Sex-Specific effects of vitamin D on autistic behavior and gastrointestinal symptoms in rats via the regulation of serotonin metabolism.

Vitamin D (VitD) deficiency (VDD) during prenatal and early brain development may be an environmental risk factor for autism spectrum disorder (ASD). While supplementation with high-dose VitD can improve core ASD symptoms, its mechanism is unclear. In addition, VitD regulates the serotonin (5-HT) pathway, which has been shown to be closely related to ASD. To explore the relationships among VitD levels, 5-HT levels and ASD symptoms, a valproic acid (VPA)-induced ASD rat model was constructed. From pregnancy to early postnatal life, VitD levels were modulated. Both VDD and ASD male rats exhibited ASD core symptoms and gastrointestinal dysfunction, with decreased 5-HT, VitD receptor (Vdr), and tryptophan hydroxylase (Tph) activity in intestinal and brain tissues. VitD supplementation alleviated ASD symptoms, improved gastrointestinal function, and increased 5-HT levels, Vdr, and Tph activity in male rats. Female rats in VDD and ASD groups showed no significant changes. Our findings suggest that 1,25(OH)2D3 enhances Tph1/2 mRNA levels via Vdr activity, increasing 5-HT levels. This study provides insights into VitD, 5-HT metabolism, and ASD, offering potential directions for subtype analysis and therapeutic interventions.