母体维生素D相关代谢组与后代哮喘结局的风险
2023/08/28
摘要
背景：妊娠期维生素D缺乏与后代呼吸系统疾病的发展有关，但这种关系的机制尚不清楚。
目的：通过母体血液代谢组学分析，研究妊娠期维生素D暴露与儿童哮喘表型之间的联系。
方法：在产后一周，使用液相色谱-质谱法从COPSAC2010母婴队列中的672名妇女和VDAART母子队列中的779名妇女中获取未靶向血液代谢组学图谱。在COPSAC2010中，我们采用多变量模型和途径富集分析来确定与妊娠期维生素D血液水平相关的代谢产物和途径，并研究它们与儿童早期哮喘表型发展的关系。这些发现在VDAART和细胞模型中得到了验证。
结果：在COPSAC2010中，产后一周较高的维生素D血液水平与不同的母体代谢组紊乱有关，鞘磷脂途径显著富集（p<0.01）。产后一周含46种代谢产物的维生素D相关母体代谢谱与0-3岁时复发性喘息（危险比（HR）=0.92[95%CI，0.86-0.98]，p=0.01）和喘息加剧（HR=0.90[0.84-0.97]，p=0.01）的风险降低有关。
在VDAART中，相同的代谢特征与0-3岁时哮喘/喘息风险的降低相似（OR=0.92[0.85-0.99]，p=0.04）。用高剂量维生素D3治疗的人支气管上皮细胞显示出细胞浆鞘脂水平增加（p<0.01）。在VDAART中，相同的代谢特征与0-3岁时哮喘/喘息风险的降低相似（OR=0.92[0.85-0.99]，p=0.04）。用高剂量维生素D3治疗的人支气管上皮细胞显示出细胞浆鞘脂水平增加（p<0.01）。
结论：这项在两个独立出生队列中进行的探索性代谢组学研究表明，妊娠期较高的维生素D暴露对后代呼吸健康的有益影响以妊娠期特定的母体代谢改变为特征，这涉及鞘磷脂途径。
Maternal vitamin D-related metabolome and offspring risk of asthma outcomes
Min Kim, Nicklas Brustad, Mina Ali, Gözde Gürdeniz, Morten Arendt, Augusto A Litonjua, Craig E Wheelock, Rachel S Kelly, Yulu Chen, Nicole Prince, Feng Guo, Xiaobo Zhou, Jakob Stokholm, Klaus Bønnelykke, Scott T Weiss, Hans Bisgaard, Jessica Lasky-Su, Bo Chawes
Abstract
Background: Gestational vitamin D deficiency is implicated in development of respiratory diseases in the offspring, but the mechanism underlying this relationship is unknown.
Objectives: To study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling.
Methods: Untargeted blood metabolomic profiles were acquired using liquid chromatography-mass spectrometry at one week postpartum from 672 women in the COPSAC2010 mother-child cohort, and at pregnancy week 32-38 from 779 women in the VDAART mother-child cohort. In COPSAC2010, we employed multivariate models and pathway-enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models.
Results: In COPSAC2010, higher vitamin D blood levels at one week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (p<.01). This vitamin D-related maternal metabolic profile at one week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (Hazard Ratio (HR)=0.92 [95% CI, 0.86-0.98], p=.01) and wheeze exacerbations (HR=0.90 [0.84-0.97], p=.01) at age 0-3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at age 0-3 in VDAART (OR=0.92 [0.85-0.99], p=0.04). Human bronchial epithelial cells treated with high-dose vitamin D3 showed an increased cytoplasmatic sphingolipid level (p<0.01).
Conclusion: This exploratory metabolomics study in two independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway.
背景：妊娠期维生素D缺乏与后代呼吸系统疾病的发展有关，但这种关系的机制尚不清楚。
目的：通过母体血液代谢组学分析，研究妊娠期维生素D暴露与儿童哮喘表型之间的联系。
方法：在产后一周，使用液相色谱-质谱法从COPSAC2010母婴队列中的672名妇女和VDAART母子队列中的779名妇女中获取未靶向血液代谢组学图谱。在COPSAC2010中，我们采用多变量模型和途径富集分析来确定与妊娠期维生素D血液水平相关的代谢产物和途径，并研究它们与儿童早期哮喘表型发展的关系。这些发现在VDAART和细胞模型中得到了验证。
结果：在COPSAC2010中，产后一周较高的维生素D血液水平与不同的母体代谢组紊乱有关，鞘磷脂途径显著富集（p<0.01）。产后一周含46种代谢产物的维生素D相关母体代谢谱与0-3岁时复发性喘息（危险比（HR）=0.92[95%CI，0.86-0.98]，p=0.01）和喘息加剧（HR=0.90[0.84-0.97]，p=0.01）的风险降低有关。
在VDAART中，相同的代谢特征与0-3岁时哮喘/喘息风险的降低相似（OR=0.92[0.85-0.99]，p=0.04）。用高剂量维生素D3治疗的人支气管上皮细胞显示出细胞浆鞘脂水平增加（p<0.01）。在VDAART中，相同的代谢特征与0-3岁时哮喘/喘息风险的降低相似（OR=0.92[0.85-0.99]，p=0.04）。用高剂量维生素D3治疗的人支气管上皮细胞显示出细胞浆鞘脂水平增加（p<0.01）。
结论：这项在两个独立出生队列中进行的探索性代谢组学研究表明，妊娠期较高的维生素D暴露对后代呼吸健康的有益影响以妊娠期特定的母体代谢改变为特征，这涉及鞘磷脂途径。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2023 Aug 7;S0091-6749(23)00980-6. doi: 10.1016/j.jaci.2023.06.030.)
(J Allergy Clin Immunol. 2023 Aug 7;S0091-6749(23)00980-6. doi: 10.1016/j.jaci.2023.06.030.)
Maternal vitamin D-related metabolome and offspring risk of asthma outcomes
Min Kim, Nicklas Brustad, Mina Ali, Gözde Gürdeniz, Morten Arendt, Augusto A Litonjua, Craig E Wheelock, Rachel S Kelly, Yulu Chen, Nicole Prince, Feng Guo, Xiaobo Zhou, Jakob Stokholm, Klaus Bønnelykke, Scott T Weiss, Hans Bisgaard, Jessica Lasky-Su, Bo Chawes
Abstract
Background: Gestational vitamin D deficiency is implicated in development of respiratory diseases in the offspring, but the mechanism underlying this relationship is unknown.
Objectives: To study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling.
Methods: Untargeted blood metabolomic profiles were acquired using liquid chromatography-mass spectrometry at one week postpartum from 672 women in the COPSAC2010 mother-child cohort, and at pregnancy week 32-38 from 779 women in the VDAART mother-child cohort. In COPSAC2010, we employed multivariate models and pathway-enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models.
Results: In COPSAC2010, higher vitamin D blood levels at one week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (p<.01). This vitamin D-related maternal metabolic profile at one week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (Hazard Ratio (HR)=0.92 [95% CI, 0.86-0.98], p=.01) and wheeze exacerbations (HR=0.90 [0.84-0.97], p=.01) at age 0-3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at age 0-3 in VDAART (OR=0.92 [0.85-0.99], p=0.04). Human bronchial epithelial cells treated with high-dose vitamin D3 showed an increased cytoplasmatic sphingolipid level (p<0.01).
Conclusion: This exploratory metabolomics study in two independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway.
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