Nod2: —a key component of the microbial intestinal crypt interface

▸ Nigro G, Rossi R, Commere P-H, et al. The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration. Cell Host Microbe 15, 792–8.

Genetic factors play an important role in the pathogenesis of Crohn's disease (CD). The most significant of these implicates aberrant immune responses central to microbial sensing/signalling and mucosa-initiated effector responses. Nucleotide oligomerisation domain 2 (Nod2) is a member of the Nod-like receptor (NLR) family of intracellular microbe sensors that are strongly involved in innate immunity. Nod2 is known to be expressed by paneth cells within intestinal crypts. However due to the complexity of this site in terms of the differing cell types present and the potential interactions with microbes, there has been debate as to the precise functions of each cell type. Nigro and colleagues used cultured murine intestinal crypt organoids along with in vivo experiments to study the crypt–microbiota interface. They demonstrated that crypt stem cells constitutively express Nod2 at much higher levels than paneth cells. Stimulation with Nod2 agonist muramyl dipeptide (MDP) allowed more stem cells to survive and led to the generation of new organoids, while not impacting on epithelial proliferation. Although these effects were independent of paneth cell responses, paneth cells were seen to play a supportive and nurturing role for stem cells. In vivo, following stress conditions, the capacity of stem cells to regenerate depended on their Nod2-driven MDP response. Although the molecular mechanisms that explain this Nod2-mediated stem cell protection are not presented, the findings potentially provide some functional explanation for CD-associated Nod2 mutations. The presence of Nod2 mutations may mean that intestinal crypt stem cells cannot benefit from microbe-mediated signals, such as those seen with MDP. This would then lead to a reduction in stem cell protection and, ultimately, a delay in …