NOD2 influences intestinal microbial resilience after antibiotic perturbation. NOD2 influences intestinal resilience

Loss-of-function variants in the nucleotide-binding oligomerization domain-2 (NOD2) gene, impairing the recognition of the bacterial cell wall component muramyl-dipeptide, are associated with an increased risk for developing Crohn’s disease (CD). A disturbed control of gut microbial communities is hypothesized as a causative mechanism contributing to increased susceptibility for chronic intestinal inflammation through this genetic variation. In this study, we demonstrate the influence of NOD2 on the longitudinal dynamics of the intestinal microbiota using wild-type C57BL/6J and knock-out NOD2 mice treated with broad-spectrum antibiotics. Sequencing of the 16S rRNA gene and ITS1 region revealed that antibiotics caused significant long-term shifts in the bacterial and fungal community composition. Importantly, we demonstrate a phenotypic variation, where the NOD2 genotype impairs resilience of the bacterial gut microbiota leading to a delayed recovery. These results provide evidence of the role of NOD2 for controlling resilience of the intestinal microbiota, and suggest that uncontrolled dynamics of intestinal microbiota after perturbation could be involved in the etiology of IBD.

核苷酸结合寡聚化结构域2（nucleotide-binding oligomerization domain-2, NOD2）基因的功能丧失型变异，可削弱机体对细菌细胞壁成分胞壁酰二肽的识别能力，与克罗恩病（Crohn’s disease, CD）的发病风险升高显著相关。有假说提出，肠道微生物群落调控失衡是该遗传变异导致慢性肠道炎症易感性增加的致病机制。本研究采用经广谱抗生素处理的野生型C57BL/6J小鼠与NOD2敲除小鼠，阐明了NOD2对肠道菌群纵向动态变化的影响。通过对16S核糖体RNA基因（16S rRNA gene）与ITS1区域（ITS1 region）进行测序，结果显示抗生素可引发细菌与真菌群落组成发生显著的长期偏移。尤为关键的是，本研究发现了一处表型变异：NOD2基因型会损害肠道细菌群落的恢复弹性，导致其恢复进程延迟。上述结果证实了NOD2在调控肠道菌群恢复弹性中的作用，并提示扰动后肠道菌群的失控动态变化可能参与炎症性肠病（Inflammatory Bowel Disease, IBD）的病因发生。