Systemic 5-fluorouracil drives competitive release of multidrug‑resistant, virulent Enterococcus faecalis lineages in the gut
Abstract
Systemic chemotherapy perturbs the intestinal ecosystem, yet its impact on within-species population dynamics remains poorly understood. Here, we show that systemic 5-fluorouracil (5FU) exerts strong strain-selective pressure on gut Enterococcus faecalis, reshaping population structure without altering overall abundance. In patients receiving 5FU and in murine models, intestinal exposure to the drug suppresses 5FU-sensitive lineages while enriching pre-existing resistant clones. Resistant lineages exhibit enhanced 5FU detoxification associated with PreT/A-like enzymes and a redox-buffering program that preserves NADPH through disruption of CDP-ribitol-dependent metabolism. Drug-sensitive strains suppress resistant competitors via secreted inhibitory activity; 5FU eliminates this constraint, enabling competitive release and clonal expansion of resistant lineages. These 5FU-selected lineages display multidrug resistance, including elevated cephalosporin tolerance linked to upregulated penicillin-binding proteins, and exhibit increased virulence in vivo. Thus, systemic chemotherapy can inadvertently select high-risk pathobiont lineages through strain-level competitive release, generating intestinal reservoirs of multidrug-resistant and virulent bacteria. These findings highlight the importance of strain-resolved microbiome analysis and reveal an ecological mechanism by which anticancer therapy may increase infectious risk.
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