Maternal vitamin A deficiency programs offspring visceral hypersensitivity through RARβ-COX-2/PGE2 signaling.

Visceral hypersensitivity (VH) is regarded as a core pathophysiological mechanism in irritable bowel syndrome (IBS). Although maternal vitamin A deficiency (VAD) during pregnancy has been linked to gastrointestinal dysfunction in offspring, its specific role in VH and the underlying mechanisms are not yet fully understood. This study aimed to explore the effects of maternal VAD on the development of VH in offspring and to assess the potential therapeutic role of postnatal vitamin A supplementation (VAS). Using a maternal VAD rat model, we observed that maternal VAD was associated with the development of VH in offspring, along with downregulated intestinal retinoic acid receptor β (RARβ) and activation of the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2)/prostaglandin E2 receptor EP2 (EP2) axis in enteric glial cells (EGCs). These changes could be partially reversed by postnatal VAS. In a NaB-induced IBS model, VA intervention appeared to alleviate VH, gastrointestinal dysmotility, and diarrhea-like symptoms, possibly through suppression of the TLR4/MyD88/NF-κB pathway. In vitro experiments indicated that retinoic acid (RA), the active metabolite of VA, may inhibit TLR4/MyD88/NF-κB activation in EGCs, leading to reduced COX-2 expression and PGE2 synthesis. These findings suggest a nutritionally regulated mechanism linking maternal VA status to offspring VH and raise the possibility that the RA-RARβ axis may serve as a potential target for early nutritional interventions in IBS.