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已发表论文
母体和子代联合补充维生素 D3 通过激活 VDR 通路、抑制神经炎症和恢复代谢稳态改善孤独症样行为
Authors Li Q, Zhang J, Lyu X, Zou L, Yuan M , Yan J, Wan X , Yang Y, Xu W, Xie J
Received 5 November 2025
Accepted for publication 25 January 2026
Published 8 February 2026 Volume 2026:19 573081
DOI https://doi.org/10.2147/IJGM.S573081
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 4
Editor who approved publication: Dr Woon-Man Kung
Qingxi Li,1,2 Jing Zhang,3 Xiaohaoran Lyu,1 Le Zou,1 Mingyang Yuan,1 Jierui Yan,3 Xing Wan,1 Yuting Yang,1 Wenming Xu,3 Jiang Xie1
1Department of Pediatrics, The Third People’s Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University), College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, People’s Republic of China; 2Department of Pediatrics, The Seventh People’s Hospital of Chenghua District, Chengdu, Sichuan, People’s Republic of China; 3Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China
Correspondence: Jiang Xie, Department of Pediatrics, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, 82 Qinglong Road, Qingyang District, Chengdu, Sichuan, 61003L, People’s Republic of China, Email xiejiang@swjtu.edu.cn Wenming Xu, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China, Email xuwenming@scu.edu.cn
Background: Autism Spectrum Disorder (ASD) is a widespread neurodevelopmental disorder with no approved medications targeting its core symptoms. Based on the “dual-hit” hypothesis combining Maternal Immune Activation (MIA) and Maternal Separation (MS), this study investigated whether combined maternal and offspring vitamin D3 supplementation could ameliorate autism-like behaviors by modulating the VDR pathway, neuroinflammation, and metabolic homeostasis.
Materials and Methods: A “dual-hit” ASD mouse model was established in C57BL/6 offspring by combining maternal immune activation (MIA) with maternal separation (MS). Pregnant mice were randomly allocated into three groups (n = 5 per group): Control, Model (MIA+MS), and Intervention (MIA+MS + high vitamin D diet). Offspring in the intervention group continued to receive vitamin D supplementation post-weaning (from 3 weeks of age) until 8 weeks. Offspring behavioral tests were conducted on postnatal days 42– 56, with the litter serving as the unit of analysis. Serum, brain tissue, colon contents, and liver samples were subsequently collected and analyzed using ELISA, Western blot, LC-MS, and immunohistochemistry.
Results: Compared with controls, MIA+MS offspring exhibited significant social deficits, anxiety, and repetitive behaviors. Combined vitamin D supplementation markedly improved social preference (P< 0.0001), reduced anxiety (P< 0.001), and decreased repetitive behaviors (P < 0.05). It also upregulated VDR expression in the brain (P< 0.01), reduced neurotoxic metabolites (indoxyl sulfate, 6-phosphogluconic acid, and kynurenine pathway intermediates), lowered pro-inflammatory cytokines (IL-1β (P< 0.001), IL-6 (P< 0.001), TNF-α (P< 0.001)), and restored carnitine metabolic homeostasis by modulating TMLHE expression and function.
Conclusion: Combined maternal and offspring vitamin D3 supplementation significantly improves autism-like behaviors in a “dual-hit” ASD model. The observed protective effects may involve activation of the VDR pathway, reduction of neuroinflammation and neurotoxic metabolites, and systemic restoration of immune and metabolic homeostasis. These findings suggest the potential utility of vitamin D in ASD prevention and intervention, warranting further investigation.
Keywords: autism spectrum disorder, vitamin D, VDR, TMLHE
1Department of Pediatrics, The Third People’s Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University), College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, People’s Republic of China; 2Department of Pediatrics, The Seventh People’s Hospital of Chenghua District, Chengdu, Sichuan, People’s Republic of China; 3Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China
Correspondence: Jiang Xie, Department of Pediatrics, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, 82 Qinglong Road, Qingyang District, Chengdu, Sichuan, 61003L, People’s Republic of China, Email xiejiang@swjtu.edu.cn Wenming Xu, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China, Email xuwenming@scu.edu.cn
Background: Autism Spectrum Disorder (ASD) is a widespread neurodevelopmental disorder with no approved medications targeting its core symptoms. Based on the “dual-hit” hypothesis combining Maternal Immune Activation (MIA) and Maternal Separation (MS), this study investigated whether combined maternal and offspring vitamin D3 supplementation could ameliorate autism-like behaviors by modulating the VDR pathway, neuroinflammation, and metabolic homeostasis.
Materials and Methods: A “dual-hit” ASD mouse model was established in C57BL/6 offspring by combining maternal immune activation (MIA) with maternal separation (MS). Pregnant mice were randomly allocated into three groups (n = 5 per group): Control, Model (MIA+MS), and Intervention (MIA+MS + high vitamin D diet). Offspring in the intervention group continued to receive vitamin D supplementation post-weaning (from 3 weeks of age) until 8 weeks. Offspring behavioral tests were conducted on postnatal days 42– 56, with the litter serving as the unit of analysis. Serum, brain tissue, colon contents, and liver samples were subsequently collected and analyzed using ELISA, Western blot, LC-MS, and immunohistochemistry.
Results: Compared with controls, MIA+MS offspring exhibited significant social deficits, anxiety, and repetitive behaviors. Combined vitamin D supplementation markedly improved social preference (P< 0.0001), reduced anxiety (P< 0.001), and decreased repetitive behaviors (P < 0.05). It also upregulated VDR expression in the brain (P< 0.01), reduced neurotoxic metabolites (indoxyl sulfate, 6-phosphogluconic acid, and kynurenine pathway intermediates), lowered pro-inflammatory cytokines (IL-1β (P< 0.001), IL-6 (P< 0.001), TNF-α (P< 0.001)), and restored carnitine metabolic homeostasis by modulating TMLHE expression and function.
Conclusion: Combined maternal and offspring vitamin D3 supplementation significantly improves autism-like behaviors in a “dual-hit” ASD model. The observed protective effects may involve activation of the VDR pathway, reduction of neuroinflammation and neurotoxic metabolites, and systemic restoration of immune and metabolic homeostasis. These findings suggest the potential utility of vitamin D in ASD prevention and intervention, warranting further investigation.
Keywords: autism spectrum disorder, vitamin D, VDR, TMLHE