Intra-abdominal Bowel Dilation in Experimental Gastroschisis Is Associated With a Modifiable Transcriptomic Program of Intestinal Dysfunction

OBJECTIVE: To characterize intestinal transcriptional profiles in gastroschisis, their temporal evolution, and response to fetal intervention. SUMMARY BACKGROUND DATA: Gastroschisis causes significant intestinal dysfunction, with intra-abdominal bowel dilation clinically shown to correlate with worse outcomes. Although inflammation and neurovascular impairment have been implicated, genome-wide transcriptional characterization of disease severity remains lacking. METHODS: Using a fetal-ovine model of complex gastroschisis, in which all gastroschisis animals demonstrated significant intra-abdominal bowel dilation at term, bulk RNA sequencing was performed on proximal small intestinal tissue from mid-gestation and term fetuses across 3 groups: normal, gastroschisis, and prenatally repaired gastroschisis. Differential gene expression (FDR≤0.05, |log2 fold change| ≥ 1.5) and pathway enrichment analyses were performed, with targeted interrogation of extracellular matrix (ECM), enteric nervous system (ENS), angiogenic, and inflammatory pathways. RESULTS: At mid-gestation, gastroschisis intestine showed minimal transcriptional differences (150 differentially expressed genes [DEGs]) and some bowel dilation. By term, dysregulation was substantial (2423 DEGs) alongside significant dilation. Normal ontogenetic intestinal maturation patterns were altered, with fewer expected developmental gene changes and discordant pathway regulation. ECM pathway aberrations emerged early and persisted, whereas ENS, angiogenic, and inflammatory pathways were only dysregulated at term. Fetal repair was associated with normalization of gene expression at term (29 DEGs vs. controls). CONCLUSIONS: Intestinal transcriptional changes in experimental gastroschisis parallel progressive bowel dilation, consistent with a mechanical stress contribution to intestinal injury. Prenatal repair normalizes both dilation and gene expression, indicating a dynamic and potentially modifiable transcriptional program that supports the rationale for early fetal intervention.