Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France.
Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France; Department of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
Cell Mol Gastroenterol Hepatol. 2021;12(3):1037-1060. doi: 10.1016/j.jcmgh.2021.05.001. Epub 2021 May 7.
BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) that encompass both ulcerative colitis and Crohn's disease are a major public health problem with an etiology that has not been fully elucidated. There is a need to improve disease outcomes and preventive measures by developing new effective and lasting treatments. Although polyunsaturated fatty acid metabolites play an important role in the pathogenesis of several disorders, their contribution to IBD is yet to be understood.
Polyunsaturated fatty acids metabolite profiles were established from biopsy samples obtained from Crohn's disease, ulcerative colitis, or control patients. The impact of a prostaglandin I (PGI) analog on intestinal epithelial permeability was tested in vitro using Caco-2 cells and ex vivo using human or mouse explants. In addition, mice were treated with PGI to observe dextran sulfate sodium (DSS)-induced colitis. Tight junction protein expression, subcellular location, and apoptosis were measured in the different models by immunohistochemistry and Western blotting.
A significant reduction of PGI in IBD patient biopsies was identified. PGI treatment reduced colonic inflammation, increased occludin expression, decreased caspase-3 cleavage and intestinal permeability, and prevented colitis development in DSS-induced mice. Using colonic explants from mouse and human control subjects, the staurosporine-induced increase in paracellular permeability was prevented by PGI. PGI also induced the membrane location of occludin and reduced the permeability observed in colonic biopsies from IBD patients.
The present study identified a PGI defect in the intestinal mucosa of IBD patients and demonstrated its protective role during colitis.
炎症性肠病（IBD）包括溃疡性结肠炎和克罗恩病，是一个重大的公共卫生问题，其病因尚未完全阐明。需要通过开发新的有效且持久的治疗方法来改善疾病结局和预防措施。尽管多不饱和脂肪酸代谢物在几种疾病的发病机制中发挥着重要作用，但它们对 IBD 的贡献仍有待了解。
从克罗恩病、溃疡性结肠炎或对照患者的活检样本中建立多不饱和脂肪酸代谢物图谱。使用 Caco-2 细胞和人或鼠离体组织在体外测试前列腺素 I (PGI) 类似物对肠上皮通透性的影响。此外，用 PGI 治疗小鼠以观察葡聚糖硫酸钠 (DSS) 诱导的结肠炎。通过免疫组织化学和 Western blot 在不同模型中测量紧密连接蛋白的表达、亚细胞定位和细胞凋亡。
在 IBD 患者的活检中发现 PGI 显著减少。PGI 治疗可减轻结肠炎症，增加紧密连接蛋白 occludin 的表达，减少 caspase-3 裂解和肠通透性，并预防 DSS 诱导的小鼠结肠炎的发生。使用来自人和鼠对照的结肠离体组织，PGI 可预防 staurosporine 诱导的细胞旁通透性增加。PGI 还诱导 occludin 的膜定位，并减少 IBD 患者结肠活检中观察到的通透性。
本研究在 IBD 患者的肠黏膜中发现了 PGI 缺陷，并证明了其在结肠炎中的保护作用。
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