NOD2 influences trajectories of intestinal microbiota recovery after antibiotic perturbation.

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 (CD). Likewise, exposure to antibiotics increases the individual risk for developing inflammatory bowel disease (IBD). 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- and 52-week-old wild-type (WT) C57BL/6J and NOD2 knock-out (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 rRNA and ITS1 sequencing. In addition, two sets of germ-free (GF) WT mice were colonized with either WT or Nod2-KO post-antibiotic donor microbiota and the severity of intestinal inflammation was monitored in the colonized mice. RESULTS:Antibiotics 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 post-antibiotic fecal microbiota of Nod2-KO mice induced an intestinal inflammatory response in the colon of GF recipient mice compared to respective microbiota from WT controls based on histopathology and gene expression analyses. CONCLUSIONS:Our data illustrate 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 CD.