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, 499 (7457), 219-22

Antibiotic Treatment Expands the Resistance Reservoir and Ecological Network of the Phage Metagenome

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Antibiotic Treatment Expands the Resistance Reservoir and Ecological Network of the Phage Metagenome

Sheetal R Modi et al. Nature.

Abstract

The mammalian gut ecosystem has considerable influence on host physiology, 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. 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.

Figures

Figure 1
Figure 1. Antibiotic resistance is enriched in phage metagenomes following drug perturbation in mice
a, b, Z-scores are shown for sequencing reads annotated as antibiotic resistance genes in phage from ciprofloxacin-treated mice (red) and phage from ampicillin-treated mice (yellow) in comparison to respective control mice. Dashed lines correspond to a Z-score of 1.65 (P = 0.05). Phage-encoded resistance genes were classified according to the drug class to which they confer resistance (a) and by their mechanism of resistance (b). c, Frequency of colonies resistant to ciprofloxacin (1 μg/ml) upon infection of microbiota with phage from ciprofloxacin-treated mice or phage from control mice (left), and frequency of colonies resistant to ampicillin (4 μg/ml) upon infection of microbiota with phage from ampicillin-treated mice or phage from control mice (right). P-values from Mann-Whitney U-test; n > 12. Mean ± s.e.m. *P < 0.05.
Figure 2
Figure 2. Broad bacterial functions are enriched in phage metagenomes following drug perturbation in mice
Network depicts KEGG pathways significantly enriched with antibiotic treatment compared to controls. Treatments are represented by large nodes; enriched pathways are represented by small nodes, grouped by their higher-level processes, and colored by the treatment condition (red – ciprofloxacin; yellow – ampicillin; orange – common to both treatments). In total, we identified 24 out of 188 pathways enriched with ciprofloxacin treatment (Z ≥ 3.46, Bonferroni corrected) and 18 out of 178 pathways enriched with ampicillin treatment (Z ≥ 3.43, Bonferroni corrected).
Figure 3
Figure 3. Investigation of bacterial functions encoded in phage
a, Bacterial enzymes from sugar metabolism to glycolysis (left) with corresponding Z-scores in phage from drug-treated mice in comparison to control mice (right). Dashed line corresponds to a Z-score of 1.65 (P = 0.05). b, Class-level taxonomic distribution of all sequences of bacterial origin identified in phage sequencing data (far left) and sequences annotated with enriched functions following drug perturbation. “Other” constitutes taxa that contributed less than 1% to all distributions.
Figure 4
Figure 4. Phage-bacterial ecological network
Dash marks represent associations between virotypes and bacterial species identified from phylogenetic analysis of reconstructed phage genomes. Phage-bacterial associations only in control metagenomes (black), only in drug-treated metagenomes (red), and commonly identified in control and drug-treated metagenomes (gray). Data are the union of associations identified in 50 assemblies of randomly sampled reads from each treatment.

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