Host-microbiota interactions: effects of Nod2 deficiency

The mucosal immune response to the increase in intestinal permeability is a condition commonly thought to promote a local inflammatory response to the increased load of systemic bacterial components of the microbiota. The increase in intestinal permeability is in fact considered a condition contributing to the pathogenesis of inflammatory bowel diseases (Ulcerative colitis and Crohn's disease), and the polymorphism of NOD2 gene, considered a risk factor for the development of Crohn's disease, is indeed associated with the presence of increased intestinal permeability, not only in patients, but also in healthy relatives bearing the same gene polymorphism. In these studies we evaluated the effect of increased intestinal permeability on local immune-response. For this purpose we developed a murine model in which the increase in intestinal permeability was achieved by intrarectal administration of agents capable of altering the epithelial barrier in the presence or in the absence of concomitant epithelial damage. We preliminary assessed the effects of increased intestinal permeability in control mice and then we applied the information obtained to mice KO for Nod2 gene. The results demonstrate that the increase in intestinal permeability, both in the control mice than in KO mice is associated with with a microbiota-dependent expansion of regulatory cells. These regulatory cells belong to a particular subset of Foxp3 neg regulatory cells expressing TGF-beta on the surface linked to its latency associated peptide (LAP + ). These cells are indeed regulatory cells in that they are able, in adoptive transfer experiments, to prevent TNBS colitis in recipient mice and are increased in homeostatic condition in Nod2-/- mice, explaining the less severe TNBS colitis observed in Nod2-/- mice. Furthermore, their increase is not only dependent on the presence of microbiota, but also by its qualitative composition as demonstrated by co-housing experiments in which Nod2-/- mice show the same TNBS colitis severity comparable to the one observed in Nod2+/+ mice after co-housing with Nod2-/- mice. These studies clearly show that the acute and chronic increase in intestinal permeability is associated with increased regulatory immune-response. This response is characterized by the increase of a particular subset of regulatory cells (CD4+ LAP+ regulatory cells) which is largely affected by the presence and composition of microbiota. They also suggest that in patients with NOD2 polymorphism, other factors intervene in determining the onset of disease.