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Published on: November 15, 2019
Intra-Abdominal Bowel Dilation in Experimental Gastroschisis is Associated with a Modifiable Transcriptomic Program
Insights
Gastroschisis causes intestinal dysfunction and dilation, with gene expression changes worsening over time. Prenatal repair in a fetal model normalized bowel dilation and gene expression, supporting early intervention.
Area of Science:
- Fetal surgery
- Genomics
- Neonatal surgery
Background:
- Gastroschisis leads to significant intestinal dysfunction and poor outcomes, often linked to intra-abdominal bowel dilation.
- Genome-wide transcriptional profiles in gastroschisis, especially concerning disease severity, are not well understood.
- Existing research implicates inflammation and neurovascular impairment, but lacks comprehensive gene expression data.
Purpose of the Study:
- To characterize intestinal transcriptional profiles in gastroschisis.
- To analyze the temporal evolution of these transcriptional changes.
- To assess the impact of fetal intervention on gastroschisis-associated intestinal dysfunction.
Main Methods:
- Utilized a fetal ovine model of complex gastroschisis with significant intra-abdominal bowel dilation.
- Performed bulk RNA sequencing on proximal small intestinal tissue from mid-gestation and term fetuses.
- Analyzed differential gene expression and pathway enrichment, focusing on ECM, ENS, angiogenic, and inflammatory pathways.
Main Results:
- Gastroschisis intestine showed minimal transcriptional differences at mid-gestation but substantial dysregulation (2,423 DEGs) by term, paralleling progressive bowel dilation.
- Normal intestinal maturation patterns were altered, with early ECM pathway aberrations and later dysregulation of ENS, angiogenic, and inflammatory pathways.
- Prenatal repair significantly normalized gene expression at term (29 DEGs vs. controls), alongside reduced bowel dilation.
Conclusions:
- Intestinal transcriptional changes in gastroschisis correlate with progressive bowel dilation, suggesting a role for mechanical stress in intestinal injury.
- Prenatal repair effectively normalizes both intestinal dilation and associated gene expression patterns.
- These findings support the rationale for early fetal intervention in gastroschisis to modify the transcriptional program and improve outcomes.
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. While 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 three groups: normal, gastroschisis, and prenatally repaired gastroschisis. Differential gene expression (FDR ≤ .05, |log 2 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 (2,423 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, while 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).
Conclusion:
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.
Mini Abstract:
In a fetal ovine model, progressive bowel dilation in gastroschisis parallels transcriptomic dysregulation of ECM remodeling, neurovascular impairment, and inflammation which is normalized by prenatal repair.
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