Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn’s disease (CD) have been shown to have an altered gut microbiome, which might be a reflection of inflammation itself or an effect of other parameters that contribute to the risk of the disease. Since NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan in the cytosol and stimulates the host immune response (Al Nabhani et al., PLoS Pathog 13:e1006177, 2017), it is hypothesized that NOD2 variants represent perfect candidates for influencing host-microbiome interactions. We hypothesized that NOD2 risk variants affect the microbiome composition of healthy first degree relative (FDR) of CD patients and thus potentially contribute to an altered microbiome state before disease onset. Based on this, we studied a large cohort of 1546 healthy FDR of CD patients and performed a focused analysis of the association of three major CD SNPs in the coding region of the NOD2 gene, which are known to confer a 15–40-fold increased risk of developing CD in homozygous or compound heterozygous individuals. Our results show that carriers of the C allele at rs2066845 was significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae. This result suggests that NOD2 polymorphisms contribute to fecal microbiome composition in asymptomatic individuals. Whether this modulation of the microbiome influences the future development of CD remains to be assessed.

中文翻译：

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克罗恩病患者健康一级亲属粪便中NOD2多态性与丹参科的关联

遗传分析已经确定了许多与炎症性肠病（IBD）发生风险相关的变异。在这些变异中，位于NOD2基因内的变异在所有IBD遗传风险变异中具有最高的比值比。而且，已显示患有克罗恩病（CD）的患者的肠道微生物组发生了变化，这可能是炎症本身的反映或其他有助于疾病风险的参数的影响。由于NOD2是一种细胞内模式识别受体，可感知细胞质中的细菌肽聚糖并刺激宿主免疫反应（Al Nabhani等人，PLoS Pathog 13：e1006177，2017），因此可以推测NOD2变体代表了影响宿主细胞的理想候选物。微生物组相互作用。我们假设NOD2风险变异会影响CD患者健康一级亲戚（FDR）的微生物组组成，因此可能会导致疾病发作前微生物组状态的改变。基于此，我们研究了一大批1546名CD患者的健康FDR，并集中分析了NOD2基因编码区中三个主要CD SNP的关联，已知这些SNP具有15-40倍的增加纯合子或复合杂合子个体出现CD的风险。我们的结果表明，在rs2066845处的C等位基因携带者与粪便细菌科Erysipelotrichaceae中相对丰度的增加显着相关。该结果表明NOD2多态性有助于无症状个体的粪便微生物组组成。