹泻导致腹泻型肠易激综合征（D-IBS）的病理生理机制在很大程度上仍不清楚。
在本研究中，我们通过母婴分离联合束缚应激建立了D-IBS大鼠模型。然后我们将造模大鼠用辛二酰苯胺异羟肟酸（SAHA）进行处理，随后测定它们的内脏敏感性。甲苯胺蓝染色用于揭示SAHA处理对D-IBS模型大鼠肥大细胞的影响。然后我们通过酶联免疫吸附测定法测量血清素（5-羟色胺；5-HT）及其受体的表达。
短发夹RNA（sh）-血清素转运体（SERT）慢病毒载体的构建证实了磷酸化（p）-信号转导子和转录激活子（STAT）/SERT对5-HT信号通路的调控。SAHA处理D-IBS模型大鼠可降低粪便含水量、肌电图积分变化率、腹部退缩反射评分和肥大细胞数量，以及5-羟色胺3A（5-HT3AR）、3B受体（5-HT3BR）和4受体（5-HT4R）的表达。该处理还提高了信号转导子和转录激活子3（STAT3）和SERT的表达。p-STAT3的激活可能逆转SAHA对D-IBS模型大鼠内脏敏感性升高的抑制作用。此外，SAHA通过抑制p-STAT3/5-HT信号通路促进SERT的转录，从而抑制D-IBS模型大鼠的内脏敏感性。
本研究强调SAHA处理可通过调控p-STAT3/SERT/5-HT信号通路缓解D-IBS。
