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Recovery of gut microbiota of healthy adults following antibiotic exposure

Nature Microbiology volume 3, pages 1255–1265 (2018)Cite this article

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Abstract

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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Fig. 1: Gut microbial diversity recovers after a broad-spectrum antibiotic intervention.
Fig. 2: Gut microbial composition dramatically changes after broad-spectrum antibiotic intervention but recovers progressively.
Fig. 3: Microbial antibiotic resistance potential changes after broad-spectrum antibiotic intervention.
Fig. 4: Resistance gene carriage impacts the odds of microbial survival and colonization.
Fig. 5: Microbial virulence factors are enriched immediately after antibiotic treatment.

Data availability

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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Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally: Albert Palleja, Kristian H. Mikkelsen, Sofia K. Forslund.

Authors and Affiliations

  1. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Albert Palleja, Alireza Kashani, Kristine H. Allin, Trine Nielsen, Tue H. Hansen, Paul Theodor Pyl, Torben Hansen, Filip K. Knop, Manimozhiyan Arumugam & Oluf Pedersen

  2. Clinical-Microbiomics A/S, Copenhagen, Denmark

    Albert Palleja & Henrik Bjorn Nielsen

  3. Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

    Kristian H. Mikkelsen, Morten F. Nielsen, Tina Vilsbøll & Filip K. Knop

  4. Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, Berlin, Germany

    Sofia K. Forslund

  5. Max Delbruck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    Sofia K. Forslund & Peer Bork

  6. Charité-Universitätsmedizin Berlin , Freie Universität Berlin Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

    Sofia K. Forslund

  7. Berlin Institute of Health, Berlin, Germany

    Sofia K. Forslund

  8. Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany

    Sofia K. Forslund, Luis Pedro Coelho, Athanasios Typas & Peer Bork

  9. Danish Diabetes Academy, Odense, Denmark

    Alireza Kashani

  10. Department of Clinical Epidemiology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark

    Kristine H. Allin

  11. BGI-Shenzhen, Shenzhen, China

    Suisha Liang, Qiang Feng, Chenchen Zhang, Huanming Yang & Jian Wang

  12. China National GeneBank, BGI-Shenzhen, Shenzhen, China

    Suisha Liang, Qiang Feng, Chenchen Zhang, Huanming Yang & Jian Wang

  13. James D. Watson Institute of Genome Sciences, Hangzhou, China

    Huanming Yang & Jian Wang

  14. Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany

    Athanasios Typas

  15. Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany

    Peer Bork

  16. Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany

    Peer Bork

  17. iCarbonX, Shenzhen, China

    Jun Wang

  18. Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China

    Jun Wang

  19. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Jun Wang

  20. State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa Macau, China

    Jun Wang

  21. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

    Torben Hansen

  22. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Filip K. Knop

Authors
  1. Albert Palleja
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Contributions

O.P., T.H. and F.K.K. devised the study protocol. M.F.N. participated in the protocol design and application and in the participant recruitment and selection. K.H.M. performed sample collections and carried out patient phenotyping. K.H.A. supervised the microbial DNA extraction. S.L., C.Z., J.W., Q.F. and H.Y. performed shotgun metagenomics sequencing and taxonomic profiling. P.T.P., L.P.C. and M.A. estimated IGC gene profiles. H.B.N. generated the MGS groups based on IGC. A.P., S.K.F. and A.K. designed and performed the data analysis. M.A., T.H., P.B. and O.P. supervised the data analysis. A.P., S.K.F., K.H.M. and M.A. wrote the paper. K.H.A., T.N., T.H.H., A.K., H.B.N., J.W., A.T., P.B., T.V., F.K.K., T.H. and O.P. revised the paper. All authors contributed to data interpretation, discussion and editing of the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Filip K. Knop, Manimozhiyan Arumugam or Oluf Pedersen.

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Supplementary information

Supplementary Information

Supplementary Figures 1–12, legends for Supplementary Tables and Supplementary Datasets.

Reporting Summary

Supplementary Table 1

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.

Supplementary Table 2

Sample information and read quality control statistics.

Supplementary Table 3

Predicted and manually curated gene assignments (taken from GenBank) for 3 well-characterized species such as Salmonella typhimurium, Enterobacter cloacae and Escherichia coli.

Supplementary Table 4

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.

Supplementary Table 5

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).

Supplementary Table 6

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).

Supplementary Dataset 1

Associated data for Figure 4.

Supplementary Dataset 2

Associated data for Figure 5.

Supplementary Dataset 3

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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