Peyton Moore, 2026 MGM Distinguished Fellows Travel Award Recipient

Peyton Moore
Rawls Lab
19th Zebrafish Disease Models meeting
September 28-30, 2026

Abstract:
The intestinal epithelium performs unique digestive physiologies facilitated by distinct regional programs along its anteroposterior axis. Immediately upon intestinal wounding, immune cells are recruited while intestinal epithelial cells (IECs) from neighboring unwounded regions migrate to restore the barrier and regenerate the epithelium. The regenerated epithelium then adapts to its new regional location along the anteroposterior axis. However, it is unclear if the regenerated epithelium adopts the program of its new regional location, retains its original regional program, or adopts a metaplastic program not found in unwounded animals. To address this gap in knowledge we use zebrafish, which share conserved small intestinal development and physiology with mammals including homologous anteroposterior organization with discrete adjacent jejunal and ileal regions. We leveraged the chemogenetic NTR2.0 system to achieve selective and conditional ablation of the entire jejunal epithelium in larvae. This leads to acute inflammation, loss of barrier function, and rapid migration of adjacent ileal IECs to repopulate the jejunum. Strikingly, wounded larvae that survive to adulthood maintain this anterior relocation of the ileum and display highly abnormal coexpression of jejunal and ileal markers. Single cell RNA-sequencing of intestines from these adults confirmed abnormal coexpression of regional markers, suggesting the regenerated intestine adopts a unique metaplastic regional program. This program includes upregulation of genes involved in innate immunity and metabolism of amino acids, lipids, and bile salts. The bile salt metabolism genes are regulated by the bile salt nuclear receptor transcription factor Farnesoid X receptor (Fxr/Nr1h4), and we find Fxr is required for survival after early-life intestinal wounding. Further inspection of innate and adaptive immune cells in the regenerated intestines revealed increased expression of antigen processing and microbial response programs. Together this work indicates that regional intestinal wounding during early life can lead to imperfect regeneration and life-long metaplastic alteration of regional intestinal anatomy.