Recognition of commensal microbes: if innate responses are NOD in balance

Evaluation of: Petnicki-Ocwieja T, Hrncir T, Liu YJ et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc. Natl Acad. Sci. USA 106, 15813–15818 (2009).Nod2 is an intracellular pattern recognition receptor binding bacterial wall muramyl dipeptide (MDP) and inducing NF-κB activation via the Rip2 pathway. NOD2 variants have been found to be the most important genetic susceptibility factor for the development of Crohn’s disease. Nod2 is expressed in the Paneth cells of the small intestine and in antigen-presenting cells of the mucosal innate immune system. Furthermore, Nod2 is a regulator of a number of secreted antimicrobial proteins such as defensins. Subsequently, the question was raised whether Nod2 activity (or a loss of activity in Nod2 variants) influences the composition of the intestinal commensal flora. The Nod2 ligand MDP is able to induce bacterial killing when intestinal crypts are incubated with MDP and the supernatants are used for microbial killing activity assays, thus indicating that upregulation of Nod2 activity induces antimicrobial activity. In Nod2-deficient crypts, the ability to kill bacteria is reduced. Consequently, the commensal bacterial flora in Nod2-deficient mice differs from that seen in wild-type mice and, in general, is found to be increased in load. Nod2 activity influences the colonization of the mucosal wall by potentially pathogenic bacteria; the commensal flora, on the other hand, influence the expression of Nod2. This indicates a balanced system in which commensal bacteria and Nod2-mediated pathways influence each other to achieve a steady state without inflammation. The controlled balance between Nod2 and the commensal flora creates a negative-feedback loop in which the bacteria positively regulate Nod2 and associated signaling molecules, which in turn regulate the commensal flora. This pathway is likely to be one of the regulative loops that exist between the intestinal flora and the gut immune system.