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

Study information

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study design

randomized controlled trial

Citation

PMID PubMed identifier for scientific articles.

30478001

DOI Digital object identifier for electronic documents.

10.1016/j.ebiom.2018.11.035

URI Uniform resource identifier for web resources.

Authors

Wei S, Mortensen MS, Stokholm J, Brejnrod AD, Thorsen J, Rasmussen MA, Trivedi U, Bisgaard H, Sørensen SJ

Journal

EBioMedicine

Year

2018

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.

Experiment 1

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Curated date: 2021/09/16

Curator: Gina

Revision editor(s): WikiWorks753, LGeistlinger, Gina

Subjects

Location of subjects: Denmark

Host species Species from which microbiome was sampled (if applicable): Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: azithromycin (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-11-,10q24.1-q25.1,aritromicina,Azenil,Azifast,Azigram,Azimakrol,azithromycine,azithromycinum,Azitromin,AZM,Hemomycin,InChIKey=MQTOSJVFKKJCRP-BICOPXKEBK,Zithromax,Zmax,azithromycin

Group 0 name Corresponds to the control (unexposed) group for case-control studies: The group given a placebo
Group 1 name Corresponds to the case (exposed) group for case-control studies: The group given an azithromycin oral solution
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: 1-3-year-olds diagnosed with recurrent asthma-like symptoms from the COPSAC2010 cohort. Exclusion criteria included macrolide allergy, heart, liver, neurological, kidney disease, and or one or more clinical signs of pneumonia. Participants were prescribed a 3-day course of oral azithromycin solution of 10mg/kg per day.
Group 0 sample size Number of subjects in the control (unexposed) group: 33
Group 1 sample size Number of subjects in the case (exposed) group: 39
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any): none mentioned

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: V4

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Statistical test: Linear Regression

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: No

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness: decreased
Richness Number of species: decreased

Signature 1

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Curated date: 2021/09/24

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Source: Supplementary table 2

Description: Short term effects: the relative abundance of significant taxa between groups at different phylogenetic levels.

Abundance in Group 1: decreased abundance in The group given an azithromycin oral solution

NCBI	Links
Actinomycetota
Bifidobacteriales
Bacillota
Bifidobacteriaceae
uncultured Bifidobacterium sp.

Revision editor(s): Gina

Signature 2

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Curated date: 2021/09/24

Curator: Gina

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Source: Supplementary table 2

Description: Short term effect: the relative abundance of significant taxa between groups at different phylogenetic levels.

Abundance in Group 1: increased abundance in The group given an azithromycin oral solution

NCBI	Links
Lachnospiraceae
Flavonifractor

Revision editor(s): Gina