代谢组学在儿童哮喘中的应用进展

doi:10.12114/j.issn.1007-9572.2021.01.043

摘要/Abstract

摘要： 支气管哮喘是儿童最常见的慢性疾病，其漏诊率高，发病机制复杂。代谢组学通过定性定量分析生物样品的低分子量分子或代谢产物的变化，为寻找生物标志物和发病机制提供了一种新途径。本文综述了代谢组学技术运用于儿童哮喘的研究，运用靶向或非靶向研究策略，以哮喘儿童及健康儿童的血液、呼出气、粪便及尿液为研究对象，试图寻找儿童哮喘的潜在生物标志物及发病机制，为儿童哮喘的诊断及治疗提供帮助。近年来代谢组学在儿童哮喘方面取得了不小的进展，但受限于个体差异、样品采集、数据分析及组学异质性等因素，代谢组学在儿童哮喘的解释方面仍面临挑战。

关键词: 哮喘, 代谢组学, 儿童, 综述

Abstract:

As the most common chronic disease in children, bronchial asthma is highly underdiagnosed with complex pathogenesis. By qualitative and quantitative analyses of changes in low molecular weight molecules or metabolites in biological samples, metabolomics provides a new method to search biomarkers and pathogenesis. We reviewed the application of metabolomics in childhood asthma, which attempts to find the potential biomarkers and pathogenesis of childhood asthma by analyzing the samples of blood, exhaled breath, feces and urine of asthmatic children and healthy children using targeted or untargeted research approaches, providing help for clinical diagnosis and treatment of childhood asthma. Considerable progress has been made in metabolomics in childhood asthma, but due to factors such as individual differences, sample collection, data analysis, and genomic heterogeneity, metabolomics analysis of childhood asthma is still facing challenges.

Key words: Asthma, Metabolomics, Child, Review

中图分类号:

R562.25

吴锐剑,黄宇戈,罗连响. 代谢组学在儿童哮喘中的应用进展[J]. 中国全科医学, 2022, 25(08): 1014-1020. DOI: 10.12114/j.issn.1007-9572.2021.01.043.

WU Ruijian, HUANG Yuge, LUO Lianxiang.

Metabolomics in Childhood Asthma [J]. Chinese General Practice, 2022, 25(08): 1014-1020.

图/表 3

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生物样本	生理特征	优点	缺点	注意事项
血浆和血清	由不同组织根据不同的生理需要或压力而分泌、排泄或丢弃的所有分子组合^[24]	提供瞬时代谢状态的综合视图，适用于大多数分析技术和平台^[25]	有创，对气道生理缺乏特异性	血浆收集首选肝素，不建议使用柠檬酸盐，血清收集建议使用塑料或玻璃制成的普通无添加剂收集管^[26]
呼出气	组成相对简单，同时包含挥发性和非挥发性分子	无创且易于获得，可重复，与气道生理有关，适合分析挥发性和非挥发性代谢物^[27]	儿童人群难以采集样本，受运动、呼吸方式和速率、鼻污染、环境温度和湿度影响^[28]	需要对样本进行预浓缩，需要高素质的技术人员和昂贵的设备
粪便	粪便由消化物质的残留物或代谢物、肠道菌群代谢物和人体代谢物组成	无创，易于收藏，可重复收集，代谢物代表宿主和肠道菌群之前的相互作用	与呼吸系统无直接关系，难以区分营养、内源和微生物群代谢产物	粪便样品具有高度的不均匀性，取样后在冰上将样品均匀化^[29]
尿液	成分稳定，相对复杂程度不及血清和血浆，反映近端组织和血液灌注远处器官的生理和病理变化^[30]	无创，方便儿科收集，可重复收集，成分丰富^[31]	缺乏与气道生理的接近性和特异性，受饮食摄入影响^[32]	建议禁食样本，建议晨起中段尿^[31]

生物样本	生理特征	优点	缺点	注意事项
血浆和血清	由不同组织根据不同的生理需要或压力而分泌、排泄或丢弃的所有分子组合^[24]	提供瞬时代谢状态的综合视图，适用于大多数分析技术和平台^[25]	有创，对气道生理缺乏特异性	血浆收集首选肝素，不建议使用柠檬酸盐，血清收集建议使用塑料或玻璃制成的普通无添加剂收集管^[26]
呼出气	组成相对简单，同时包含挥发性和非挥发性分子	无创且易于获得，可重复，与气道生理有关，适合分析挥发性和非挥发性代谢物^[27]	儿童人群难以采集样本，受运动、呼吸方式和速率、鼻污染、环境温度和湿度影响^[28]	需要对样本进行预浓缩，需要高素质的技术人员和昂贵的设备
粪便	粪便由消化物质的残留物或代谢物、肠道菌群代谢物和人体代谢物组成	无创，易于收藏，可重复收集，代谢物代表宿主和肠道菌群之前的相互作用	与呼吸系统无直接关系，难以区分营养、内源和微生物群代谢产物	粪便样品具有高度的不均匀性，取样后在冰上将样品均匀化^[29]
尿液	成分稳定，相对复杂程度不及血清和血浆，反映近端组织和血液灌注远处器官的生理和病理变化^[30]	无创，方便儿科收集，可重复收集，成分丰富^[31]	缺乏与气道生理的接近性和特异性，受饮食摄入影响^[32]	建议禁食样本，建议晨起中段尿^[31]

