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Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks
  1. Andrey Morgun1,7,
  2. Amiran Dzutsev2,
  3. Xiaoxi Dong1,
  4. Renee L Greer3,
  5. D Joseph Sexton4,
  6. Jacques Ravel5,
  7. Martin Schuster4,
  8. William Hsiao6,
  9. Polly Matzinger7,
  10. Natalia Shulzhenko3,7
  1. 1College of Pharmacy, Oregon State University, Corvallis, Oregon, USA
  2. 2Cancer and Inflammation Program, National Cancer Institute/Leidos Biomedical Research, Inc., Frederick, Maryland, USA
  3. 3College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, USA
  4. 4Department of Microbiology, Oregon State University, Corvallis, Oregon, USA
  5. 5Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
  6. 6University of British Columbia, Vancouver, British Columbia, Canada
  7. 7Ghost Lab, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
  1. Correspondence to Dr Natalia Shulzhenko, 105 Dryden, Oregon State University, Corvallis, OR 97331, USA; natalia.shulzhenko{at}oregonstate.edu and Dr Andrey Morgun, 203 Pharmacy, Oregon State University, Corvallis, OR 97331, USA; anemorgun{at}hotmail.com

Abstract

Objective Despite widespread use of antibiotics for the treatment of life-threatening infections and for research on the role of commensal microbiota, our understanding of their effects on the host is still very limited.

Design Using a popular mouse model of microbiota depletion by a cocktail of antibiotics, we analysed the effects of antibiotics by combining intestinal transcriptome together with metagenomic analysis of the gut microbiota. In order to identify specific microbes and microbial genes that influence the host phenotype in antibiotic-treated mice, we developed and applied analysis of the transkingdom network.

Results We found that most antibiotic-induced alterations in the gut can be explained by three factors: depletion of the microbiota; direct effects of antibiotics on host tissues and the effects of remaining antibiotic-resistant microbes. Normal microbiota depletion mostly led to downregulation of different aspects of immunity. The two other factors (antibiotic direct effects on host tissues and antibiotic-resistant microbes) primarily inhibited mitochondrial gene expression and amounts of active mitochondria, increasing epithelial cell death. By reconstructing and analysing the transkingdom network, we discovered that these toxic effects were mediated by virulence/quorum sensing in antibiotic-resistant bacteria, a finding further validated using in vitro experiments.

Conclusions In addition to revealing mechanisms of antibiotic-induced alterations, this study also describes a new bioinformatics approach that predicts microbial components that regulate host functions and establishes a comprehensive resource on what, why and how antibiotics affect the gut in a widely used mouse model of microbiota depletion by antibiotics.

  • ANTIBIOTICS
  • GENE EXPRESSION
  • MUCOSAL IMMUNITY

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