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Published on: June 24, 2020
Gasdermin D-Mediated Release of IL-33 Results in Fetal Brain Developmental Abnormalities During Maternal Colitis
Huiyang Jia1,2,3, Shukui Zhang1,2,3, Kai Ma1,2,3
1State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Insights
Maternal inflammatory bowel disease (IBD) in mothers leads to neurodevelopmental issues in offspring. This occurs through pyroptosis in the gut, causing excessive neural stem cell growth and behavioral deficits in newborns.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Maternal inflammatory bowel disease (IBD) is linked to a higher risk of autism spectrum disorder (ASD) in children.
- The underlying biological mechanisms connecting maternal IBD to offspring neurodevelopmental outcomes are not well understood.
Purpose of the Study:
- To investigate the mechanisms by which maternal IBD influences fetal brain development and offspring neurobehavior.
- To identify specific molecular pathways involved in the maternal-fetal transfer of IBD-associated risks.
Main Methods:
- Utilized a mouse model of maternal colitis to study offspring development.
- Assessed brain weight, neural stem cell (NSC) proliferation, and behavioral phenotypes in offspring.
- Analyzed Gsdmd cleavage, IL-33 levels, and LPS leakage in maternal and fetal tissues.
Main Results:
- Offspring from colitic dams displayed increased brain weight, excessive NSC proliferation, and behavioral deficits.
- Elevated Gsdmd cleavage in the maternal colon correlated with fetal brain developmental abnormalities.
- Increased IL-33 release from the maternal colonic epithelium, dependent on Gsdmd, drove NSC proliferation.
Conclusions:
- Excessive pyroptosis in the maternal colonic epithelium is a key mechanism linking maternal IBD to offspring neurodevelopmental defects.
- This process disrupts neuroimmune homeostasis in the developing offspring.
- The findings highlight the gut-brain axis in the context of maternal immune activation and offspring neurodevelopment.
Abstract:
Maternal inflammatory bowel disease (IBD) is associated with an increased incidence of autism spectrum disorder in offspring. The mechanism behind this phenomenon remains largely unknown. Here, we found that offspring from colitic dams exhibit increased brain weight. These offspring also show excessive neural stem cell (NSC) proliferation and behavioral deficits. Furthermore, Gsdmd cleavage is elevated in the colonic epithelium of colitic dams. This increase is associated with developmental abnormalities in the fetal brain. Mechanistically, excessive NSC proliferation is driven by increased IL-33 release from the maternal colonic epithelium in a Gsdmd-dependent manner. In contrast, we found no evidence that maternal luminal LPS leakage or increased fetal microglia accounts for this phenotype. Our study demonstrates that excessive pyroptosis in the maternal colonic epithelium leads to neurodevelopmental defects and disrupts neuroimmune homeostasis in the offspring.
