摘要
背景：流行病学证据表明，食品添加剂摄入可能带来健康风险。本研究通过代谢组学分析，旨在探究食品添加剂与儿童哮喘之间的潜在关联机制。
方法：研究共纳入120例哮喘儿童及120例对照组儿童。采用超高效液相色谱-串联质谱法（UPLC-MS/MS）对血清中10种食品添加剂的浓度进行定量分析，包括甜蜜素、纽甜、阿斯巴甜、糖精钠、安赛蜜、三氯蔗糖、苯甲酸、脱氢乙酸、日落黄及丽春红4R。通过逻辑回归分析和卡方检验评估食品添加剂与哮喘的关联性；采用超高效液相色谱-质谱法（UPLC-MS）进行血清代谢谱分析。对筛选得到的哮喘相关代谢物，进一步开展通路富集分析及中介效应分析。在C57BL/6小鼠中，给予安赛蜜、糖精钠、苯甲酸钠或其混合物与卵清蛋白（OVA）联合处理，检测气道炎症程度及IgE、IL-4、IL-17A水平，并评估免疫细胞分化情况及CD4+T细胞代谢组学特征。
结果：脱氢乙酸、苯甲酸及甜蜜素的检出率均超过60%。其中，苯甲酸、脱氢乙酸及安赛蜜与哮喘存在显著关联。中介分析筛选出14种代谢物，可作为苯甲酸、脱氢乙酸与儿童哮喘关联的中介因子，包括磷脂酰胆碱（14:0/14:0）、溶血磷脂酰胆碱（17:0）、甘油磷酸胆碱、磷脂酰胆碱（18:1(9Z)e/2:0）、磷脂酰乙醇胺（18:2(9Z,12Z)/14:0）、谷氨酸、谷氨酰胺、葡萄糖神经酰胺（d18:1/16:0）、鞘氨醇、1-磷酸鞘氨醇、精胺、亚精胺、组氨酸及乙酰胆碱。这些代谢物显著富集于甘油磷脂代谢、β-丙氨酸代谢、谷胱甘肽代谢、鞘脂代谢、精氨酸与脯氨酸代谢、精氨酸生物合成及组氨酸代谢通路。在小鼠模型中，食品添加剂可显著加重肺组织炎症，升高支气管肺泡灌洗液（BALF）及血清中IgE、IL-4、IL-17A的水平，并增加BALF中嗜酸性粒细胞比例。此外，流式细胞术结果显示，肠系膜淋巴结（MLN）及肺组织中Th1/Th2、Th17/Treg及变应性树突状细胞/耐受性树突状细胞的平衡显著改变。MLN来源CD4+T细胞代谢组学分析表明，食品添加剂主要干扰苯丙氨酸、酪氨酸和色氨酸的生物合成及甘油磷脂代谢通路，涉及的关键代谢物包括磷脂酰胆碱（36:4）、血小板活化因子、溶血磷脂酰乙醇胺（P-16:0）、磷脂酰丝氨酸（14:0/5-异前列腺素F2VI）、磷脂酰乙醇胺（14:1(9Z)/15:0）、二甲基组胺、二十二碳二烯酸、环十一烷羧酸、L-乙酰肉碱、磷酸胆碱、神经酰胺（d18:2/20:0）、甘油二酯（22:1n9/0:0/20:4n6）、5′-甲硫腺苷、L-酪氨酸及N-棕榈酰亮氨酸。
结论：食品添加剂可能通过诱导代谢调控异常，破坏辅助性T细胞及抗原提呈细胞的稳态，进而打破免疫耐受，最终加重哮喘病情。
关键词：抗原提呈细胞；儿童哮喘；树突状细胞；食品添加剂；辅助性T细胞；代谢
Methods: A total of 120 children with asthma and 120 control subjects were recruited. Serum concentrations of ten food additives - including cyclamate, neotame, aspartame, sodium saccharin, acesulfame, sucralose, benzoic acid, dehydroacetic acid, sunset yellow, and ponceau 4R - were quantified using UPLC-MS/MS. The associations between food additives and asthma were evaluated by logistic regression and chi-square tests. Serum metabolic profiling was performed by UPLC-MS. Identified asthma-associated metabolites were subsequently analyzed for pathway enrichment and mediation effects. In murine studies, acesulfame, sodium saccharin, sodium benzoate, or their mixtures were co-administered with OVA to C57BL/6 mice. Airway inflammation, IgE, IL-4, IL-17A, immune cell differentiation, and CD4+ T cell metabolomics profiles were assessed.
