Gut Microbial Diversity in Antibiotic-Naive Children After Systemic Antibiotic Exposure: A Randomized Controlled Trial

Abstract

Background: Antibiotic exposure can alter the gut microbiome. We evaluate the effects of azithromycin on the gut microbiome diversity of children from an antibiotic-naive community in Niger.

Methods: A population-based sample of 80 children aged 1-60 months in the Dosso region of Niger was randomized to receive a single dose of either oral azithromycin or placebo. Fecal samples were collected immediately before treatment and 5 days after treatment for 16S rRNA gene sequencing. The prespecified outcome was α-diversity (inverse Simpson's α-diversity index), with secondary outcomes of β and γ Simpson's and Shannon's diversities.

Results: At 5 days after treatment, 40 children aged 1-60 months were analyzed in the azithromycin-treated group and 40 children in the placebo-treated group. Diversity of the gut microbiome was significantly lower in the treated group (inverse Simpson's α-diversity, 5.03; 95% confidence interval [CI], 4.08-6.14) than in the placebo group (6.91; 95% CI, 5.82-8.21; P = .03). Similarly, the Shannon's α-diversity was lower in the treated group (10.60; 95% CI, 8.82-12.36) than the placebo group (15.42; 95% CI, 13.24-17.80; P = .004). Simpson's community-level (γ) diversity decreased with azithromycin exposure from 17.72 (95% CI, 13.80-20.21) to 10.10 (95% CI, 7.80-11.40; P = .00008), although β-diversity was not significantly reduced (2.56, 95% CI, 1.88-3.12; to 2.01, 95% CI, 1.46-2.51; P = .26).

Conclusions: Oral administration of azithromycin definitively decreases the diversity of the gut microbiome of children in an antibiotic-naive community.

Clinical trials registration: NCT02048007.

Keywords: antibiotics.; azithromycin; children; gut microbiome; randomized controlled trial.

Figure 1.

Trial profile. Eighty of the eighty-seven healthy and eligible children aged 1–60 months from a single village were randomly assigned to either the placebo or azithromycin treated group, with samples from 80 children subjected to 16S rRNA gene analysis. No children were lost to follow-up.

Figure 2.

The gut microbial composition (A) of children and alpha-diversity indices (B, C) between treatment groups. A, The 10 most abundant genera were depicted for each sample between treatment groups at baseline and at 5 days after treatment. Distributions of the Simpson’s index (B) and the Shannon’s index (C) for the placebo-treated (gray lines) and azithromycin-treated (orange lines) groups.

Figure 3.

Differentially abundant genera between the placebo- and azithromycin-treated children. Genera are shaded gray when significantly more abundant in the placebo group (P < .001) and shaded orange when significantly more abundant in the azithromycin-treated group. Abbreviation: LDA, linear discriminant analysis.