To minimize the impact of antibiotics, gut microorganisms harbour and exchange antibiotics resistance genes, collectively called their resistome. Using shotgun sequencing-based metagenomics, we analysed the partial eradication and subsequent regrowth of the gut microbiota in 12 healthy men over a 6-month period following a 4-day intervention with a cocktail of 3 last-resort antibiotics: meropenem, gentamicin and vancomycin. Initial changes included blooms of enterobacteria and other pathobionts, such as Enterococcus faecalis and Fusobacterium nucleatum, and the depletion of Bifidobacterium species and butyrate producers. The gut microbiota of the subjects recovered to near-baseline composition within 1.5 months, although 9 common species, which were present in all subjects before the treatment, remained undetectable in most of the subjects after 180 days. Species that harbour β-lactam resistance genes were positively selected for during and after the intervention. Harbouring glycopeptide or aminoglycoside resistance genes increased the odds of de novo colonization, however, the former also decreased the odds of survival. Compositional changes under antibiotic intervention in vivo matched results from in vitro susceptibility tests. Despite a mild yet long-lasting imprint following antibiotics exposure, the gut microbiota of healthy young adults are resilient to a short-term broad-spectrum antibiotics intervention and their antibiotics resistance gene carriage modulates their recovery processes.
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The high-quality reads have been deposited in the European Nucleotide Archive with accession number ERP022986. Relative abundances of taxa and functional features can be downloaded at http://arumugamlab.sund.ku.dk/SuppData/Palleja_et_al_2018_ABX/.
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This work was funded by an international alliance grant from The Novo Nordisk Foundation Center for Basic Metabolic Research, which is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (grant no. NNF10CC1016515). Our work was also funded by the TARGET research initiative (Danish Strategic Research Council [0603–00484B]), the Danish Diabetes Academy supported by the Novo Nordisk Foundation, the Danish Council for Independent Research (Medical Sciences), and the Danish Diabetes Association. S.K.F. was funded by FP7 METACARDIS HEALTH-F4-2012-305312.
The authors declare no competing interests.
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Supplementary Figures 1–12, legends for Supplementary Tables and Supplementary Datasets.
Comparison between taxa and KEGG function abundances at baseline (D0) and at subsequent time points (D8, D42, D180) using a two-sided Wilcoxon signed-rank test.
Sample information and read quality control statistics.
Predicted and manually curated gene assignments (taken from GenBank) for 3 well-characterized species such as Salmonella typhimurium, Enterobacter cloacae and Escherichia coli.
Species that differentially changed their abundance (two-sided Wilcoxon signed-rank test) following antibiotic treatment (from Supplementary Table 1) contrasted with their extent of relative growth inhibition from Maier et al.38.
Extent of enrichment (significantly higher number of genes) of ARGs for the drugs used in this study (and multidrug efflux pumps) in species enriched under intervention versus not (from Supplementary Table 1).
Gene-level differentially abundant ARGs under intervention, relative to their significantly differential prevalence in genomes in enriched versus depleted species among those differentially abundant under intervention (from Supplementary Table 1).
Associated data for Figure 4.
Associated data for Figure 5.
Associated data for Supplementary Figure 6.
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Palleja, A., Mikkelsen, K.H., Forslund, S.K. et al. Recovery of gut microbiota of healthy adults following antibiotic exposure. Nat Microbiol 3, 1255–1265 (2018). https://doi.org/10.1038/s41564-018-0257-9
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