Lamm Vladimir, Huang Katherine, Deng Ruishu, Cao Siyan, Wang Miao, Soleymanjahi Saeed, Promlek Thanyarat, Rodgers Rachel, Davis Deanna, Nix Darren, Escudero Guadalupe Oliva, Xie Yan, Chen Chien-Huan, Gremida Anas, Rood Richard P, Liu Ta-Chiang, Baldridge Megan T, Deepak Parakkal, Davidson Nicholas O, Kaufman Randal J, Ciorba Matthew A
Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
medRxiv. 2025 Apr 4:2025.04.02.25322684. doi: 10.1101/2025.04.02.25322684.
In inflammatory bowel disease, protein misfolding in the endoplasmic reticulum (ER) potentiates epithelial barrier dysfunction and impairs mucosal healing. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, acts as a chemical chaperone to reduce protein aggregation and colitis severity in preclinical models. We conducted an open label trial evaluating oral TUDCA as therapy in patients with active ulcerative colitis (UC).
Patients with moderate-to-severely active UC (Mayo score ≥6, endoscopic subscore ≥1) received oral TUDCA at 1.75 or 2 g/day for 6 weeks. Exclusion criteria included known hepatic disorders or change in UC therapy within 60 days. Clinical disease activity questionnaires, endoscopy with biopsy, blood, and stool were collected at enrollment and after 6 weeks. The primary outcome measure was change in ER stress markers while safety, tolerability and change in UC disease activity were secondary outcomes.
Thirteen participants completed the study with eleven evaluable for clinical response. TUDCA was well-tolerated with transient dyspepsia being the most common side effect. Mucosal biopsies revealed significant reductions in ER stress and inflammation as well as an increase in markers of epithelial restitution. Clinical, endoscopic, and histologic disease activity were significantly improved at week 6 (mean total Mayo Score: 9 to 4.5, p<0.001).
Six weeks of oral TUDCA treatment was well-tolerated in patients with active ulcerative colitis and promoted mucosal healing, lessened ER stress, and reduced clinical disease activity. A randomized controlled trial of adjunctive TUDCA therapy in patients with UC is warranted.
ClinicalTrials.gov (NCT04114292).
在炎症性肠病中，内质网（ER）中的蛋白质错误折叠会加剧上皮屏障功能障碍并损害黏膜愈合。牛磺熊去氧胆酸（TUDCA）是一种天然存在的胆汁酸，在临床前模型中作为化学伴侣发挥作用，可减少蛋白质聚集并减轻结肠炎的严重程度。我们进行了一项开放标签试验，评估口服TUDCA作为活动性溃疡性结肠炎（UC）患者的治疗方法。
中度至重度活动性UC患者（梅奥评分≥6，内镜亚评分≥1）接受口服TUDCA，剂量为1.75或2克/天，持续6周。排除标准包括已知的肝脏疾病或在60天内UC治疗方案的改变。在入组时和6周后收集临床疾病活动问卷、内镜检查及活检、血液和粪便样本。主要结局指标是内质网应激标志物的变化，而安全性、耐受性和UC疾病活动的变化为次要结局指标。
13名参与者完成了研究，其中11名可评估临床反应。TUDCA耐受性良好，短暂性消化不良是最常见的副作用。黏膜活检显示内质网应激和炎症显著减轻，上皮修复标志物增加。在第6周时，临床、内镜和组织学疾病活动均有显著改善（平均总梅奥评分：从9降至4.5，p<0.001）。
口服TUDCA治疗6周对活动性溃疡性结肠炎患者耐受性良好，并促进了黏膜愈合，减轻了内质网应激，降低了临床疾病活动度。有必要对UC患者进行辅助TUDCA治疗的随机对照试验。
ClinicalTrials.gov（NCT04114292）
