减少抗生素使用、肠道微生物群和儿童哮喘发病率的关系：基于人群和前瞻性队列研究的证据
2020/04/07
摘要
背景：欧洲和北美部分地区儿童哮喘发病率正在下降。婴儿期使用抗生素与哮喘风险增加有关。在本研究中，我们试图验证哮喘发病率降低与抗生素处方减少有关以及由肠道菌群群落变化介导的假说。
方法：本研究为基于人群的前瞻性队列分析。在人群层面，我们使用来自加拿大不列颠哥伦比亚省（人口4.7百万）抗生素处方量和哮喘诊断的年发病率数据，评估抗生素处方（1岁以下）和哮喘发病率（1-4岁）之间的关系。在个体水平上，对加拿大健康婴儿纵向发育（CHILD）前瞻性出生队列中的2644名儿童进行了全身抗生素使用（年龄<1岁）与哮喘诊断（年龄5岁）的相关性调查。在同一队列中，我们对917名儿童进行了机制研究，利用粪便样本（年龄≤1岁）的16S rRNA基因测序数据，评估肠道微生物群的组成与抗生素暴露和哮喘发病率的关系。
结果：在2000-2014年的人群水平上，儿童（1-4岁）哮喘发病率从每1000名儿童27.3例（26.8-28.3）绝对下降到每1000名儿童20.2例（19.5-20.8）（相对下降26.0%）。研究期间的哮喘发病率降低与婴儿期（年龄<1岁）抗生素使用减少有关，从每1000名婴儿1253.8个处方（95%可信区间1219.3-1288.9）减少到每1000名婴儿489.1个处方（467.6-511.2）（Spearman相关 r=0.81；p<0.0001）。抗生素处方每增加10%，哮喘发病率增加24%（调整后RR值为1.24[95%CI 1.20-1.28]；p<0.0001）。在CHILD队列中，排除因呼吸道症状而接受抗生素治疗的儿童后，儿童哮喘与婴儿抗生素使用相关（校正比值比[aOR]2.15[95%CI 1.37-3.39]；p=0.0009），具有显著的剂量反应；2182名5岁前未接触抗生素的儿童中114名（5.2%）患有哮喘，284名接触1个疗程抗生素治疗的儿童中23名（8.1%）患有哮喘，49名接触2个疗程抗生素治疗的儿童中5名（10.2%）患有哮喘，34名接触3到4个疗程抗生素治疗的儿童中6名（17.6%）患有哮喘（aOR 1.44[1.16-1.79]；p=0.0008）。1岁时，肠道微生物群α-多样性增加（定义为四分位（IQR）（25%至75%）与5岁时哮喘风险降低32%相关（aOR（以四分位数表示）为0.68[0.46-0.99]，；p=0.046）。在结构方程模型中，我们发现1岁时的肠道菌群以α-多样性、β-多样性和经抗生素暴露修饰的扩增子序列变异为特征，是1岁前门诊抗生素暴露和5岁前哮喘确诊之间的一个重要媒介（β=0.08；p=0.027）。
解释：我们的发现表明，近年来观察到的儿童哮喘发病率的降低可能是婴儿期谨慎使用抗生素的意外获益，通过保护肠道微生物群落发挥作用。
Decreasing antibiotic use, the gut microbiota, and asthma incidence in children: evidence from population-based and prospective cohort studies.
Patrick DM, Sbihi H, Dai DLY, Al Mamun A, Rasali D, Rose C, Marra F, Boutin RCT, Petersen C, Stiemsma LT, Winsor GL, Brinkman FSL, Kozyrskyj AL, Azad MB, Becker AB, Mandhane PJ, Moraes TJ, Sears MR, Subbarao P, Finlay BB, Turvey SE.
Abstract
BACKGROUND: Childhood asthma incidence is decreasing in some parts of Europe and North America. Antibiotic use in infancy has been associated with increased asthma risk. In the present study, we tested the hypothesis that decreases in asthma incidence are linked to reduced antibiotic prescribing and mediated by changes in the gut bacterial community.
METHODS: This study comprised population-based and prospective cohort analyses. At the population level, we used administrative data from British Columbia, Canada (population 4·7 million), on annual rates of antibiotic prescriptions and asthma diagnoses, to assess the association between antibiotic prescribing (at age <1 year) and asthma incidence (at age 1-4 years). At the individual level, 2644 children from the Canadian Healthy Infant Longitudinal Development (CHILD) prospective birth cohort were examined for the association of systemic antibiotic use (at age <1 year) with the diagnosis of asthma (at age 5 years). In the same cohort, we did a mechanistic investigation of 917 children with available 16S rRNA gene sequencing data from faecal samples (at age ≤1 year), to assess how composition of the gut microbiota relates to antibiotic exposure and asthma incidence.
