Effect of amoxicillin on the gut microbiome of children with severe acute malnutrition in Madarounfa, Niger: a retrospective metagenomic analysis of a placebo-controlled trial.
Effect of amoxicillin on the gut microbiome of children with severe acute malnutrition in Madarounfa, Niger: a retrospective metagenomic analysis of a placebo-controlled trial.
复制标题
DOI：
10.1016/s2666-5247(23)00213-6
复制
发表时间：
2023-11
期刊：
影响因子：
38.2
通讯作者：
Dantas, Gautam
中科院分区：
文献类型：
--
作者：
Schwartz, Drew J.;Langdon, Amy;Sun, Xiaoqing;Langendorf, Celine;Berthe, Fatou;Grais, Rebecca F.;Trehan, Indi;Isanaka, Sheila;Dantas, Gautam
患有严重急性营养不良的儿童在门诊接受抗生素治疗。我们的目的是确定7天阿莫西林对严重急性营养不良儿童肠道微生物组和抗生素耐药组的急性和长期变化的影响。我们对一项在尼日尔Madarounfa接受门诊治疗的重度急性营养不良儿童（6-59个月）中开展的阿莫西林随机、双盲、安慰剂对照试验（NCT 01613547）进行了次要分析。我们从整个队列中随机选择了161名儿童（n=2399），从2013年9月23日至2014年2月3日进行了为期12周的随访。我们在人体测量的基础上，从这161名儿童中选择了一个方便样本，用于2年后（2015年9月28日至10月27日）的随访。儿童在基线、第1周、第4周、第8周、第12周以及2年随访队列中的第104周提供粪便样本。我们进行了宏基因组测序，然后对粪便样品进行了微生物组和耐药基因组分析。38名无严重急性营养不良的儿童和6名与原始队列基线年龄相匹配的严重急性营养不良的儿童被用作参考对照。在12周的随访组中，阿莫西林导致肠道微生物组丰富度从37.6种立即下降（95% CI 32.6 - 42.7）和Shannon多样性指数（SDI）2.18（95% CI 1.97 - 2.39）至第1周时27.7种（95% CI 22.9 - 32.6）种和SDI 1.55（95% CI 1.35 - 1.75）。阿莫西林使肠道抗生素耐药基因丰度从基线时的4800（3391-6208）增加至第1周时的6044个读数/百万个酶（95% CI 4704-7384），3周后恢复至基线。35名儿童被纳入2年随访;与安慰剂治疗的儿童相比，阿莫西林治疗的儿童（n=22）肠道微生物组中的物种数量增加（n=13; 60.7 [95% CI 54.7 - 66.6] vs 36.9 [29.4 - 44.3]）。与年龄匹配的安慰剂治疗儿童相比，阿莫西林治疗儿童的普雷沃菌属增加，双歧杆菌属减少，表明微生物组更成熟，成人样。阿莫西林治疗导致急性但非持续的抗菌素耐药基因增加，并在严重急性营养不良治疗后2年改善肠道微生物组成熟。比尔和梅林达·盖茨基金会;无国界医生组织巴黎行动中心;国家过敏和传染病研究所;国家普通医学科学研究所;尤尼斯·肯尼迪·施莱佛国家儿童健康和人类发展研究所;小爱德华·马林克罗特基金会;多丽丝·杜克基金会。
Children with severe acute malnutrition are treated with antibiotics as outpatients. We aimed to determine the effect of 7 days of amoxicillin on acute and long-term changes to the gut microbiome and antibiotic resistome in children treated for severe acute malnutrition. We conducted a secondary analysis of a randomised, double-blinded, placebo-controlled trial (NCT01613547) of amoxicillin in children (aged 6–59 months) with severe acute malnutrition treated as outpatients in Madarounfa, Niger. We randomly selected 161 children from the overall cohort (n=2399) for initial 12-week follow-up from Sept 23, 2013 to Feb 3, 2014. We selected a convenience sample of those 161 children, on the basis of anthropometric measures, for follow-up 2 years later (Sept 28 to Oct 27, 2015). Children provided faecal samples at baseline, week 1, week 4, week 8, week 12, and, for those in the 2-year follow-up cohort, week 104. We conducted metagenomic sequencing followed by microbiome and resistome profiling of faecal samples. 38 children without severe acute malnutrition and six children with severe acute malnutrition matching the baseline ages of the original cohort were used as reference controls. In the 12-week follow-up group, amoxicillin led to an immediate decrease in gut microbiome richness from 37·6 species (95% CI 32·6–42·7) and Shannon diversity index (SDI) 2·18 (95% CI 1·97–2·39) at baseline to 27·7 species (95% CI 22·9–32·6) species and SDI 1·55 (95% CI 1·35–1·75) at week 1. Amoxicillin increased gut antibiotic resistance gene abundance to 6044 reads per kilobase million (95% CI 4704–7384) at week 1, up from 4800 (3391–6208) at baseline, which returned to baseline 3 weeks later. 35 children were included in the 2-year follow-up; the amoxicillin-treated children (n=22) had increased number of species in the gut microbiome compared with placebo-treated children (n=13; 60·7 [95% CI 54·7–66·6] vs 36·9 [29·4–44·3]). Amoxicillin-treated children had increased Prevotella spp and decreased Bifidobacterium spp relative to age-matched placebo-treated children, indicating a more mature, adult-like microbiome. Amoxicillin treatment led to acute but not sustained increases in antimicrobial resistance genes and improved gut microbiome maturation 2 years after severe acute malnutrition treatment. Bill & Melinda Gates Foundation; Médecins sans Frontières Operational Center Paris; National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Edward Mallinckrodt Jr Foundation; Doris Duke Foundation.