Dextran sodium sulfate (DSS) induces necrotizing enterocolitis-like lesions in neonatal mice

Background
Necrotizing enterocolitis (NEC) is an inflammatory bowel disease of preterm human newborns with yet unresolved etiology. An established neonatal murine model for NEC employs oral administration of lipopolysaccharides (LPS) combined with hypoxia/hypothermia. In adult mice, feeding dextran sodium sulfate (DSS) represents a well-established model for experimental inflammatory bowel disease. Here we investigated the effect of DSS administration on the neonatal murine intestine in comparison with the established NEC model.
Methods
3-day-old C57BL/6J mice were either fed formula containing DSS or LPS. LPS treated animals were additionally stressed by hypoxia/hypothermia twice daily. After 72 h, mice were euthanized, their intestinal tissue harvested and analyzed by histology, qRT-PCR and flow cytometry. For comparison, adult C57BL/6J mice were fed with DSS for 8 days and examined likewise. Untreated, age matched animals served as controls.
Results
Adult mice treated with DSS exhibited colonic inflammation with significantly increased Cxcl2 mRNA expression. In contrast, tissue inflammation in neonatal mice treated with DSS or LPS plus hypoxia/hypothermia was present in colon and small intestine as well. Comparative analysis of neonatal mice revealed a significantly increased lesion size and intestinal Cxcl2 mRNA expression after DSS exposure. Whereas LPS administration mainly induced local neutrophil recruitment, DSS treated animals displayed increased monocytes/macrophages infiltration.
Conclusions
Our study demonstrates the potential of DSS to induce NEC-like lesions accompanied by a significant humoral and cellular immune response in the small and large intestine of neonatal mice. The new model therefore represents a good alternative to LPS plus hypoxia/hypothermia administration requiring no additional physical stress.

Background
坏死性小肠结肠炎（Necrotizing enterocolitis, NEC）是一种发生于人类早产新生儿的炎症性肠病，其病因至今尚未明确。目前成熟的新生小鼠NEC模型采用口服脂多糖（lipopolysaccharides, LPS）联合低氧/低体温造模。在成年小鼠中，饲喂葡聚糖硫酸钠（dextran sodium sulfate, DSS）是一种经典的实验性炎症性肠病造模方法。本研究旨在对比分析DSS给药对新生小鼠肠道的影响，并与已成熟的NEC小鼠模型进行比较。
Methods
选取3日龄C57BL/6J小鼠，分别饲喂含DSS或LPS的配方乳。接受LPS处理的小鼠每日额外施加两次低氧/低体温应激。造模72小时后，对小鼠实施安乐死，采集其肠道组织，通过组织病理学检测、实时定量聚合酶链反应（qRT-PCR）及流式细胞术进行分析。为设置平行对照，另选取成年C57BL/6J小鼠饲喂DSS 8天，随后进行相同项目的检测。以未经任何处理的同月龄小鼠作为空白对照组。
Results
饲喂DSS的成年小鼠可出现结肠炎症，且其肠道Cxcl2 mRNA表达水平显著升高。与之相比，接受DSS处理或LPS联合低氧/低体温处理的新生小鼠，其结肠与小肠均检测到组织炎症。对新生小鼠的对比分析显示，经DSS暴露处理后，小鼠肠道病变面积显著增大，且肠道Cxcl2 mRNA表达水平明显升高。LPS给药主要诱导局部中性粒细胞募集，而DSS处理组小鼠则表现出单核细胞/巨噬细胞浸润程度升高。
Conclusions
本研究证实，DSS可在新生小鼠的小肠与大肠中诱导出类似NEC的病变，并伴随显著的体液与细胞免疫应答。因此，这种新型造模方法无需额外施加物理应激，可作为LPS联合低氧/低体温造模方案的优良替代选择。