Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania.
Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania.
Am J Physiol Gastrointest Liver Physiol. 2018 Oct 1;315(4):G580-G591. doi: 10.1152/ajpgi.00135.2018. Epub 2018 Jun 28.
Infants with congenital diarrheal disorders caused by enteroendocrine cell dysgenesis, or the loss of intestinal endocrine cells, causes severe malabsorptive diarrhea, though the mechanism is not fully understood. The transcription factor "aristaless-related homeobox" (Arx) is specifically expressed in intestinal endocrine cells. This study seeks to characterize the early malabsorptive phenotype of mice deficient for Arx using cell-type specific gene ablation in Villin-Cre; Arx ( Arx) mice. In neonatal mice, the loss of intestinal Arx caused the loss of intestinal hormones, such as cholecystokinin, secretin, neurotensin, glucose-dependent insulinotropic peptide, glucagon-like peptide (GLP)-1 and GLP-2 but also upregulation of somatostatin. Arx mice exhibited steatorrhea with the loss of lipid transport in duodenal enterocytes, upregulation of lysozyme-positive Paneth cells, and a secondary increase in antimicrobial peptides, specifically Reg3β. When the epithelium from Arx mice was cultured ex vivo into enteroids, however, the Reg3β upregulation was lost under the sterile conditions. Thus, Arx is required for the appropriate lineage allocation of multiple enteroendocrine subtypes. We concluded that altered hormonal signaling caused by Arx deficiency results in lipid malabsorption, premature Paneth cell differentiation, and an inflammatory response, including neutrophilic infiltrates and a microbiota-triggered upregulation of Reg3β. NEW & NOTEWORTHY The enteroendocrine transcription factor aristaless-related homeobox (Arx) plays a key role in lineage specification. Changes in hormonal expression mediated by Arx lead to lipid malabsorption and premature Paneth cell development. Furthermore, global profiling of whole intestine from Arx-deficient mice revealed significant upregulation of antimicrobial peptides. This antimicrobial response in Arx-deficient animals is lost under sterile culture conditions of enteroids.
先天性腹泻疾病患儿的肠内分泌细胞发育不良或肠内分泌细胞缺失，导致严重的吸收不良性腹泻，但其发病机制尚不完全清楚。转录因子“aristaless 相关同源盒”（Arx）特异性表达于肠内分泌细胞。本研究旨在利用肠上皮细胞特异性基因敲除 Villin-Cre；Arx（Arx）小鼠，来研究 Arx 缺失导致的早期吸收不良表型。在新生小鼠中，肠道 Arx 的缺失导致了肠道激素如胆囊收缩素、胰泌素、神经降压素、葡萄糖依赖性胰岛素释放肽、胰高血糖素样肽-1 和胰高血糖素样肽-2 的缺失，同时也导致了生长抑素的上调。Arx 小鼠表现出脂肪泻，十二指肠肠上皮细胞的脂质转运丢失，溶菌酶阳性 Paneth 细胞上调，以及抗菌肽，特别是 Reg3β 的继发性增加。然而，当 Arx 小鼠的上皮细胞在体外培养成肠类器官时，在无菌条件下，Reg3β 的上调丢失了。因此，Arx 对于多种肠内分泌细胞亚型的适当谱系分配是必需的。我们得出结论，Arx 缺乏导致的激素信号改变导致脂质吸收不良、Paneth 细胞过早分化以及炎症反应，包括中性粒细胞浸润和微生物触发的 Reg3β 上调。新的和值得注意的是肠内分泌转录因子 aristaless 相关同源盒（Arx）在谱系特化中发挥关键作用。由 Arx 介导的激素表达变化导致脂质吸收不良和 Paneth 细胞发育过早。此外，对 Arx 缺陷小鼠整个肠道的全基因组分析显示抗菌肽显著上调。在肠类器官的无菌培养条件下，Arx 缺陷动物的这种抗菌反应消失了。
