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Nucleotide-binding Oligomerization Domain-2 ( NOD2 ) mutations are associated with an increased risk to develop Crohn’s Disease. In previous studies, we have shown that  Nod2−/−  mice manifest increased proportion of Lamina Propria (LP) CD4+ LAP+ Foxp3− regulatory cells, when compared with  Nod2 +/+ mice, while CD4+ Foxp3 + regulatory cells were not affected. Here, we investigated the  Nod2  gut microbiota, by 16S rRNA pyrosequencing, at steady state and after TNBS-colitis induction in mice reared separately or in cohousing, correlating the microbial profiles with LP regulatory T cells proportion and tissue cytokines content. We found that enrichment of  Rikenella  and  Alistipes  ( Rikenellaceae ) in  Nod2−/−  mice at 8 weeks of age reared separately was associated with increased proportion of CD4+ LAP+ Foxp3− cells and less severe TNBS-colitis. In co-housed mice the acquisition of  Rickenellaceae  by  Nod2 +/+ mice was associated with increased CD4+ LAP+ Foxp3− proportion and less severe colitis. Severe colitis was associated with enrichment of gram-negative pathobionts ( Escherichia  and  Enterococcus ), while less severe colitis with protective bacteria ( Barnesiella ,  Odoribacter  and  Clostridium IV ). Environmental factors acting on genetic background with different outcomes according to their impact on microbiota, predispose in different ways to inflammation. These results open a new scenario for therapeutic attempt to re-establish eubiosis in Inflammatory Bowel Disease patients with NOD2 polymorphisms.

Nod2 Deficiency in mice is Associated with Microbiota Variation Favouring the Expansion of mucosal CD4+ LAP+ Regulatory Cells