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

The murine intestine reactivates developmental gene programs following various forms of damage in vivo and in vitro; however, injury response mechanisms used by the human intestine remain unclear. Using adult human small intestinal epithelium-only organoids ("enteroids"), we characterized the early response to eight injury conditions and injury-associated signaling pathways (P53, PGE2, YAP, TGFB) to interrogate whether human developmental genes were activated. P53 activation and decreased proliferation were common features across treatments. Most (7/8) injuries did not activate human development genes. Butyrate is a notable exception given it inhibited P53 and promoted a human developmental transcriptional signature. We observe that P53 induces a human adult gene signature while TGFB and YAP promote a developmental signature. Together our data characterizes various transcriptional responses to injury, supports injury-associated signaling pathways as regulators of human adult and developmental genes, and highlights how our data can be mined to predict injury-specific interventions for epithelial protection.