Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats
Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats
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DOI：
10.1073/pnas.0500178102
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发表时间：
2005-02-22
影响因子：
11.1
通讯作者：
Fasano, A
中科院分区：
文献类型：
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作者：
Watts, T;Berti, I;Fasano, A
在许多人类自身免疫性疾病中观察到肠道通透性增加，包括1型糖尿病(T1D)及其动物模型-BB-WOR糖尿病易感大鼠。我们最近描述了zonlin，一种调节细胞间紧密连接的蛋白质。本研究的目的是确定佐林依赖的肠道通透性增加是否在T1D的发病机制中起作用。在易患BB糖尿病的T1D大鼠模型中，肠腔内zonrin水平是对照BB糖尿病抵抗大鼠的35倍。Zonlin上调与小肠跨上皮电阻值降低相一致，随后产生了针对胰岛β细胞的自身抗体，这比临床上明显的T1D发病早了大约25天。在那些易患糖尿病但未发展为糖尿病的大鼠中，管腔内带蛋白和跨血管内皮细胞电阻与糖尿病抵抗动物对照组中检测到的相似。阻断zonlin受体可将T1D的累积发生率降低70%，尽管腔内zonrin持续上调。此外，治疗应答者没有血清转换为胰岛细胞抗体。综上所述，这些发现提示，佐菌灵诱导的小肠屏障功能丧失参与了BB糖尿病易感动物模型T1D的发病机制。
Increased intestinal permeability has been observed in numerous human autoimmune diseases, including type-1 diabetes (T1D) and its' animal model, the BB-wor diabetic prone rat. We have recently described zonulin, a protein that regulates intercellular tight junctions. The objective of this study was to establish whether zonulin-dependent increased intestinal permeability plays a role in the pathogenesis of T1D. In the BB diabetic-prone rat model of T1D, intestinal intraluminal zonulin levels were elevated 35-fold compared to control BB diabetic-resistant rats. Zonulin up-regulation was coincident with decreased small intestinal transepithelial electrical resistance, and was followed by the production of autoantibodies against pancreatic beta cells, which preceded the onset of clinically evident T1D by approximate to25 days. In those diabetic prone rats that did not progress to diabetes, both intraluminal zonulin and transepithelial electrical resistance were similar to those detected in diabetic-resistant animal controls. Blockade of the zonulin receptor reduced the cumulative incidence of T1D by 70%, despite the persistence of intraluminal zonulin up-regulation. Moreover, treatment responders did not seroconvert to islet cell antibodies. Combined together, these findings suggest that the zonulin-induced loss in small intestinal barrier function is involved in the pathogenesis of T1D in the BB diabetic-prone animal model.