Results: The detection rates for dehydroacetic acid, benzoic acid and sodium cyclamate exceeded 60%. Benzoic acid, dehydroacetic acid and acesulfame were significantly associated with asthma. Mediation analysis identified fourteen metabolites as mediators in the relationship between benzoic acid and dehydroacetic acid, and childhood asthma, including PC(14:0/14:0), LysoPC(17:0), glycerophosphocholine, PC(18:1(9Z)e/2:0), PE(18:2(9Z,12Z)/14:0), glutamic acid, glutamine, GlcCer(d18:1/16:0), sphingosine, sphingosine-1-phosphate, spermine, spermidine, histidine, and acetylcholine. These metabolites were enriched in glycerophospholipid metabolism, β-alanine metabolism, glutathione metabolism, sphingolipid metabolism, arginine and proline metabolism, arginine biosynthesis, and histidine metabolism pathways. In murine models, food additives significantly exacerbated lung tissue inflammation and elevated levels of IgE, IL-4, and IL-17A in both BALF and serum, and also increased eosinophil percentages in BALF. Furthermore, flow cytometry showed significant alterations in Th1/Th2, Th17/Treg and allergic DC/tolerogenic DC balance within the mesenteric lymph node (MLN) and the lung tissue. Metabolomic profiling of CD4+ T-cells from the MLN demonstrated that food additives primarily disrupted phenylalanine, tyrosine, and tryptophan biosynthesis, and glycerophospholipid metabolism pathways. This disruption involved key metabolites including PC(36:4), platelet-activating factor, LysoPE(P-16:0), PS(14:0/5-iso PGF2VI), PE(14:1(9Z)/15:0), Na,Na-dimethylhistamine, docosadienoic acid, cyclohexaneundecanoic acid, L-acetylcarnitine, phosphorycholine, Cer(d18:2/20:0), DG(22:1n9/0:0/20:4n6), 5'-methylthioadenosine, L-tyrosine, and N-palmitoyl leucine.
Conclusion: Food additives may aggravate asthma by metabolically dysregulating the homeostasis of helper T-cells and antigen-presenting cells, thereby disrupting immune tolerance.
Keywords: antigen-presenting cells; childhood asthma; dendritic cells; food additives; helper T cells; metabolism.
背景：流行病学证据表明，食品添加剂摄入可能带来健康风险。本研究通过代谢组学分析，旨在探究食品添加剂与儿童哮喘之间的潜在关联机制。
方法：研究共纳入120例哮喘儿童及120例对照组儿童。采用超高效液相色谱-串联质谱法（UPLC-MS/MS）对血清中10种食品添加剂的浓度进行定量分析，包括甜蜜素、纽甜、阿斯巴甜、糖精钠、安赛蜜、三氯蔗糖、苯甲酸、脱氢乙酸、日落黄及丽春红4R。通过逻辑回归分析和卡方检验评估食品添加剂与哮喘的关联性；采用超高效液相色谱-质谱法（UPLC-MS）进行血清代谢谱分析。对筛选得到的哮喘相关代谢物，进一步开展通路富集分析及中介效应分析。在C57BL/6小鼠中，给予安赛蜜、糖精钠、苯甲酸钠或其混合物与卵清蛋白（OVA）联合处理，检测气道炎症程度及IgE、IL-4、IL-17A水平，并评估免疫细胞分化情况及CD4+T细胞代谢组学特征。
结果：脱氢乙酸、苯甲酸及甜蜜素的检出率均超过60%。其中，苯甲酸、脱氢乙酸及安赛蜜与哮喘存在显著关联。中介分析筛选出14种代谢物，可作为苯甲酸、脱氢乙酸与儿童哮喘关联的中介因子，包括磷脂酰胆碱（14:0/14:0）、溶血磷脂酰胆碱（17:0）、甘油磷酸胆碱、磷脂酰胆碱（18:1(9Z)e/2:0）、磷脂酰乙醇胺（18:2(9Z,12Z)/14:0）、谷氨酸、谷氨酰胺、葡萄糖神经酰胺（d18:1/16:0）、鞘氨醇、1-磷酸鞘氨醇、精胺、亚精胺、组氨酸及乙酰胆碱。这些代谢物显著富集于甘油磷脂代谢、β-丙氨酸代谢、谷胱甘肽代谢、鞘脂代谢、精氨酸与脯氨酸代谢、精氨酸生物合成及组氨酸代谢通路。在小鼠模型中，食品添加剂可显著加重肺组织炎症，升高支气管肺泡灌洗液（BALF）及血清中IgE、IL-4、IL-17A的水平，并增加BALF中嗜酸性粒细胞比例。此外，流式细胞术结果显示，肠系膜淋巴结（MLN）及肺组织中Th1/Th2、Th17/Treg及变应性树突状细胞/耐受性树突状细胞的平衡显著改变。MLN来源CD4+T细胞代谢组学分析表明，食品添加剂主要干扰苯丙氨酸、酪氨酸和色氨酸的生物合成及甘油磷脂代谢通路，涉及的关键代谢物包括磷脂酰胆碱（36:4）、血小板活化因子、溶血磷脂酰乙醇胺（P-16:0）、磷脂酰丝氨酸（14:0/5-异前列腺素F2VI）、磷脂酰乙醇胺（14:1(9Z)/15:0）、二甲基组胺、二十二碳二烯酸、环十一烷羧酸、L-乙酰肉碱、磷酸胆碱、神经酰胺（d18:2/20:0）、甘油二酯（22:1n9/0:0/20:4n6）、5′-甲硫腺苷、L-酪氨酸及N-棕榈酰亮氨酸。
结论：食品添加剂可能通过诱导代谢调控异常，破坏辅助性T细胞及抗原提呈细胞的稳态，进而打破免疫耐受，最终加重哮喘病情。
关键词：抗原提呈细胞；儿童哮喘；树突状细胞；食品添加剂；辅助性T细胞；代谢
（南方医科大学南方医院 彭晓阡 陈垚欣 赵海金）
（Chen M, Xu X, Jiang X, et al. The study of the relationship between food additives and the childhood asthma based on metabolome analysis. Front Immunol. 2025;16:1671022. Published 2025 Sep 26. doi:10.3389/fimmu.2025.1671022）
