title: Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks.
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.
  
  
  METHODS
  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.
authors.affiliation: College of Pharmacy, Oregon State University, Corvallis, Oregon, USA Ghost Lab, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Morgun
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute/Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
authors.forename: Amiran
authors.initials: A
authors.lastname: Dzutsev
authors.affiliation: College of Pharmacy, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Dong
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Renee L
authors.initials: RL
authors.lastname: Greer
authors.affiliation: Department of Microbiology, Oregon State University, Corvallis, Oregon, USA.
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Sexton
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Ravel
authors.affiliation: Department of Microbiology, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Schuster
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Hsiao
authors.affiliation: Ghost Lab, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Polly
authors.initials: P
authors.lastname: Matzinger
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, USA Ghost Lab, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Shulzhenko
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects* / Q000235:genetics*; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000900:Anti-Bacterial Agents
keywords: ANTIBIOTICS; GENE EXPRESSION; MUCOSAL IMMUNITY