Background & Aims

Loss-of-function variants in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) impair the recognition of the bacterial cell wall component muramyl-dipeptide and are associated with an increased risk for developing Crohn’s disease. Likewise, exposure to antibiotics increases the individual risk for developing inflammatory bowel disease. Here, we studied the long-term impact of NOD2 on the ability of the gut bacterial and fungal microbiota to recover after antibiotic treatment.

Methods

Two cohorts of 20-week-old and 52-week-old wild-type (WT) C57BL/6J and NOD2 knockout (Nod2-KO) mice were treated with broad-spectrum antibiotics and fecal samples were collected to investigate temporal dynamics of the intestinal microbiota (bacteria and fungi) using 16S ribosomal RNA and internal transcribed spacer 1 sequencing. In addition, 2 sets of germ-free WT mice were colonized with either WT or Nod2-KO after antibiotic donor microbiota and the severity of intestinal inflammation was monitored in the colonized mice.

Results

Antibiotic exposure caused long-term shifts in the bacterial and fungal community composition. Genetic ablation of NOD2 was associated with delayed body weight gain after antibiotic treatment and an impaired recovery of the bacterial gut microbiota. Transfer of the postantibiotic fecal microbiota of Nod2-KO mice induced an intestinal inflammatory response in the colons of germ-free recipient mice compared with respective microbiota from WT controls based on histopathology and gene expression analyses.

Conclusions

Our data show that the bacterial sensor NOD2 contributes to intestinal microbial community composition after antibiotic treatment and may add to the explanation of how defects in the NOD2 signaling pathway are involved in the etiology of Crohn’s disease.

中文翻译：

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NOD2影响抗生素扰动后肠道菌群恢复的轨迹。

背景与目标

核苷酸结合的低聚结构域含蛋白2（NOD2）中功能丧失的变体损害了细菌细胞壁成分muramyl-depteptide的识别，并增加了患克罗恩氏病的风险。同样，接触抗生素会增加个体发展为炎症性肠病的风险。在这里，我们研究了NOD2对肠道细菌和真菌微生物群经过抗生素治疗后恢复的能力的长期影响。

方法

用广谱抗生素治疗了两个20周龄和52周龄野生型（WT）C57BL / 6J和NOD2基因敲除（Nod2- KO）小鼠，并收集了粪便样品以研究其时间动态。肠道菌群（细菌和真菌），使用16S核糖体RNA和内部转录的spacer 1测序。另外，在抗生素供体微生物群之后，用WT或Nod2- KO将2只无菌WT小鼠定植，并在定植的小鼠中监测肠道炎症的严重性。

结果

抗生素暴露导致细菌和真菌群落组成的长期变化。抗生素治疗后，NOD2的遗传消融与体重增加延迟以及细菌肠道菌群恢复受损有关。基于组织病理学和基因表达分析，与来自WT对照的相应微生物相比，Nod2- KO小鼠的抗生素后粪便微生物群的转移在无菌受体小鼠的结肠中引起肠道炎症反应。

结论

我们的数据表明，细菌传感器NOD2在抗生素治疗后有助于肠道微生物群落组成，并且可能会增加对NOD2信号通路缺陷如何与克罗恩病病因有关的解释。