肠道微生物与自闭症谱系障碍

自闭症谱系障碍(autism spectrum disorder,ASD)是一种精神致残的重要疾病,严重影响儿童身心健康,给家庭和社会带来沉重的负担。患者常出现不同程度胃肠道症状和伴有肠道微生物组成的改变,以此为切入点,近年越来越多的研究聚焦于ASD和肠道微生物的关系上。本文介绍了肠道微生物组成、肠―脑轴及ASD患者肠道微生物的主要变化,并从多个方面阐述了ASD与肠道微生物的关系。     

孤独症谱系障碍儿童早期神经发育水平和智能特征分析

目的:探讨孤独症谱系障碍(Autism spectrum disorder,ASD)儿童早期神经发育水平及智能分区特征,为提高ASD的早期识别和诊断提供理论依据.方法:运用Gesell发育评估量表对18月龄至48月龄以内的27例ASD患儿和30例发育迟缓(Mental retardation,MR)患儿的发育商(Dev...     

Mutations in the gene encoding CADM1 are associated with autism spectrum disorder

The unified idea on the molecular pathogenesis of Autism Spectrum Disorder (ASD) is still unknown although mutations in genes encoding neuroligins and SHANK3 have been shown in a small part of the patients. RA175/SynCAM1/CADM1(CADM1), a member of immunoglobulin superfamily, is another synaptic cell adhesion molecule. To clarify the idea that impaired synaptogenesis underlies the pathogenesis of ASD, we examined the relationship between mutations in the CADM1 gene and ASD. We found two missense mutations, C739A(H246N) and A755C(Y251S), in the CADM1 gene of male Caucasian ASD patients and their family members. Both mutations were located in the third immunoglobulin domain, which is essential for trans-active interaction. The mutated CADM1 exhibited less amount of high molecular weight with the matured oligosaccharide, defective trafficking to the cell surface, and more susceptibility to the cleavage and or degradation. Our findings provide key support for the unified idea that impaired synaptogenesis underlies the pathogenesis of ASD.     

Radial cytoarchitecture and patterns of cortical connectivity in autism

To explain the pattern of preserved and superior abilities found in autism spectrum disorders, a hypothesis has emerged, which assumes that there is a developmental bias towards the formation of short-range connections. This would result in excessive activity and overconnectivity within susceptible local networks. These networks might become partially isolated and acquire novel functional properties. In turn, this would affect the formation of long-range circuits and systems governing top-down control and integration. Despite many tantalizing clues, mechanisms relating pathogenesis and altered cell function to the ‘disconnection’ of integrative and focal activity remain obscure. However, recent post-mortem studies of brains of individuals with autism have shown characteristic differences in the morphometry of radial cell minicolumns, which add credence to the connectivity hypothesis.     

科尔沁沙地不同种源元宝枫功能性状变异及其环境驱动因子

【目的】研究不同种源地木本油料植物功能性状变异及其环境驱动因子,对其核心育种群体构建和良种选育具有重要的意义。【方法】文章以分布于科尔沁沙地周围的乌丹塔拉、松树山、代钦塔拉3个中国现存最大的元宝枫天然林为研究对象,测定其叶片和种子功能性状、土壤理化性质,同时结合气候数据,采用方差分析、相关性分析、RDA排序分析以及构建PLS-SEM模型等方法,研究内蒙地区不同种源地元宝枫功能性状的变异程度以及性状与环境之间的相关性,探究元宝枫功能性状与环境因子之间的关系。【结果】结果表明：（1）3地元宝枫各个功能性状的差异性明显,各性状的变异系数表现为比叶面积（SLA）>油酸含量（OA）>种子长宽比（ZC∶ZK）>碳氮比（C∶N）>神经酸含量（NA）>种子油脂含量（OC）>亚油酸（LOA）>叶片碳含量（LCC）,种源间变异系数范围为3.81%～19.51%,种源内变异系数范围为3.60%～14.64%,种源间变异大于种源内变异;（2）3个种源地中,代钦塔拉地区油脂、亚油酸含量最高,乌旦塔拉地区的神经酸含量最高;（3）相关性结果显示,元宝枫功能性状与环境因子间存在显著的相关关系;（4）RDA分析结果显示,环境因子可以解释24.1%的元宝枫功能性状变异,土壤有机质（SOM）和气温季节性变异系数（BIO-4）为主导生态因子,气象和土壤共同决定元宝枫功能性状的变异,且气象因子起主导作用;（5）PLS-SEM模型显示,元宝枫叶片及种子性状与油脂指标之间的路径系数较小,协同作用不显著,年均温是元宝枫油脂相关指标的主要影响因子,且其与油脂相关性表现出负相关,即较低的温度有利于元宝枫种实油脂的积累。【结论】研究表明,气象是驱动元宝枫功能性状变异的主导环境因子,且气温是决定元宝枫种实油脂含量的关键因子,该研究结果可为油用元宝枫定向培育提供理论基础。     

