Gasdermin D‐Mediated Release of IL‐33 Results in Fetal Brain Developmental Abnormalities During Maternal Colitis

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.