Table 1.

The NOD2 gene mutation and its impact on the microbiota in IBD.

	Genes Studied	Conclusions of the Study
Animal studies	NOD2 gene	In mouse models of colitis, the NOD2 gene mutation is associated with dysbiosis, which does not cause changes in mucosal or immune tissue [36]. Mice with NOD2 gene mutation show inefficient recognition and clearance of bacterial pathogens. They have been observed to have statistically significant increases in Porphyromonadaceae (Bacteroidetes), Enterobacteriaceae, Sutterellaceae (Proteobacteria) and Coriobacteriaceae (Actinobacteria) [37].
Research involving humans	NOD2 gene	In 474 patients with IBD, there was an association between the dose of NOD2 risk alleles, consisting of rs104895431, rs104895467, rs2066844, rs2066845, rs5743277, rs5743293, and the increased relative abundance of Enterobacteriaceae. The association may be independent of the disease and may play a role in the pathogenesis only in individuals with other risk factors [38]. Carriers of the C allele at rs2066845 were significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae. NOD2 polymorphisms contribute to the composition of the fecal microbiome in asymptomatic individuals. It is unknown whether this modulation of the microbiome affects the future development of CD [39]. An association has been confirmed between the ileal phenotype of CD-affected individuals with a reduced relative abundance of the Ruminococcaceae family and an increased relative abundance of the Actinobacteria group and the Firmicutes/Bacillus class [40]. In a cohort of 1,514 healthy individuals, the NOD2 locus was associated with the enterobactin biosynthesis pathway, which is highly correlated with the abundance of E. coli. The authors suggested that enterobactin produced by E. coli inhibits myeloperoxidase (MPO), a bactericidal host enzyme, thus providing a survival advantage that allows E. coli to bypass the innate host immune response in inflammatory bowel disease [41]. An increase in anaerobic bacteria from the Enterobacteriaceae family has been shown in the microbiota of CD patients compared to controls without IBD [42]. The ATG16L1 (Autophagy-related 16-like 1 protein) and NOD2 genes probably played an essential role in the beneficial immunomodulatory properties of Bacteroides fragilis, which protects mice from experimental colitis [43]. Candida albicans was shown to be the most abundant species in CD-positive patients, as well as in those with CD-associated NOD2 mutations. More studies have been required to determine whether Candida is an intestinal commensal or a pathogen in patients with CD [44].