不同碳水化合物对孤独症患儿肠道菌群体外发酵产生短链脂肪酸的影响

目的 探究孤独症谱系障碍（autism spectrum disorder,ASD）患儿与健康儿童的肠道菌群利用不同碳水化合物产生短链脂肪酸（short-chain fatty acids,SCFAs）的差异。方法 前瞻性病例对照研究。选择2016年12月至2017年10月解放军总医院儿科门诊的15例ASD患儿为研究对象,并匹配15名健康儿童为对照组;收集研究对象粪便,稀释成10%悬浊液,然后分别接种到以乳果糖（LAU）、乳糖（LAT）、棉籽糖（RAF）、低聚半乳糖（GOS）、低聚异麦芽糖（IMO）和低聚甘露糖（MOS）为单碳源的肠道微生态小型模拟发酵系统中批量发酵24 h,检测SCFAs浓度、底物降解率和产气气压。结果 ASD组患儿粪便SCFAs浓度与对照组差异无统计学意义,在YCFA（无碳源对照培养基,蛋白发酵为主）培养基发酵后总SCFAs、乙酸和丙酸均低于对照组,差异有统计学意义（Z=-2.509、-2.509、-3.007,P=0.011、0.011、0.002）;在添加LAT、RAF、GOS、IMO和MOS的培养基发酵后总SCFAs浓度显著高于对照组,差异有统计学意义（Z=2.385、2.344、2.675、2.344、2.302,P=0.016、0.019、0.007、0.019、0.021）,而含LAU的培养基发酵后,两组研究对象总SCFAs浓度比较差异无统计学意义。结论 ASD患儿肠道菌群利用蛋白发酵产SCFAs能力显著低于健康对照,利用碳水化合物产SCFAs能力显著高于健康对照。6种发酵底物中,乳果糖是最适合ASD患儿的碳水化合物,有改善ASD患儿肠道菌群产SCFAs的潜力。     

孤独症谱系障碍小鼠肠道屏障功能研究

研究孤独症谱系障碍（ASD）模型小鼠肠道屏障功能及肠道动力的改变情况,为微生物−肠−脑轴在ASD发病中的作用提供理论基础。

C57bl/6J雌鼠和雄鼠交配,丙戊酸钠（VPA）诱导的ASD模型及对照组小鼠分别于孕12.5天皮下注射VPA或生理盐水。BTBR模型组为BTBR T⁺Itpr3^tf/J小鼠交配所产幼雄鼠。各组小鼠出生3周后,每窝随机选择2只雄鼠,各组5窝,共计10只,纳入相应组别。各组小鼠6周开始按如下顺序进行行为学检测：旷场实验、埋珠实验、三室社交实验、发声检测和自我梳理实验,各检测间隔5 d。评估小鼠肠道动力（粪便含水量及小肠推进率）和小鼠肠道屏障功能：FITC-葡聚糖灌胃后光谱仪检测小鼠血清中FITC-葡聚糖水平;Western blot检测各组小鼠结肠TREK1,CLDN1,CLDN3,OCLN及ZO1蛋白的表达;qPCR检测各组小鼠结肠Il6,Tnf-α和Ifn-γ mRNA的表达情况。

行为学检测结果显示：与对照组相比,BTBR组和VPA组小鼠穿越旷场中间区次数和停留时间显著降低（P＜0.05）;于目标小鼠侧室的停留时间率显著降低（P＜0.05）;埋珠率和自我梳理时间均显著升高（P＜0.05）;在（20～50）kHz和（50～100）kHz频率范围的发声次数及持续时间均显著降低（P＜0.05）。与对照组相比,BTBR组小鼠粪便含水量显著降低（P＜0.05）,而VPA组小鼠的差异无统计学意义（P＞0.05）。BTBR组和VPA组小鼠小肠推进率与对照组相比无差异（P＞0.05）。此外,与对照组相比,BTBR组和VPA组小鼠血清FITC−葡聚糖水平均升高,结肠TREK1,CLDN1,CLDN3,OCLD蛋白的表达水平降低,结肠Il6,Tnf-α和Ifn-γ mRNA的表达显著升高,差异均具有统计学意义（P＜0.05）,而ZO1的表达差异无统计学意义（P＞0.05）。

鉴于BTBR及VPA模型小鼠均表现出与ASD患者类似的广泛行为障碍,上述模型可作为ASD研究的可靠参考。与此同时,两种ASD小鼠模型均出现肠道紧密连接蛋白表达下调,肠道屏障通透性和促炎细胞因子水平的增高,表明微生物−肠−脑轴在ASD发病中扮演重要角色,且对治疗ASD症状具有潜在临床价值。

     

Mining the 3′UTR of Autism-implicated Genes for SNPs Perturbing MicroRNA Regulation

Autism spectrum disorder(ASD) refers to a group of childhood neurodevelopmental disorders with polygenic etiology. The expression of many genes implicated in ASD is tightly regulated by various factors including microRNAs(miRNAs), a class of noncoding RNAs 22 nucleotides in length that function to suppress translation by pairing with ‘miRNA recognition elements'(MREs) present in the 30untranslated region(30UTR) of target mRNAs. This emphasizes the role played by miRNAs in regulating neurogenesis, brain development and differentiation and hence any perturbations in this regulatory mechanism might affect these processes as well. Recently, single nucleotide polymorphisms(SNPs) present within 30UTRs of mRNAs have been shown to modulate existing MREs or even create new MREs. Therefore, we hypothesized that SNPs perturbing miRNA-mediated gene regulation might lead to aberrant expression of autism-implicated genes, thus resulting in disease predisposition or pathogenesis in at least a subpopulation of ASD individuals. We developed a systematic computational pipeline that integrates data from well-established databases. By following a stringent selection criterion, we identified 9 MRE-modulating SNPs and another 12 MRE-creating SNPs in the 30UTR of autism-implicated genes. These high-confidence candidate SNPs may play roles in ASD and hence would be valuable for further functional validation.