中国科学院心理健康重点实验室知识库

背景：肠易激综合征（IBS）的发生与生物钟节律紊乱有关，IBS症状常具有昼夜波动等节律紊乱特征。肠嗜铬细胞（EC细胞）及其色氨酸羟化酶-1(TPH1)-5-羟色胺（5-HT）信号通路是目前公认的参与IBS发生的关键病理生理学机制。目的：探讨生物钟核心基因Bmal1是否通过调控EC细胞及其TPH1-5-HT信号通路参与IBS的发生。方法：采用IBS模型和对照Sprague-Dawley大鼠以及Bmal1肠道特异性敲除（Bmal1~(△IEC)）和野生型（WT）C57BL/6小鼠进行研究。以连续单一刺激方法建立IBS模型。以免疫荧光染色检测结肠Bmal1、EC细胞嗜铬粒蛋白A(Cg A)、TPH1和5-HT表达。结果：大鼠实验：Bmal1主要表达于结肠上皮细胞，在EC细胞中亦有表达。与对照组相比，授时因子时间点（ZT）ZT8:00和ZT24:00时，IBS模型组结肠Bmal1表达明显增高，且模型组ZT8:00的Bmal1表达明显高于ZT16:00和ZT24:00，差异均有统计学意义（P均<0.05）。小鼠实验：与WT组相比，Bmal1~(△IEC)组结肠EC细胞数量明显减少，TPH1、5-HT表达明显降低，差异均有统计学意义（P均<0.05）。结论：IBS模型大鼠结肠生物钟基因Bmal1的表达存在昼夜异常波动，Bmal1表达的昼夜紊乱可通过EC细胞及其TPH1-5-HT信号通路参与IBS的发生。

Background: Disrupted circadian rhythms have been associated with the development of irritable bowel syndrome (IBS). In some IBS patients, the symptoms may present with circadian fluctuations. Enterochromaffin cells (EC cells) and tryptophan hydroxylase 1 (TPH1)-5-hydroxytryptamine (5-HT) signaling pathway are currently recognized as the key pathophysiological mechanism of IBS- Aims: To explore whether Bmall the core circadian clock gene, is involved in the occurrence of IBS by re ulatin TPH1-5-HT si nalin pathway in EC cells. Methods: Normal Spra ue-Dawley (SD) rats and IBS-model SD rats, as well as wild type (WT) and intestine-specific Bmall knockout (Bmall ∆IEC) C57BL/6 mice were used in this study. The IBS model was established by method of single prolonged stress. Colonic expressions of Bmall, TPH1, 5-HT, and chromogranin A (CgA) in EC cells were detected by immunofluorescence staining. Results: Results of rats experiment: Bmall was prominently expressed in colonic epithelial cells, and it could also be found in EC cells. Compared with the normal control group, the expression of Bmall in colon of IBS model group was significantly increased at zeitgeber time (ZT) points ZT8:00 and ZT24:00 (all P<0.05). Furthermore, within the IBS model group, expression of Bmall at ZT8: 00 was significantly increased than that at ZT16:00 and ZT24:00 (all P<0.05). Results of mice experiment: Compared with WT group, the number of EC cells, and the expressions of TPH1 and 5-HT in colon of Bmall ∆IEC group were all significantly reduced (all P<0.05). Conclusions: Expression of the colon clock gene Bmall in IBS model rats has circadian disruptions. The disrupted Bmall expression might be involved in the pathogenesis of IBS via TPH1-5-HT signaling pathway in EC cells.

重庆市自然科学基金面上项目（CSTB2022NSCQ-MSX1508）;; 重庆市基础研究与前沿探索项目（cstc2018jcyj AX0620）;; 陆军军医大学科技创新能力提升专项项目（2022XLC07）;; 陆军特色医学中心人才创新能力培养计划（2019XLC3062）