Department of Cell Biology, Section Immunology, University Medical Center Groningen, University of Groningen, PO Box 196, 9700 AD Groningen, the Netherlands.
Diabetologia. 2010 Dec;53(12):2621-8. doi: 10.1007/s00125-010-1903-9. Epub 2010 Sep 19.
AIMS/HYPOTHESIS: Impaired intestinal barrier function is observed in type 1 diabetes patients and animal models of the disease. Exposure to diabetogenic antigens from the intestinal milieu due to a compromised intestinal barrier is considered essential for induction of the autoimmune process leading to type 1 diabetes. Since a hydrolysed casein (HC) diet prevents autoimmune diabetes onset in diabetes-prone (DP)-BioBreeding (BB) rats, we studied the role of the HC diet on intestinal barrier function and, therefore, prevention of autoimmune diabetes onset in this animal model.
DP-BB rats were fed the HC diet from weaning onwards and monitored for autoimmune diabetes development. Intestinal permeability was assessed in vivo by lactulose-mannitol test and ex vivo by measuring transepithelial electrical resistance (TEER). Levels of serum zonulin, a physiological tight junction modulator, were measured by ELISA. Ileal mRNA expression of Myo9b, Cldn1, Cldn2 and Ocln (which encode the tight junction-related proteins myosin IXb, claudin-1, claudin-2 and occludin) and Il-10, Tgf-ß (also known as Il10 and Tgfb, respectively, which encode regulatory cytokines) was analysed by quantitative PCR.
The HC diet reduced autoimmune diabetes by 50% in DP-BB rats. In DP-BB rats, prediabetic gut permeability negatively correlated with the moment of autoimmune diabetes onset. The improved intestinal barrier function that was induced by HC diet in DP-BB rats was visualised by decreasing lactulose:mannitol ratio, decreasing serum zonulin levels and increasing ileal TEER. The HC diet modified ileal mRNA expression of Myo9b, and Cldn1 and Cldn2, but left Ocln expression unaltered.
CONCLUSIONS/INTERPRETATION: Improved intestinal barrier function might be an important intermediate in the prevention of autoimmune diabetes by the HC diet in DP-BB rats. Effects on tight junctions, ileal cytokines and zonulin production might be important mechanisms for this effect.
目的/假设：1 型糖尿病患者和疾病动物模型中存在肠道屏障功能受损的现象。由于肠道屏障受损，肠道环境中的致糖尿病抗原暴露被认为是诱导导致 1 型糖尿病的自身免疫过程的关键。由于水解酪蛋白（HC）饮食可预防易感糖尿病（DP）-生物繁殖（BB）大鼠的自身免疫性糖尿病发病，我们研究了 HC 饮食对肠道屏障功能的作用，以及该饮食在这种动物模型中预防自身免疫性糖尿病发病的作用。
DP-BB 大鼠从断奶开始就喂食 HC 饮食，并监测自身免疫性糖尿病的发展情况。通过乳果糖甘露醇试验在体内评估肠道通透性，通过测量跨上皮电阻（TEER）在体外评估肠道通透性。通过 ELISA 法测量血清 zonulin（一种生理性紧密连接调节剂）的水平。通过定量 PCR 分析回肠 Myo9b、Cldn1、Cldn2 和 Ocln（编码紧密连接相关蛋白肌球蛋白 IXb、claudin-1、claudin-2 和 occludin）和 Il-10、Tgf-ß（也分别称为 Il10 和 Tgfb，编码调节细胞因子）的 mRNA 表达。
HC 饮食使 DP-BB 大鼠的自身免疫性糖尿病发病率降低了 50%。在 DP-BB 大鼠中，糖尿病前期肠道通透性与自身免疫性糖尿病发病时间呈负相关。HC 饮食在 DP-BB 大鼠中诱导的改善的肠道屏障功能通过降低乳果糖：甘露醇比值、降低血清 zonulin 水平和增加回肠 TEER 来体现。HC 饮食改变了 DP-BB 大鼠回肠 Myo9b 和 Cldn1 和 Cldn2 的 mRNA 表达，但保留了 Ocln 的表达不变。
结论/解释：改善的肠道屏障功能可能是 HC 饮食在 DP-BB 大鼠中预防自身免疫性糖尿病的一个重要中间环节。对紧密连接、回肠细胞因子和 zonulin 产生的影响可能是这种作用的重要机制。
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