Mechanisms of intestinal repair and inflammation

The intestine must sustain barrier integrity and immune balance despite constant microbial and chemical stress; failure of these homeostatic mechanisms contributes to sepsis, inflammatory bowel disease, and related disorders. Yet the in vivo pathways that preserve epithelial function and coordinate immune responses remain incompletely defined. To address this gap, we developed zebrafish models that enable genetic analysis and real-time imaging of intestinal injury and repair. Because classic murine injury models (e.g., DSS, TNBS, oxazolone) are not suitable for zebrafish, we have established two alternative systems. First, we established a chemical model using the NSAID glafenine, revealing that injury results from inhibition of MDR efflux pumps rather than cyclooxygenase activity, thereby implicating epithelial MDR function in homeostasis. Second, we have developed a transgene-driven, region-specific epithelial ablation model that is uncovering new adaptive mechanisms of regeneration. Extending this work to systemic immunity, we demonstrated in gnotobiotic zebrafish that microbiome colonization shapes neutrophil development and function beyond the gut, in part through microbial induction of the secreted effector Serum amyloid A in the distal intestine and liver. Together, these studies define conserved mechanisms linking epithelial homeostasis, microbial signals, and systemic inflammatory control.