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Randomized Controlled Trial
. 2018 Dec:38:265-272.
doi: 10.1016/j.ebiom.2018年11月03日5. Epub 2018 Nov 23.

Short- and long-term impacts of azithromycin treatment on the gut microbiota in children: A double-blind, randomized, placebo-controlled trial

Affiliations
Randomized Controlled Trial

Short- and long-term impacts of azithromycin treatment on the gut microbiota in children: A double-blind, randomized, placebo-controlled trial

Shaodong Wei et al. EBioMedicine. 2018 Dec.

Abstract

Background: Macrolides are commonly prescribed for respiratory infections and asthma-like episodes in children. While their clinical benefits have been proved, concerns regarding the side-effects of their therapeutic use have been raised. Here we assess the short- and long-term impacts of azithromycin on the gut microbiota of young children.

Methods: We performed a randomized, double-blind, placebo-controlled trial in a group of children aged 12-36 months, diagnosed with recurrent asthma-like symptoms from the COPSAC2010 cohort. Each acute asthma-like episode was randomized to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo. Azithromycin reduced episode duration by half, which was the primary end-point and reported previously. The assessment of gut microbiota after treatment was the secondary end-point and reported in this study. Fecal samples were collected 14 days after randomization (N = 59, short-term) and again at age 4 years (N = 49, long-term, of whom N = 18 were placebo treated) and investigated by 16S rRNA gene amplicon sequencing.

Findings: Short-term, azithromycin caused a 23% reduction in observed richness and 13% reduction in Shannon diversity. Microbiota composition was shifted primarily in the Actinobacteria phylum, especially a reduction of abundance in the genus Bifidobacterium. Long-term (13-39 months after treatment), we did not observe any differences between the azithromycin and placebo recipients in their gut microbiota composition.

Interpretation: Azithromycin treatment induced a perturbation in the gut microbiota 14 days after randomization but did not have long-lasting effects on the gut microbiota composition. However, it should be noted that our analyses included a limited number of fecal samples for the placebo treated group at age 4 years. FUND: Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation, China Scholarship Council.

Keywords: Antibiotics; Asthma; Azithromycin; Children; Gut microbiota; RCT.

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Figures

Fig. 1
Fig. 1
(a) Trial profile showing the study design of the first participation specifically and all possible following participations. Dashed lines refer to possible sources a sample was from. (b) Barplot showing the distribution of treatments at the first to sixth participation in the DB-RCTs and at 4 years. AZT at 4 years corresponds to children with at least a single azithromycin treatment, whereas placebo are the children who did not receive any azithromycin treatments.
Fig. 2
Fig. 2
Short-term effect: Alpha diversity over age between groups. Distribution of observed richness and Shannon diversity for the AZT (red lines) and the placebo (blue lines) groups. The line indicates the linear regression of the correlation between age and alpha diversity.
Fig. 3
Fig. 3
Short-term effect: The top 20 taxa with the highest importance score (Gini index) by the Random Forest algorithm for distinguishing treatment groups and their corresponding relative abundances.
Fig. 4
Fig. 4
Long-term effect: Alpha and beta diversity between groups. (a) Dotplot showing the distribution of observed richness and Shannon diversity for the AZT (red) and placebo (blue) groups. Black dots indicate the mean; error bars indicate the standard deviation. (b) Weighted UniFrac distances between AZT (red) and placebo (blue) groups, visualized by principal coordinates analysis (PCoA), with ellipses encircling 75% of samples from each group.

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