Department of Pediatrics, Affiliated Foshan Maternity & Child Healthcare Hospital, The Second School of Clinical Medicine of Southern Medical University, Foshan, 528000, People's Republic of China.
Hainan Women and Children's Medical Center, Haikou, 570206, People's Republic of China.
BMC Neurosci. 2022 Feb 14;23(1):8. doi: 10.1186/s12868-022-00693-0.
Retinoic acid-related orphan receptor alpha (RORA) has been reported to be suppressed in autistic patients and is associated with autism spectrum disorders (ASD), although the potential role and mechanism of RORA on gastrointestinal (GI) symptoms in ASD patients is still not reported. In this study, we aim to investigate the contribution of RORA to GI symptoms through a maternal diabetes-mediated autism-like mouse model.
Male offspring of diabetic dams were treated with either superoxide dismutase (SOD) mimetic MnTBAP or RORA agonist SR1078, or were crossbred with intestine epithelial cells (IEC)-specific RORA knockout (RORA) mouse. Gene expression, oxidative stress and inflammation were measured in brain tissues, peripheral blood mononuclear cells (PBMC) and IEC, and GI symptoms were evaluated. Our results showed that SOD mimetic MnTBAP completely, while RORA agonist SR1078 partly, reversed maternal diabetes-mediated oxidative stress and inflammation in the brain, PBMC and IEC, as well as GI symptoms, including intestine permeability and altered gut microbiota compositions. IEC-specific RORA deficiency either mimicked or worsened maternal diabetes-mediated GI symptoms as well as oxidative stress and inflammation in IEC, while there was little effect on maternal diabetes-mediated autism-like behaviors.
We conclude that RORA suppression contributes to maternal diabetes-mediated GI symptoms in autism-like mouse offspring, this study provides a potential therapeutical target for maternal diabetes-mediated GI symptoms in offspring through RORA activation.
维甲酸相关孤儿受体α（RORA）已被报道在自闭症患者中受到抑制，与自闭症谱系障碍（ASD）有关，尽管 RORA 对 ASD 患者胃肠道（GI）症状的潜在作用和机制尚未报道。在这项研究中，我们旨在通过母体糖尿病介导的自闭症样小鼠模型研究 RORA 对 GI 症状的贡献。
糖尿病母鼠的雄性后代接受超氧化物歧化酶（SOD）模拟物 MnTBAP 或 RORA 激动剂 SR1078 治疗，或与肠上皮细胞（IEC）特异性 RORA 敲除（RORA）小鼠杂交。在脑组织、外周血单核细胞（PBMC）和 IEC 中测量基因表达、氧化应激和炎症，并评估 GI 症状。我们的结果表明，SOD 模拟物 MnTBAP 完全，而 RORA 激动剂 SR1078 部分逆转了母体糖尿病介导的大脑、PBMC 和 IEC 中的氧化应激和炎症以及 GI 症状，包括肠道通透性和肠道微生物群组成的改变。IEC 特异性 RORA 缺失模拟或加重了母体糖尿病介导的 GI 症状以及 IEC 中的氧化应激和炎症，而对母体糖尿病介导的自闭症样行为几乎没有影响。
我们得出结论，RORA 抑制导致自闭症样小鼠后代中母体糖尿病介导的 GI 症状，本研究通过 RORA 激活为母体糖尿病介导的后代 GI 症状提供了一个潜在的治疗靶点。
