What question did this study set out to answer?

This study aims to determine the role of NOD2 signaling in accelerating fetal-like stem cell reprogramming in the intestinal epithelium during tissue repair.

February 16, 2026Open Access

Poster Session I - A32 NOD2 DRIVES REGENERATIVE FETAL-LIKE REPROGRAMMING IN THE INTESTINAL EPITHELIUM

Key Points

This study aims to determine the role of NOD2 signaling in accelerating fetal-like stem cell reprogramming in the intestinal epithelium during tissue repair.
Mice were subjected to radiation to induce inflammatory injury in the small intestine.
Transcriptional assessments were done using single-cell RNA sequencing (scRNA-Seq) and qPCR.
Histological analyses and flow cytometry were used to evaluate epithelial restitution kinetics.
In vitro models of small intestinal organoids were employed to mimic inflammatory injury scenarios.
The intestinal microbiota enhanced epithelial restitution via an inflammation-driven repair response.
Fetal-like intestinal epithelial cells expressing specific markers emerged following intestinal injury.
NOD2 was found to be expressed in fetal-like IECs, linking it to the recovery process after injury.
In vitro studies showed NOD2 stimulation led to an inflammatory gene signature and enterocyte recovery.
NOD2 deficiency increased epithelial cell death after radiation injury, whereas activation of NOD2 boosted fetal-like IEC formation.

Abstract

Abstract Background Inflammatory injury to the intestine triggers a reprogramming of the intestinal epithelium to a fetal-like state that drives rapid restoration of the epithelial barrier. Although the intestinal microbiota is a key modulator of inflammation, its role in influencing epithelial fetal-like stem cell reprogramming and consequent restitution remains unclear. Aims We aim to identify how host-microbiota interactions regulate intestinal epithelial restitution following damage. Our hypothesis is that intestinal epithelial NOD2 signaling accelerates epithelial fetal-like stem cell reprogramming to promote tissue repair following intestinal injury. Methods Mice were irradiated (IR, 12Gγ) to induce synchronous inflammatory injury to small intestine. Intestinal restitution kinetics were assessed transcriptionally (scRNA-Seq, qPCR), histologically, and by flow cytometry. In vivo observations were supported with in vitro small intestinal organoid models of inflammatory injury. Results We demonstrated that the intestinal microbiota accelerated epithelial restitution through an amplified inflammation-associated repair response that promoted the emergence of fetal-like intestinal epithelial cells (IECs) expressing Ly6a and Clu. NOD2, a sensor of bacterial peptidoglycan, whose gene has mutations associated with CD, was expressed in fetal-like IECs following injury. In ileal organoids, NOD2 stimulation potentiated an inflammatory gene signature associated with interferon (IFN) signaling, which was concomitant with enterocyte recovery. Deficiency in NOD2 exacerbated epithelial apoptosis following IR injury, while epithelial-specific NOD2 signaling increased the emergence of fetal-like IECs and consequently, increased epithelial proliferation. Conclusions These findings identify a critical role for NOD2-dependent microbial detection in regulating the expansion of fetal-like IECs following injury, which contributes to the protective effect of this microbial sensor in resolving intestinal inflammation. Funding Agencies CIHR

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