A Novel CHRM3-Driven Preclinical Model of Irritable Bowel Syndrome

IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Junmin Yang, Xueyang Li, Chong Wang, Xiaoyu Yang, Pan Zheng, Jie Liang, Li Zhang, Liang Xia, Jianhua Wan
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Abstract

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder that significantly reduces patients' quality of life. However, current animal models have limitations in replicating the complex pathophysiology of IBS. In this study, we successfully developed a mouse model by mating intestinal epithelium-specific Cre tool mice with chemically modified human muscarinic acetylcholine receptor 3 (hCHRM3) mice, resulting in specific expression of the hCHRM3 in the intestinal epithelial cells. Activation of the hCHRM3 with clozapine-N-oxide (CNO) mimicked IBS attacks. The model mice exhibited typical IBS symptoms such as diarrhea, pain, and visceral hypersensitivity, along with pathological changes like intestinal edema and inflammatory cell infiltration, and disruption of the intestinal mucosal barrier. RNA sequencing revealed significant differentially expressed genes between the model and control groups, with KEGG and GO enrichment analyses indicating significant enrichment of immune and inflammation-related pathways. Additionally, the model mice showed increased levels of short-chain fatty acids and imbalances in the diversity and composition of the gut microbiota. This new IBS mouse model effectively simulates the symptoms and pathological processes of human IBS, providing a powerful tool for in-depth research into the pathogenesis of IBS and the development of therapeutic strategies.

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一种新的chrm3驱动的肠易激综合征临床前模型
肠易激综合征(IBS)是一种常见的功能性胃肠道疾病,严重降低患者的生活质量。然而,目前的动物模型在复制肠易激综合征复杂的病理生理方面存在局限性。在本研究中,我们通过将肠上皮特异性Cre工具小鼠与化学修饰的人毒碱乙酰胆碱受体3 (hCHRM3)小鼠配对,成功建立了小鼠模型,使hCHRM3在肠上皮细胞中特异性表达。氯氮平- n -氧化物(CNO)激活hCHRM3模拟IBS发作。模型小鼠表现出腹泻、疼痛、内脏过敏等典型IBS症状,并伴有肠水肿、炎症细胞浸润、肠黏膜屏障破坏等病理改变。RNA测序显示模型组和对照组之间存在显著差异表达基因,KEGG和GO富集分析表明免疫和炎症相关通路显著富集。此外,模型小鼠显示短链脂肪酸水平增加,肠道微生物群的多样性和组成不平衡。该新型IBS小鼠模型有效地模拟了人类IBS的症状和病理过程,为深入研究IBS发病机制和制定治疗策略提供了有力的工具。
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来源期刊
The FASEB Journal
The FASEB Journal 生物-生化与分子生物学
CiteScore
9.20
自引率
2.10%
发文量
6243
审稿时长
3 months
期刊介绍: The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.
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