The Cytosolic Bacterial Peptidoglycan Sensor Nod2 Affords Stem Cell Protection and Links Microbes to Gut Epithelial Regeneration

•The bacterial peptidoglycan motif MDP induces higher yield of intestinal organoids in vitro•Nod2 is expressed in Lgr5+ intestinal epithelial stem cells•Stem cell-expressed Nod2 is sufficient to provide cytoprotection•MDP protects stem cells from stress in vivo in a Nod2-dependent manner

SummaryThe intestinal crypt is a site of potential interactions between microbiota products, stem cells, and other cell types found in this niche, including Paneth cells, and thus offers a potential for commensal microbes to influence the host epithelium. However, the complexity of this microenvironment has been a challenge to deciphering the underlying mechanisms. We used in vitro cultured organoids of intestinal crypts from mice, reinforced with in vivo experiments, to examine the crypt-microbiota interface. We find that within the intestinal crypt, Lgr5+ stem cells constitutively express the cytosolic innate immune sensor Nod2 at levels much higher than in Paneth cells. Nod2 stimulation by its bona fide agonist, muramyl-dipeptide (MDP), a peptidoglycan motif common to all bacteria, triggers stem cell survival, which leads to a strong cytoprotection against oxidative stress-mediated cell death. Thus, gut epithelial restitution is Nod2 dependent and triggered by the presence of microbiota-derived molecules.

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