萝卜硫素治疗孤独症谱系障碍的代谢组学机制研究  

Metabolomics mechanism of sulforaphane in the treatment of autism spectrum disorders

作　　者：戴思 侯艳婷 林晶晶 沈屹东[1] 程道猛[2] 吴仁容[1] 欧建君[1] Dai Si;Hou Yanting;Lin Jingjing;Shen Yidong;Cheng Daomeng;Wu Renrong;Ou Jianjun(Department of Psychiatry,National Clinical Research Center for Mental Disorders,and National Center for Mental Disorders,the Second Xiangya Hospital of Central South University,Changsha 410011,China;The Affiliated Brain Hospital of Guangzhou Medical University(Guangzhou Huiai Hospital),Guangzhou 510370,China)

机构地区：[1]中南大学湘雅二医院精神科、国家精神疾病医学中心、国家精神心理疾病临床医学研究中心,长沙410011 [2]广州医科大学附属脑科医院(广州市惠爱医院),广州510370

出　　处：《中华精神科杂志》2024年第6期337-344,共8页Chinese Journal of Psychiatry

基　　金：国家自然科学基金项目(面上项目81974217)。

摘　　要：目的:探索萝卜硫素治疗孤独症谱系障碍(autism spectrum disorder,ASD)的分子机制以及与疗效相关的代谢组学标志物并构建疗效预测模型。方法:纳入2016年8月至2019年5月就诊于中南大学湘雅二医院和广州市惠爱医院的ASD患儿40例。采用随机数字表法将患儿分为萝卜硫素治疗组(n=26)和安慰剂组(n=14)。采用OSU孤独症评定量表-DSM-Ⅳ(OSU Autism Rating Scale-DSM-Ⅳ,OARS-4)评估ASD患儿在基线、治疗第4、8和12周的临床症状变化,利用广义线性混合模型比较OARS-4得分在组别和时间上的差异。采集ASD患儿治疗前后的血浆样本,利用超高效液相色谱-高分辨质谱法进行非靶向代谢组学的检测,使用方差分析-成分分析筛选差异代谢物,并进行代谢通路分析。通过Spearman相关分析分析与萝卜硫素治疗疗效显著相关的差异代谢物,最后使用Fisher判别分析筛选疗效预测指标。结果:经12周治疗后,萝卜硫素组临床症状改善显著优于安慰剂组(F=14.11,P<0.001)。2组间共201种代谢物存在差异,主要富集于甘油磷脂代谢和初级胆汁酸生物合成通路。Spearman相关分析显示,牛磺酸、磷脂酰丝氨酸和溶血磷脂酰丝氨酸与ASD患儿症状变化呈正相关(r=0.643、0.401、0.414,P<0.05或0.001),而溶血磷脂酰乙醇胺、鞘磷脂类和甘油三酯类代谢物与症状变化呈负相关(r=-0.481~-0.392,均P<0.05),其中鞘磷脂(d35∶1)和牛磺酸进入了Fisher判别分析模型,总疗效预测的正确率为84.6%(22/26)。结论:萝卜硫素改善ASD相关临床症状的分子机制可能与细胞膜磷脂代谢有关,鞘磷脂(d35∶1)和牛磺酸可能成为预测萝卜硫素治疗ASD疗效的指标。Objective The aim of this study was to explore the molecular mechanisms of sulforaphane in the treatment of autism spectrum disorders(ASD),identify metabolomic biomarkers associated with efficacy and construct efficacy prediction models.Methods Forty children with ASD who were treated in Second Xiangya Hospital of Central South University and Guangzhou Huiai Hospital were recruited from August 2016 to May 2019.The patients were randomly allocated into sulforaphane treatment group(n=26)and placebo group(n=14).The OSU Autism Rating Scale-DSM-Ⅳ(OARS-4)was used to assess the change in clinical symptoms of children with ASD at baseline,week 4,week 8 and week 12 of treatment.A generalized linear mixed model was used to compare the differences in OARS-4 scale scores between groups and time.Plasma samples were collected from patients before and after treatment for untargeted metabolomic detection using ultra performance liquid chromatography-high resolution mass spectrometry(UPLC-HRMS).Differential metabolites were screened using ANOVA-component analysis,and metabolic pathway analysis was performed.Then,spearman correlation analysis was performed to find differential metabolites significantly associated with the efficacy of sulforaphane treatment,and finally Fisher′s discriminant analysis was used to screen for efficacy predictors.Result After 12 weeks of treatment,the clinical symptoms improvement was significantly better in the sulforaphane group than in the placebo group(F=14.11,P<0.001).There were differences in a total of 201 metabolites between the two groups,which were mainly significantly enriched in glycerophospholipid metabolism and primary bile acid biosynthesis pathways.Spearman′s correlation analysis showed that taurine,phosphatidylserine and lysophosphatidylserine were significantly positively associated with symptom changes in patients with ASD(r=0.643,0.401,0.414,P<0.05 or 0.001),while lysophosphatidylethanolamine,sphingomyelin and triglyceride metabolites were significantly negatively associated wi

关 键 词：孤独性障碍 代谢组学 生物学标记 萝卜硫素 

分 类 号：R749.94[医药卫生—神经病学与精神病学]