Primary sclerosing cholangitis (PSC) is a progressive fibrosing cholestatic liver disease that is strongly associated with inflammatory bowel disease (IBD). PSC-associated IBD (PSC-IBD) displays a unique phenotype characterized by right-side predominant colon inflammation and increased risk of colorectal cancer compared to non-PSC-IBD. The frequent association and unique phenotype of PSC-IBD suggest distinctive underlying disease mechanisms from other chronic liver diseases or IBD alone. Multidrug resistance protein 2 knockout (Mdr2^−/−) mice develop spontaneous cholestatic liver injury and fibrosis mirroring human PSC. As a novel model of PSC-IBD, we treated Mdr2^−/− mice with dextran sulfate sodium (DSS) to chemically induce colitis (Mdr2^−/−/DSS). Mdr2^−/− mice demonstrate alterations in fecal bile acid composition and enhanced colitis susceptibility with increased colonic adhesion molecule expression, particularly mucosal addressin-cell adhesion molecule 1 (MAdCAM-1). In vitro, ursodeoxycholic acid (UDCA) co-treatment resulted in a dose dependent attenuation of TNF-α-induced endothelial MAdCAM-1 expression. In the combined Mdr2^−/−/DSS model, UDCA supplementation attenuated colitis severity and downregulated intestinal MAdCAM-1 expression. These findings suggest a potential mechanistic role for alterations in bile acid signaling in modulating MAdCAM-1 expression and colitis susceptibility in cholestasis-associated colitis. Together, our findings provide a novel model and new insight into the pathogenesis and potential treatment of PSC-IBD.

原发性硬化性胆管炎 (PSC) 是一种进行性纤维化胆汁淤积性肝病，与炎症性肠病 (IBD) 密切相关。PSC 相关 IBD (PSC-IBD) 显示出一种独特的表型，其特征是与非 PSC-IBD 相比，以右侧为主的结肠炎症和结直肠癌风险增加。PSC-IBD 的频繁关联和独特的表型表明与其他慢性肝病或单独的 IBD 不同的潜在疾病机制。多药耐药蛋白 2 敲除 (Mdr2 ^-/- ) 小鼠出现自发性胆汁淤积性肝损伤和纤维化，与人类 PSC 相似。作为 PSC-IBD 的新型模型，我们用葡聚糖硫酸钠 (DSS)处理 Mdr2 ^{-/-小鼠以化学诱导结肠炎 (Mdr2 -/-} /DSS)。MDR2^−/−小鼠表现出粪便胆汁酸成分的改变和结肠炎易感性增强，结肠粘附分子表达增加，尤其是粘膜寻址素细胞粘附分子 1 (MAdCAM-1)。在体外，熊去氧胆酸 (UDCA) 联合治疗导致 TNF-α 诱导的内皮 MAdCAM-1 表达呈剂量依赖性减弱。在组合的 Mdr2 ^-/- /DSS 模型中，UDCA 补充剂减轻了结肠炎的严重程度并下调了肠道 MAdCAM-1 的表达。这些发现表明胆汁酸信号转导的改变在调节胆汁淤积相关性结肠炎中的 MAdCAM-1 表达和结肠炎易感性方面具有潜在的机制作用。总之，我们的研究结果为 PSC-IBD 的发病机制和潜在治疗提供了一个新模型和新见解。