NOD2 drives regenerative fetal-like reprogramming in the intestinal epithelium

Although the intestinal microbiota is a key modulator of inflammation, its role in driving epithelial fetal-like reversion and promoting restitution remains unclear. Using irradiation (IR) injury as a model for small intestinal epithelium restitution, we found that the intestinal microbiota accelerated epithelial restitution by amplifying a repair-associated inflammatory response that promoted the emergence of fetal-like intestinal epithelial cells (IECs), marked by Ly6a and Clu.

NOD2, the strongest genetic link to the development of Crohn’s disease, was expressed in fetal-like IECs following injury. Notably, stimulation of NOD2 by its peptidoglycan ligand in an ileal organoid model potentiated an inflammatory gene signature characterized by interferon (IFN) signaling, coinciding with enterocyte recovery. NOD2 deficiency exacerbated epithelial apoptosis following IR injury, while epithelial-specific NOD2 signaling promoted the emergence of fetal-like IECs and enhanced epithelial proliferation.