FINDINGS: At the population level between 2000 and 2014, asthma incidence in children (aged 1-4 years) showed an absolute decrease of 7·1 new diagnoses per 1000 children, from 27·3 (26·8-28·3) per 1000 children to 20·2 (19·5-20·8) per 1000 children (a relative decrease of 26·0%). Reduction in incidence over the study period was associated with decreasing antibiotic use in infancy (age <1 year), from 1253·8 prescriptions (95% CI 1219·3-1288·9) per 1000 infants to 489·1 (467·6-511·2) per 1000 infants (Spearman's r=0·81; p<0·0001). Asthma incidence increased by 24% with each 10% increase in antibiotic prescribing (adjusted incidence rate ratio 1·24 [95% CI 1·20-1·28]; p<0·0001). In the CHILD cohort, after excluding children who received antibiotics for respiratory symptoms, asthma diagnosis in childhood was associated with infant antibiotic use (adjusted odds ratio [aOR] 2·15 [95% CI 1·37-3·39]; p=0·0009), with a significant dose-response; 114 (5·2%) of 2182 children unexposed to antibiotics had asthma by age 5 years, compared with 23 (8·1%) of 284 exposed to one course, five (10·2%) of 49 exposed to two courses, and six (17·6%) of 34 exposed to three or more courses (aOR 1·44 [1·16-1·79]; p=0·0008). Increasing α-diversity of the gut microbiota, defined as an IQR increase (25th to 75th percentile) in the Chao1 index, at age 1 year was associated with a 32% reduced risk of asthma at age 5 years (aOR for IQR increase 0·68 [0·46-0·99]; p=0·046). In a structural equation model, we found the gut microbiota at age 1 year, characterised by α-diversity, β-diversity, and amplicon sequence variants modified by antibiotic exposure, to be a significant mediator between outpatient antibiotic exposure in the first year of life and asthma diagnosis at age 5 years (β=0·08; p=0·027).
INTERPRETATION: Our findings suggest that the reduction in the incidence of paediatric asthma observed in recent years might be an unexpected benefit of prudent antibiotic use during infancy, acting via preservation of the gut microbial community.
背景：欧洲和北美部分地区儿童哮喘发病率正在下降。婴儿期使用抗生素与哮喘风险增加有关。在本研究中，我们试图验证哮喘发病率降低与抗生素处方减少有关以及由肠道菌群群落变化介导的假说。
方法：本研究为基于人群的前瞻性队列分析。在人群层面，我们使用来自加拿大不列颠哥伦比亚省（人口4.7百万）抗生素处方量和哮喘诊断的年发病率数据，评估抗生素处方（1岁以下）和哮喘发病率（1-4岁）之间的关系。在个体水平上，对加拿大健康婴儿纵向发育（CHILD）前瞻性出生队列中的2644名儿童进行了全身抗生素使用（年龄<1岁）与哮喘诊断（年龄5岁）的相关性调查。在同一队列中，我们对917名儿童进行了机制研究，利用粪便样本（年龄≤1岁）的16S rRNA基因测序数据，评估肠道微生物群的组成与抗生素暴露和哮喘发病率的关系。
结果：在2000-2014年的人群水平上，儿童（1-4岁）哮喘发病率从每1000名儿童27.3例（26.8-28.3）绝对下降到每1000名儿童20.2例（19.5-20.8）（相对下降26.0%）。研究期间的哮喘发病率降低与婴儿期（年龄<1岁）抗生素使用减少有关，从每1000名婴儿1253.8个处方（95%可信区间1219.3-1288.9）减少到每1000名婴儿489.1个处方（467.6-511.2）（Spearman相关 r=0.81；p<0.0001）。抗生素处方每增加10%，哮喘发病率增加24%（调整后RR值为1.24[95%CI 1.20-1.28]；p<0.0001）。在CHILD队列中，排除因呼吸道症状而接受抗生素治疗的儿童后，儿童哮喘与婴儿抗生素使用相关（校正比值比[aOR]2.15[95%CI 1.37-3.39]；p=0.0009），具有显著的剂量反应；2182名5岁前未接触抗生素的儿童中114名（5.2%）患有哮喘，284名接触1个疗程抗生素治疗的儿童中23名（8.1%）患有哮喘，49名接触2个疗程抗生素治疗的儿童中5名（10.2%）患有哮喘，34名接触3到4个疗程抗生素治疗的儿童中6名（17.6%）患有哮喘（aOR 1.44[1.16-1.79]；p=0.0008）。1岁时，肠道微生物群α-多样性增加（定义为四分位（IQR）（25%至75%）与5岁时哮喘风险降低32%相关（aOR（以四分位数表示）为0.68[0.46-0.99]，；p=0.046）。在结构方程模型中，我们发现1岁时的肠道菌群以α-多样性、β-多样性和经抗生素暴露修饰的扩增子序列变异为特征，是1岁前门诊抗生素暴露和5岁前哮喘确诊之间的一个重要媒介（β=0.08；p=0.027）。
解释：我们的发现表明，近年来观察到的儿童哮喘发病率的降低可能是婴儿期谨慎使用抗生素的意外获益，通过保护肠道微生物群落发挥作用。
(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)
(Lancet Respir Med. 2020 Mar 24. pii: S2213-2600(20)30052-7. doi: 10.1016/S2213-2600(20)30052-7.)
