从脑肠轴探讨维生素A改善孤独症临床症状的作用及机制

Autism spectrum disorder (ASD) is a kind of pervasive developmental disorder, and has currently become a common cause of mental disability in children. However, so far there is no exact treatment for the core behavioral symptoms. Some studies suggest that ASD children have a wide range of the dietary preferences problem, and there were 61% ASD children with at least one gastrointestinal symptom. Our previous studies found that 65% of ASD chilsren accompanied with intestinal problem, and the level of serum retinal in ASD children was significantly decreased compared with that of health children. VA supplementation alleviated the intestinal symptoms and reduced level of serum 5-HT in children with ASD, but also decreased score of CARS and attenuated behavioral symptoms in children suffered with ASD. Therefore, whether would we take the results of our previous NSFC project- VA significant enhancing intestinal barrier function to intervention in ASD chidlren with VA, which can achieve ASD core behavior symptoms via the brain-gut axis regulation system? The present project will take improvement of intestinal barrier function as a key ponit, to clarify the role of VA in improving gastrointestinal problems in the children with ASD to alleviate their core behavioral symptoms through clinical investigation and analysis. And then combining animal model with cell level in vitro studies are used to reveal the possible molecular mechanisms and target of VA improving clinical symptoms of ASD children. The project will provide a new clinical treatment for children with gastrointestinal ASD.

孤独症谱系障碍（ASD）是一种广泛性发育障碍类疾病，目前已成为儿童精神类致残的常见疾病。目前尚无针对ASD核心症状的确切治疗方法。有研究表明ASD儿童广泛存在饮食偏好，且61% ASD儿童伴有至少一种胃肠道症状。我们前期研究发现65%的ASD儿童伴有肠道症状，且其血清VA水平明显低于正常儿童， VA补充后可缓解ASD儿童的肠道症状，减少血清5-HT含量，而且还降低ASD儿童CARS得分，减轻ASD行为症状。那么我们能否利用前一个NSFC研究结果-VA显著增强肠道屏障功能特性，对ASD儿童进行VA干预，进而通过脑肠轴系统达到治疗ASD行为呢？本项目拟以改善肠道屏障功能为切入点，通过临床调查分析阐明补充VA改善ASD儿童胃肠道问题缓解其核心行为症状的作用，再利用动物模型及体外细胞水平研究，揭示补充VA改善ASD临床症状的可能分子机制及作用靶点，为临床治疗胃肠型ASD儿童提供一条新的治疗方案。

孤独症谱系障碍（ASD）是一种广泛性神经发育障碍疾病，且其伴发胃肠道问题比例较高。本项目首先在14省市多中心的1222例ASD儿童流行病学调查发现，有53.60%的ASD儿童共患胃肠问题，其中40.10%共患便秘，比例最高，且ASD共患便秘儿童的ABC及SRS得分均明显增高；同时发现便秘型ASD儿童的血清中VA水平显著降低，且与便秘呈负相关。ASD及TD儿童粪便非靶向代谢组学分析表明两组在氨基酸（特别是色氨酸）代谢及维生素代谢通路中均存在显著差异，进一步提示共患胃肠问题ASD儿童的VA营养水平存在密切关联。其次，在不同VA营养水平、有无胃肠问题的小样本ASD相关性分析基础上，我们采用了两种不同VA干预方式（RNI-VAS和WD-VAS），WD-VAS补充方式不仅可以显著提升ASD儿童血清视黄醇水平，而且还可以提高OXT水平，降低SRS得分。第三，我们在VPA诱导的ASD样大鼠模型基础上，叠加了VA缺乏模型，发现孕期开始的VA缺乏不仅会加重ASD样行为，而且还会降低子代肠神经功能；进一步研究表明孕期开始的VA缺乏下调RAR受体表达水平，降低了子代肠道胆碱能及氮能神经元发育，进而减弱肠神经的功能。第四，拓展研究方面，粪菌移植ASD儿童的移植鼠中，其盲肠、血浆、皮层均富集到色氨酸和5-HT代谢通路，且与ASD儿童粪便中差异代谢物一致。而不同VA营养水平（VAN、VAD和VAS）ASD儿童的粪菌移植后的RNAseq检测，多种数据库均富集到了神经相关信号通路的差异，提示VA与ASD肠脑轴相关，为后续深入研究奠定了夯实的实验基础。该项研究已发表SCI论文15篇，中文4篇，参加国际国内学术大会近20人次，其中分组报告2人次，优秀论文1人次；培养毕业研究生6名，其中博士研究生4名，硕士研究生2名。