代谢物	机制
短链脂肪酸：乙酸盐、丙酸盐、丁酸盐	直接激活G蛋白偶联受体（如GPR41、GPR43、GRP109A），抑制组蛋白脱乙酰基酶，作为能量底物^[62]；换行诱导T调节细胞分化，减少嗜酸粒细胞运输和存活^[55]，以及促进黏膜抗体产生^[63]
多不饱和脂肪酸：omega-3脂肪酸（二十碳五烯酸和二十二碳六烯酸）、omega-6脂肪酸（亚油酸及其代谢物花生四烯酸）	增加短链脂肪酸的产生，被人体肠道微生物代谢产生共轭亚油酸（CLA）和12，13-二羟基-9-十八烯酸（12，13-diHOME）。换行免疫失衡情况下，补充CLA能减少肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ和白介素（IL）-5的产生以及嗜酸粒细胞来源神经毒素的释放^[64]；12，13-diHOME可激活树突状细胞中的PPARγ调控基因的表达，并减少体外的抗炎细胞因子分泌和Treg细胞数量，从而增加肺部炎症^[65]
胆汁酸：胆酸、鹅脱氧胆酸、脱氧胆酸、石胆酸、熊去氧胆酸	熊去氧胆酸通过连接树突状细胞的法尼醇X受体（FXR），促进IL-12的产生，促进树突状细胞的迁移，减少肺部嗜酸性气道炎症^[66]；鹅去氧胆酸通过阻断炎性细胞浸润，从而抑制Th2细胞因子IL-4、IL-5、IL-13的分泌^[67]
色氨酸：犬尿氨酸、5-羟色胺、褪黑激素、吲哚、吲哚酸、粪臭素、色胺	吲哚胺2，3-双加氧酶-1代谢色氨酸产生犬尿氨酸衍生物，通过降低色氨酸的利用率^[68]和促进T调节细胞来减轻T细胞炎症^[69]；色氨酸衍生物可以激活芳香烃受体^[70]，刺激ILC3细胞产生IL-22并抑制ILC2功能，促进耐受性树突状细胞^[71]、Th17和T调节细胞分化^[72]
鞘脂：1-磷酸鞘氨醇、1-磷酸神经酰胺	1-磷酸鞘氨醇与T细胞表面S1P受体结合，控制T细胞从淋巴结进入血液^[73]；从头合成鞘脂的减少会降低细胞内镁含量并影响平滑肌收缩力^[74]

代谢物	机制
短链脂肪酸：乙酸盐、丙酸盐、丁酸盐	直接激活G蛋白偶联受体（如GPR41、GPR43、GRP109A），抑制组蛋白脱乙酰基酶，作为能量底物^[62]；换行诱导T调节细胞分化，减少嗜酸粒细胞运输和存活^[55]，以及促进黏膜抗体产生^[63]
多不饱和脂肪酸：omega-3脂肪酸（二十碳五烯酸和二十二碳六烯酸）、omega-6脂肪酸（亚油酸及其代谢物花生四烯酸）	增加短链脂肪酸的产生，被人体肠道微生物代谢产生共轭亚油酸（CLA）和12，13-二羟基-9-十八烯酸（12，13-diHOME）。换行免疫失衡情况下，补充CLA能减少肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ和白介素（IL）-5的产生以及嗜酸粒细胞来源神经毒素的释放^[64]；12，13-diHOME可激活树突状细胞中的PPARγ调控基因的表达，并减少体外的抗炎细胞因子分泌和Treg细胞数量，从而增加肺部炎症^[65]
胆汁酸：胆酸、鹅脱氧胆酸、脱氧胆酸、石胆酸、熊去氧胆酸	熊去氧胆酸通过连接树突状细胞的法尼醇X受体（FXR），促进IL-12的产生，促进树突状细胞的迁移，减少肺部嗜酸性气道炎症^[66]；鹅去氧胆酸通过阻断炎性细胞浸润，从而抑制Th2细胞因子IL-4、IL-5、IL-13的分泌^[67]
色氨酸：犬尿氨酸、5-羟色胺、褪黑激素、吲哚、吲哚酸、粪臭素、色胺	吲哚胺2，3-双加氧酶-1代谢色氨酸产生犬尿氨酸衍生物，通过降低色氨酸的利用率^[68]和促进T调节细胞来减轻T细胞炎症^[69]；色氨酸衍生物可以激活芳香烃受体^[70]，刺激ILC3细胞产生IL-22并抑制ILC2功能，促进耐受性树突状细胞^[71]、Th17和T调节细胞分化^[72]
鞘脂：1-磷酸鞘氨醇、1-磷酸神经酰胺	1-磷酸鞘氨醇与T细胞表面S1P受体结合，控制T细胞从淋巴结进入血液^[73]；从头合成鞘脂的减少会降低细胞内镁含量并影响平滑肌收缩力^[74]