(Lancet Respir Med. 2020 Mar 24. pii: S2213-2600(20)30052-7. doi: 10.1016/S2213-2600(20)30052-7.)
Decreasing antibiotic use, the gut microbiota, and asthma incidence in children: evidence from population-based and prospective cohort studies.
Patrick DM, Sbihi H, Dai DLY, Al Mamun A, Rasali D, Rose C, Marra F, Boutin RCT, Petersen C, Stiemsma LT, Winsor GL, Brinkman FSL, Kozyrskyj AL, Azad MB, Becker AB, Mandhane PJ, Moraes TJ, Sears MR, Subbarao P, Finlay BB, Turvey SE.
Abstract
BACKGROUND: Childhood asthma incidence is decreasing in some parts of Europe and North America. Antibiotic use in infancy has been associated with increased asthma risk. In the present study, we tested the hypothesis that decreases in asthma incidence are linked to reduced antibiotic prescribing and mediated by changes in the gut bacterial community.
METHODS: This study comprised population-based and prospective cohort analyses. At the population level, we used administrative data from British Columbia, Canada (population 4·7 million), on annual rates of antibiotic prescriptions and asthma diagnoses, to assess the association between antibiotic prescribing (at age <1 year) and asthma incidence (at age 1-4 years). At the individual level, 2644 children from the Canadian Healthy Infant Longitudinal Development (CHILD) prospective birth cohort were examined for the association of systemic antibiotic use (at age <1 year) with the diagnosis of asthma (at age 5 years). In the same cohort, we did a mechanistic investigation of 917 children with available 16S rRNA gene sequencing data from faecal samples (at age ≤1 year), to assess how composition of the gut microbiota relates to antibiotic exposure and asthma incidence.
FINDINGS: At the population level between 2000 and 2014, asthma incidence in children (aged 1-4 years) showed an absolute decrease of 7·1 new diagnoses per 1000 children, from 27·3 (26·8-28·3) per 1000 children to 20·2 (19·5-20·8) per 1000 children (a relative decrease of 26·0%). Reduction in incidence over the study period was associated with decreasing antibiotic use in infancy (age <1 year), from 1253·8 prescriptions (95% CI 1219·3-1288·9) per 1000 infants to 489·1 (467·6-511·2) per 1000 infants (Spearman's r=0·81; p<0·0001). Asthma incidence increased by 24% with each 10% increase in antibiotic prescribing (adjusted incidence rate ratio 1·24 [95% CI 1·20-1·28]; p<0·0001). In the CHILD cohort, after excluding children who received antibiotics for respiratory symptoms, asthma diagnosis in childhood was associated with infant antibiotic use (adjusted odds ratio [aOR] 2·15 [95% CI 1·37-3·39]; p=0·0009), with a significant dose-response; 114 (5·2%) of 2182 children unexposed to antibiotics had asthma by age 5 years, compared with 23 (8·1%) of 284 exposed to one course, five (10·2%) of 49 exposed to two courses, and six (17·6%) of 34 exposed to three or more courses (aOR 1·44 [1·16-1·79]; p=0·0008). Increasing α-diversity of the gut microbiota, defined as an IQR increase (25th to 75th percentile) in the Chao1 index, at age 1 year was associated with a 32% reduced risk of asthma at age 5 years (aOR for IQR increase 0·68 [0·46-0·99]; p=0·046). In a structural equation model, we found the gut microbiota at age 1 year, characterised by α-diversity, β-diversity, and amplicon sequence variants modified by antibiotic exposure, to be a significant mediator between outpatient antibiotic exposure in the first year of life and asthma diagnosis at age 5 years (β=0·08; p=0·027).
INTERPRETATION: Our findings suggest that the reduction in the incidence of paediatric asthma observed in recent years might be an unexpected benefit of prudent antibiotic use during infancy, acting via preservation of the gut microbial community.
上一篇：
肺铁水平和调节在哮喘的发病机制和严重程度中的关键作用
下一篇：
多种过敏原特异性IgE抗体之间的连通性及其与重症哮喘的关系