（Chen M, Xu X, Jiang X, et al. The study of the relationship between food additives and the childhood asthma based on metabolome analysis. Front Immunol. 2025;16:1671022. Published 2025 Sep 26. doi:10.3389/fimmu.2025.1671022）
Abstract
Background: Epidemiological evidence suggests health risks arise from intake of food additives. This study aims to investigate the mechanisms linking food additives to childhood asthma through a metabolomics strategy.Methods: A total of 120 children with asthma and 120 control subjects were recruited. Serum concentrations of ten food additives - including cyclamate, neotame, aspartame, sodium saccharin, acesulfame, sucralose, benzoic acid, dehydroacetic acid, sunset yellow, and ponceau 4R - were quantified using UPLC-MS/MS. The associations between food additives and asthma were evaluated by logistic regression and chi-square tests. Serum metabolic profiling was performed by UPLC-MS. Identified asthma-associated metabolites were subsequently analyzed for pathway enrichment and mediation effects. In murine studies, acesulfame, sodium saccharin, sodium benzoate, or their mixtures were co-administered with OVA to C57BL/6 mice. Airway inflammation, IgE, IL-4, IL-17A, immune cell differentiation, and CD4+ T cell metabolomics profiles were assessed.
Results: The detection rates for dehydroacetic acid, benzoic acid and sodium cyclamate exceeded 60%. Benzoic acid, dehydroacetic acid and acesulfame were significantly associated with asthma. Mediation analysis identified fourteen metabolites as mediators in the relationship between benzoic acid and dehydroacetic acid, and childhood asthma, including PC(14:0/14:0), LysoPC(17:0), glycerophosphocholine, PC(18:1(9Z)e/2:0), PE(18:2(9Z,12Z)/14:0), glutamic acid, glutamine, GlcCer(d18:1/16:0), sphingosine, sphingosine-1-phosphate, spermine, spermidine, histidine, and acetylcholine. These metabolites were enriched in glycerophospholipid metabolism, β-alanine metabolism, glutathione metabolism, sphingolipid metabolism, arginine and proline metabolism, arginine biosynthesis, and histidine metabolism pathways. In murine models, food additives significantly exacerbated lung tissue inflammation and elevated levels of IgE, IL-4, and IL-17A in both BALF and serum, and also increased eosinophil percentages in BALF. Furthermore, flow cytometry showed significant alterations in Th1/Th2, Th17/Treg and allergic DC/tolerogenic DC balance within the mesenteric lymph node (MLN) and the lung tissue. Metabolomic profiling of CD4+ T-cells from the MLN demonstrated that food additives primarily disrupted phenylalanine, tyrosine, and tryptophan biosynthesis, and glycerophospholipid metabolism pathways. This disruption involved key metabolites including PC(36:4), platelet-activating factor, LysoPE(P-16:0), PS(14:0/5-iso PGF2VI), PE(14:1(9Z)/15:0), Na,Na-dimethylhistamine, docosadienoic acid, cyclohexaneundecanoic acid, L-acetylcarnitine, phosphorycholine, Cer(d18:2/20:0), DG(22:1n9/0:0/20:4n6), 5'-methylthioadenosine, L-tyrosine, and N-palmitoyl leucine.
Conclusion: Food additives may aggravate asthma by metabolically dysregulating the homeostasis of helper T-cells and antigen-presenting cells, thereby disrupting immune tolerance.
Keywords: antigen-presenting cells; childhood asthma; dendritic cells; food additives; helper T cells; metabolism.
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