Liu Zhi, Zhang Hong, Wang Jingjing, Yao Yutong, Wang Xiaoyi, Liu Yang, Fang Weijia, Liu Xingyin, Zheng Yi
Department of Microbiology, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Core Facility Center, The First Afliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Microbiol Res. 2025 Aug;297:128191. doi: 10.1016/j.micres.2025.128191. Epub 2025 Apr 22.
The intestinal mucus barrier has emerged as a promising therapeutic target for inflammatory bowel disease. Understanding its regulatory mechanisms is critical for elucidating ulcerative colitis (UC) pathogenesis, improving diagnostics, guiding treatments, and preventing relapse. Chloride Channel Accessory 1 (Clca1), a constituent of the mucus layer, remains understudied in colitis. Here, we investigated Clca1's role in mucosal immunity and intestinal homeostasis using experimental colitis models. Clca1-deficient (Clca1) mice displayed compromised mucus layer integrity, reduced neutrophil infiltration, and gut microbiota dysbiosis. Notably, Clca1 mice exhibited exacerbated colitis severity following dextran sulfate sodium (DSS) challenge, accompanied by a diminished goblet cell populations. Fecal microbiota transplantation (FMT) studies revealed that gut microbiota critically modulates divergent phenotypic outcomes between genotypes. Our findings establish Clca1 as a multifunctional regulator of mucus barrier integrity through mechanisms involving goblet cell maintenance, neutrophil-mediated immunity, and host-microbiota crosstalk. These results advance the understanding of UC pathogenesis and identify Clca1-associated pathways as potential targets for barrier restoration therapies.
肠道黏液屏障已成为炎性肠病一个很有前景的治疗靶点。了解其调控机制对于阐明溃疡性结肠炎（UC）的发病机制、改善诊断、指导治疗以及预防复发至关重要。氯离子通道辅助蛋白1（Clca1）是黏液层的一个组成部分，在结肠炎中仍未得到充分研究。在此，我们使用实验性结肠炎模型研究了Clca1在黏膜免疫和肠道稳态中的作用。Clca1基因缺陷（Clca1 -/-）小鼠表现出黏液层完整性受损、中性粒细胞浸润减少和肠道微生物群失调。值得注意的是，Clca1 -/-小鼠在硫酸葡聚糖钠（DSS）攻击后表现出结肠炎严重程度加剧，同时杯状细胞数量减少。粪便微生物群移植（FMT）研究表明，肠道微生物群关键地调节了不同基因型之间的不同表型结果。我们的研究结果表明，Clca1是黏液屏障完整性的多功能调节因子，其机制涉及杯状细胞维持、中性粒细胞介导的免疫以及宿主 - 微生物群相互作用。这些结果推进了对UC发病机制的理解，并确定Clca1相关途径为屏障恢复疗法的潜在靶点。
