Journal Article

Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome

Spina, Catherine S., Modi, Sheetal R., Collins, James J., Lee, Henry H.

2013

Overview

By exploring the phageome in mice, antibiotic treatment is shown to lead to enrichment of phage-encoded genes that are related to antibiotic resistance. Gut bacteria top-up their antibiotic resistance from a phage-gene reservoir Phages naturally coexist in abundance with their bacterial hosts in the mammalian gut. Antibiotic treatment can negatively affect the gut environment and cause immune and metabolic deficiencies. Previously the disruption of intestinal homeostasis has been studied mainly at the level of bacterial species, but here James Collins and colleagues use comparative metagenomics to profile gut phage populations following antibiotic treatment in mice. They find that exposure to ciprofloxacin or ampicillin enriches phage-encoded genes related to antibiotic resistance. Furthermore, phages from antibiotic-treated mice are able to increase resistance in an aerobically cultured naive microbiota. These results suggest that antibiotic treatment increases the frequency of phage integration and stimulates broad host range, which promotes a functional reservoir that is both genetically diverse and highly accessible to gut bacteria. The mammalian gut ecosystem has considerable influence on host physiology 1 , 2 , 3 , 4 , but the mechanisms that sustain this complex environment in the face of different stresses remain obscure. Perturbations to the gut ecosystem, such as through antibiotic treatment or diet, are at present interpreted at the level of bacterial phylogeny 5 , 6 , 7 . Less is known about the contributions of the abundant population of phages to this ecological network. Here we explore the phageome as a potential genetic reservoir for bacterial adaptation by sequencing murine faecal phage populations following antibiotic perturbation. We show that antibiotic treatment leads to the enrichment of phage-encoded genes that confer resistance via disparate mechanisms to the administered drug, as well as genes that confer resistance to antibiotics unrelated to the administered drug, and we demonstrate experimentally that phages from treated mice provide aerobically cultured naive microbiota with increased resistance. Systems-wide analyses uncovered post-treatment phage-encoded processes related to host colonization and growth adaptation, indicating that the phageome becomes broadly enriched for functionally beneficial genes under stress-related conditions. We also show that antibiotic treatment expands the interactions between phage and bacterial species, leading to a more highly connected phage–bacterial network for gene exchange. Our work implicates the phageome in the emergence of multidrug resistance, and indicates that the adaptive capacity of the phageome may represent a community-based mechanism for protecting the gut microflora, preserving its functional robustness during antibiotic stress.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/212 / 631/326/432 / 631/553 / Aerobiosis / Ampicillin - pharmacology / Analysis / Animals / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacteriophages / Bacteriophages - drug effects / Bacteriophages - genetics / Bacteriophages - isolation & purification / Ciprofloxacin - pharmacology / Complications and side effects / Drinking water / Drug resistance / Drug resistance in microorganisms / Drug Resistance, Microbial - drug effects / Drug Resistance, Microbial - genetics / Ecosystems / Feces - microbiology / Feces - virology / Female / Gene Transfer, Horizontal - drug effects / Gene Transfer, Horizontal - genetics / Genes / Genes, Viral - drug effects / Genes, Viral - genetics / Genetic aspects / Genetic engineering / Genome, Viral - genetics / Genomes / Health aspects / Host Specificity - drug effects / Humanities and Social Sciences / letter / Metagenome - drug effects / Metagenome - genetics / Mice / Microbiology / multidisciplinary / Phylogeny / Physiological aspects / Protein synthesis / Proteins / Reservoirs / Science / Stress / Symbiosis - drug effects / Symbiosis - genetics