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bioRxiv · 10.64898/2026.08.21.746334

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

Villanueva, J. W.·Tsai, Y.-H.·Wu, A.·Caldwell, C.·Vallie, A.·Buerk, M.·Huang, S.·Spence, J. R.
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Abstract

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.

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Villanueva, J. W., Tsai, Y.-H., Wu, A., Caldwell, C., Vallie, A., Buerk, M., Huang, S., Spence, J. R.. 2026-08-24. Diverse Intestinal Injuries Drive Heterogeneous Transcriptional Responses and Limited Reactivation of Developmental Gene Programs in Human Enteroids. https://doi.org/10.64898/2026.08.21.746334

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