Long-Term Use of Proton Pump Inhibitors Disrupts Intestinal Tight Junction Barrier and Exaggerates Experimental Colitis.
Long-Term Use of Proton Pump Inhibitors Disrupts Intestinal Tight Junction Barrier and Exaggerates Experimental Colitis.
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长期使用质子泵抑制剂会破坏肠道紧密连接屏障并加剧实验性结肠炎。
DOI：
10.1093/ecco-jcc/jjac168
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Nighot,Pras
中科院分区：
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作者：
Nighot,Meghali;Liao,Pei-Luan;Morris,Nathan;McCarthy,Dennis;Dharmaprakash,Viszwapriya;UllahKhan,Inam;Dalessio,Shannon;Saha,Kushal;Ganapathy,AshwinkumarSubramaniam;Wang,Alexandra;Ding,Wei;Yochum,Gregory;Koltun,Walter;Nighot,Pras
背景质子泵抑制剂（PPI）广泛用于治疗多种胃食管疾病。PPI诱导的胃内pH升高可能改变胃肠道生理学。位于顶端细胞间接触处的紧密连接[TJ]充当细胞旁屏障。TJ屏障功能障碍是炎症性肠病（IBD）的重要致病因素。最近的研究表明，PPI可能会促进IBD患者的疾病发作。PPIs在肠通透性中的作用尚不清楚。目的本研究的目的是研究PPIs对肠TJ屏障功能的影响。方法人肠上皮细胞培养和类器官模型和小鼠IBD模型的葡聚糖硫酸钠[DSS]和自发性小肠结肠炎中IL-10−/−小鼠被用来研究PPIs在肠道通透性中的作用。结果PPIs通过增加主要TJ调节剂来增加TJ屏障通透性，肌球蛋白轻链激酶[MLCK]活性和表达，以p38 MAPK依赖的方式。PPI诱导的细胞外pH增加通过p38 MAPK引起MLCK激活。在DSS结肠炎和IL-10−/−小肠结肠炎的两个独立模型中，小鼠长期PPI给药夸大了肠道TJ渗透性和疾病严重程度的增加。在MLCK−/−小鼠中，PPI对TJ屏障的破坏被阻止。人类数据库研究显示，增加与PPI使用IBD patients.ConclusionsOur研究结果表明，长期使用PPI增加肠道TJ渗透性和夸大实验性结肠炎通过MLCK表达和活性的增加。
BackgroundProton pump inhibitors [PPIs] are widely used to treat a number of gastro-oesophageal disorders. PPI-induced elevation in intragastric pH may alter gastrointestinal physiology. The tight junctions [TJs] residing at the apical intercellular contacts act as a paracellular barrier. TJ barrier dysfunction is an important pathogenic factor in inflammatory bowel disease [IBD]. Recent studies suggest that PPIs may promote disease flares in IBD patients. The role of PPIs in intestinal permeability is not clear.AimThe aim of the present study was to study the effect of PPIs on the intestinal TJ barrier function.MethodsHuman intestinal epithelial cell culture and organoid models and mouse IBD models of dextran sodium sulphate [DSS] and spontaneous enterocolitis in IL-10−/−mice were used to study the role of PPIs in intestinal permeability.ResultsPPIs increased TJ barrier permeability via an increase in a principal TJ regulator, myosin light chain kinase [MLCK] activity and expression, in a p38 MAPK-dependent manner. The PPI-induced increase in extracellular pH caused MLCK activation via p38 MAPK. Long-term PPI administration in mice exaggerated the increase in intestinal TJ permeability and disease severity in two independent models of DSS colitis and IL-10−/−enterocolitis. The TJ barrier disruption by PPIs was prevented in MLCK−/−mice. Human database studies revealed increased hospitalizations associated with PPI use in IBD patients.ConclusionsOur results suggest that long-term use of PPIs increases intestinal TJ permeability and exaggerates experimental colitis via an increase in MLCK expression and activity.