Kumei Shima, Ishioh Masatomo, Nozu Tsukasa, Okumura Toshikatsu
Department of General Medicine, Asahikawa Medical University, Japan.
Department of General Medicine, Asahikawa Medical University, Japan; Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.
Biochim Biophys Acta Gen Subj. 2023 May;1867(5):130344. doi: 10.1016/j.bbagen.2023.130344. Epub 2023 Mar 6.
In this study, we attempted to clarify a role of prostaglandin (PG) I and its specific receptor, IP in the pathogenesis of irritable bowel syndrome (IBS) using a maternal separation (MS)-induced IBS model. Administration of beraprost (BPS), a specific IP agonist, improved visceral hypersensitivity and depressive state with decreased serum CRF level in the IBS rats. To clarify the mechanism of the effect of BPS, we performed serum metabolome analysis and 1-methylnicotinamide (1-MNA) was identified as a possible candidate for a clue metabolite of pathogenesis of IBS. The serum 1-MNA levels revealed inverse correlation to the level of visceral sensitivity, and positive correlation to a depression marker, immobilizing time. Administration of 1-MNA induced visceral hypersensitivity and depression with increased levels of serum CRF. Since fecal 1-MNA is known for a marker of dysbiosis, we examined the composition of fecal microbiota by T-RFLP analysis. The proportion of clostridium cluster XI, XIVa and XVIII was significantly changed in MS-induced IBS rats treated with BPS. Fecal microbiota transplant of BPS-treated rats improved visceral hypersensitivity and depression in IBS rats. These results suggest for the first time that PGI-IP signaling plays an important role in IBS phenotypes such as visceral hypersensitivity and depressive state. BPS modified microbiota, thereby inhibition of 1-MNA-CRF pathway, followed by improvement of MS-induced IBS phenotype. These results suggest that the PGI-IP signaling could be considered to be a therapeutic option for IBS.
在本研究中，我们试图通过母体分离（MS）诱导的肠易激综合征（IBS）模型来阐明前列腺素（PG）I及其特异性受体IP在IBS发病机制中的作用。给予特异性IP激动剂贝拉前列腺素（BPS）可改善IBS大鼠的内脏超敏反应和抑郁状态，并降低血清促肾上腺皮质激素释放因子（CRF）水平。为了阐明BPS作用的机制，我们进行了血清代谢组分析，并确定1-甲基烟酰胺（1-MNA）可能是IBS发病机制线索代谢物的候选物。血清1-MNA水平与内脏敏感性水平呈负相关，与抑郁标志物（固定不动时间）呈正相关。给予1-MNA可诱导内脏超敏反应和抑郁，并使血清CRF水平升高。由于粪便1-MNA是肠道菌群失调的标志物，我们通过末端限制性片段长度多态性（T-RFLP）分析检测了粪便微生物群的组成。在用BPS治疗的MS诱导的IBS大鼠中，梭菌属XI、XIVa和XVIII簇的比例发生了显著变化。将BPS治疗大鼠的粪便微生物群移植可改善IBS大鼠的内脏超敏反应和抑郁。这些结果首次表明，PGI-IP信号通路在IBS表型（如内脏超敏反应和抑郁状态）中起重要作用。BPS改变了微生物群，从而抑制了1-MNA-CRF通路，进而改善了MS诱导的IBS表型。这些结果表明，PGI-IP信号通路可被视为IBS的一种治疗选择。
