Background & Aims: Congenital Tufting Enteropathy (CTE) is an intractable diarrheal disease of infancy caused by mutation of Epithelial Cell Adhesion Molecule (EpCAM). The cellular and molecular basis of CTE pathology has been elusive. We hypothesized that the loss of EpCAM in CTE results in altered lineage differentiation and defects in absorptive enterocytes thereby contributing to CTE pathogenesis. Methods: Intestine from CTE mice was evaluated for specific markers by RT-qPCR, western blotting and immunostaining. Body weight, blood glucose and intestinal enzyme activity were also investigated. A CTE enteroid model was used to assess whether the decreased census of secretory cells could be rescued. Results: CTE mice exhibited alterations in brush-border function, disaccharidase activity and glucose absorption, potentially contributing to nutrient malabsorption and impaired weight gain. Altered cell differentiation in CTE mice led to decreased secretory cells and increased numbers of absorptive cells, though the absorptive enterocytes lacked key features, causing brush border malfunction. Further, treatment with Notch signaling inhibitor, DAPT, increased the numbers of major secretory cell types in CTE enteroids. Conclusions: Alterations in intestinal epithelial cell differentiation in CTE mice favor an increase in absorptive cells at the expense of secretory cells. Although the proportion of absorptive enterocytes is increased, they lack key functional properties. We conclude that these effects underlie pathogenic features of CTE such as malabsorption and diarrhea, and ultimately the failure to thrive seen in patients. The ability of DAPT to reverse aberrant differentiation suggests a possible therapeutic strategy.

中文翻译：

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在先天簇绒肠病小鼠模型中异常上皮分化有助于发病机理。

背景与目的：先天簇状肠病（CTE）是由上皮细胞粘附分子（EpCAM）突变引起的顽固性婴儿腹泻病。CTE病理学的细胞和分子基础难以捉摸。我们假设，CTE中EpCAM的缺失会导致谱系分化的改变和吸收性肠细胞的缺陷，从而导致CTE的发病机理。方法：通过RT-qPCR，western blotting和免疫染色评估CTE小鼠肠道的特异性标记。还研究了体重，血糖和肠道酶活性。使用CTE肠样模型评估是否可以挽救减少的分泌细胞普查。结果：CTE小鼠的刷毛边界功能，二糖苷酶活性和葡萄糖吸收发生变化，可能导致营养吸收不良和体重增加受损。尽管吸收性肠上皮细胞缺乏关键特征，但导致刷缘功能障碍，CTE小鼠中细胞分化的改变导致分泌细胞减少和吸收性细胞数量增加。此外，用Notch信号抑制剂DAPT治疗可增加CTE小肠中主要分泌细胞类型的数量。结论：CTE小鼠肠道上皮细胞分化的改变有利于吸收细胞的增加，但分泌细胞的损失却增加了。尽管吸收性肠上皮细胞的比例增加，但它们缺乏关键的功能特性。我们得出的结论是，这些影响是CTE的致病特征（例如吸收不良和腹泻）的基础，并最终导致患者无法壮成长。