Diverse Intestinal Injuries Drive Heterogeneous Transcriptional Responses and Limited Reactivation of Developmental Gene Programs in Human Enteroids

In a study examining the effects of diverse intestinal injuries on human enteroids, researchers discovered heterogeneous transcriptional responses and limited reactivation of developmental gene programs. The murine intestine is known to reactivate developmental genes following various forms of damage, but the response mechanisms of the human intestine are still unclear.

To address this, the researchers used adult human small intestinal epithelium-only organoids, also known as enteroids, to investigate the early response to eight injury conditions and injury-associated signaling pathways, including P53, PGE2, YAP, and TGFB.

The findings revealed that P53 activation and decreased proliferation were common features across all treatments. Most of the injuries, seven out of eight, did not activate human developmental genes. However, one notable exception was the use of butyrate, which inhibited P53 and promoted a human developmental transcriptional signature. The researchers observed that P53 induces a human adult gene signature, while TGFB and YAP promote a developmental signature.

These results characterize the various transcriptional responses to injury and demonstrate that injury-associated signaling pathways play a crucial role in regulating human adult and developmental genes. The study highlights the potential of using enteroids to predict injury-specific interventions for epithelial protection.