Cell Signaling Laboratory, Department of Biological Sciences, Birla Institute of Technology, and Science-Pilani Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, Hyderabad, 500078, Telangana , India.
Sci Rep. 2024 Oct 16;14(1):24285. doi: 10.1038/s41598-024-75516-9.
Long-standing chronic inflammation of the digestive tract leads to Inflammatory Bowel Diseases (IBD), comprising Crohn's Disease (CD) and Ulcerative colitis (UC). The persistent prevalence of these conditions in the gut is a predisposing factor for Colitis-Associated Cancer (CAC), one of the most common sub-types of Colorectal Cancer (CRC), emphasizing the role of inflammation in tumorigenesis. Therefore, targeted intervention of chronic intestinal inflammation is a potential strategy for preclusion and treatment of inflammation-driven malignancies. The association between bile acids (BA) and gut immune homeostasis has been explored in the recent past. However, the exact downstream mechanism by which secondary BA successfully regulating intestinal inflammation and inflammation-dependent CAC is unclear. Our study demonstrated that Ursodeoxycholic acid (UDCA), a secondary bile acid of host gut microbial origin, finetunes the dialogue between activated macrophages and intestinal epithelial cells, modulating inflammation-driven epithelial-mesenchymal transition (EMT), a hallmark of cancer. UDCA treatment and dependency on the TGR5/GPBAR1 receptor significantly upregulated the Suppressor of Cytokine Signaling 1 (SOCS1) expression, contributing to the regulation of pro-inflammatory cytokines in activated macrophages. In this study, we also noticed heightened expression of SOCS1 in UDCA-mitigated CAC in the AOM-DSS mouse model with reduced inflammatory gene expression. Overall, our observations highlight the possible utility of UDCA for inflammation-driven intestinal cancer.
长期存在的消化道慢性炎症可导致炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC）。这些疾病在肠道中持续存在是结肠炎相关癌症（CAC）的一个诱发因素，CAC 是结直肠癌（CRC）最常见的亚型之一，这强调了炎症在肿瘤发生中的作用。因此，靶向干预慢性肠道炎症是预防和治疗炎症驱动性恶性肿瘤的一种潜在策略。最近已经探讨了胆汁酸（BA）与肠道免疫稳态之间的联系。然而，次级 BA 成功调节肠道炎症和炎症依赖性 CAC 的确切下游机制尚不清楚。我们的研究表明，熊去氧胆酸（UDCA），一种宿主肠道微生物来源的次级胆汁酸，微调了活化巨噬细胞和肠上皮细胞之间的对话，调节炎症驱动的上皮-间充质转化（EMT），这是癌症的一个标志。UDCA 治疗和对 TGR5/GPBAR1 受体的依赖性显著上调了细胞因子信号转导抑制因子 1（SOCS1）的表达，有助于调节活化巨噬细胞中的促炎细胞因子。在这项研究中，我们还注意到，在 AOM-DSS 小鼠模型中，UDCA 减轻 CAC 时 SOCS1 的表达水平升高，炎症基因表达减少。总的来说，我们的观察结果强调了 UDCA 用于炎症驱动性肠道癌症的可能性。
