Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism.
Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism.
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DOI：
10.1186/s13229-016-0109-5
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发表时间：
2016
期刊：
影响因子：
6.2
通讯作者：
Persico AM
中科院分区：
文献类型：
--
作者：
Gevi F;Zolla L;Gabriele S;Persico AM
由于缺乏实验室生物标志物，自闭症谱系障碍（ASD）仍然通过行为观察进行诊断，这可以极大地帮助临床医生提供更早，更可靠的诊断。人类生物体液的代谢组学提供了一种敏感的工具，以确定代谢物谱可能用作ASD的生物标志物。最初的代谢组学研究，分析ASD和对照个体的尿液和血浆，表明自闭症患者可能共享一些代谢异常，尽管技术，种族，年龄范围和“控制”状态的定义存在差异。在30名ASD儿童和30名匹配的对照组（年龄范围2-7，M：F = 22：8）中，使用亲水相互作用色谱（HILIC）-UHPLC和质谱法（一种高度灵敏、准确和无偏倚的方法）在早期探索ASD特异性尿代谢组学模式。然后对代谢产物进行多变量统计分析，并按代谢途径分组。尿代谢产物显示年轻ASD和对照儿童之间的最大差异属于色氨酸和嘌呤代谢途径。此外，维生素B6，核黄素，苯丙氨酸-酪氨酸-色氨酸的生物合成，泛酸和CoA，和嘧啶代谢显着不同。ASD儿童优先将色氨酸转化为黄尿酸和喹啉酸（犬尿氨酸途径的两种催化剂），以犬尿烯酸尤其是褪黑激素为代价。此外，肠道微生物组有助于改变色氨酸代谢，产生吲哚基3-乙酸和吲哚基乳酸的水平增加。年轻的意大利自闭症儿童最独特的代谢途径在很大程度上与在母体免疫激活或遗传操作后的ASD啮齿动物模型中发现的代谢途径重叠。这些结果是一致的嘌呤驱动的细胞危险反应的建议，伴随着过量生产的癫痫和兴奋性毒性喹啉酸，大量减少褪黑激素的合成，肠道生态失调。这些代谢异常可能是常与ASD相关的几种合并症的基础，如癫痫发作、睡眠障碍和胃肠道症状，并可能导致自闭症的严重程度。它们的诊断敏感性、疾病特异性和种族间变异性值得进一步研究。本文的在线版本（doi：10.1186/s13229-016-0109-5）包含补充材料，可供授权用户使用。
Autism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of “control” status. ASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2–7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway. Urinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate. The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation. The online version of this article (doi:10.1186/s13229-016-0109-5) contains supplementary material, which is available to authorized users.
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影响因子：
7.4
作者：
Alpert, Andrew J.
通讯作者：
Alpert, Andrew J.
影响因子：
4.3
作者：
Emond, Patrick;Mavel, Sylvie;Andres, Christian R.
通讯作者：
Andres, Christian R.
影响因子：
3.7
作者：
Kohane IS;McMurry A;Weber G;MacFadden D;Rappaport L;Kunkel L;Bickel J;Wattanasin N;Spence S;Murphy S;Churchill S
通讯作者：
Churchill S
影响因子：
25.8
作者：
Frans, Emma M.;Sandin, Sven;Reichenberg, Abraham;Langstrom, Niklas;Lichtenstein, Paul;McGrath, John J.;Hultman, Christina M.
通讯作者：
Hultman, Christina M.
影响因子：
2.6
作者：
Altieri, Laura;Neri, Cristina;Persico, Antonio M.
通讯作者：
Persico, Antonio M.