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Intra-abdominal Bowel Dilation in Experimental Gastroschisis Is Associated With a Modifiable Transcriptomic Program
Mary Elizabeth Guerra1, Tomohiro Arai2, Luc Joyeux1,2
1Department of Surgery, Division of Pediatric Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
Insights
Gastroschisis causes intestinal dysfunction, with gene expression changes worsening over gestation. Prenatal repair in a fetal model normalized intestinal dilation and gene expression, supporting early intervention.
Area of Science:
- Developmental biology
- Genomics
- Fetal surgery
Background:
- Gastroschisis leads to significant intestinal dysfunction and poor outcomes, often linked to intra-abdominal bowel dilation.
- While inflammation and neurovascular issues are suspected, a comprehensive understanding of gastroschisis's transcriptional landscape and disease severity is lacking.
Purpose of the Study:
- To investigate the intestinal transcriptional profiles in gastroschisis.
- To analyze the temporal changes in these profiles throughout gestation.
- To evaluate the impact of fetal intervention on these transcriptional patterns.
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 normal, gastroschisis, and prenatally repaired fetuses at mid-gestation and term.
- Conducted differential gene expression and pathway enrichment analyses, focusing on extracellular matrix (ECM), enteric nervous system (ENS), angiogenic, and inflammatory pathways.
Main Results:
- Gastroschisis intestine showed minimal transcriptional differences at mid-gestation but substantial dysregulation by term (2423 DEGs).
- Normal intestinal maturation patterns were disrupted, with early ECM pathway aberrations and later dysregulation of ENS, angiogenic, and inflammatory pathways.
- Fetal repair significantly normalized gene expression at term (29 DEGs vs. controls).
Conclusions:
- Intestinal transcriptional alterations in gastroschisis parallel progressive bowel dilation, suggesting mechanical stress contributes to injury.
- Prenatal repair effectively normalizes both bowel dilation and gene expression, highlighting a modifiable transcriptional program and supporting early fetal intervention.
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.
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