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Stanford University researchers report that ciprofloxacin use drives persistent antibiotic resistance in human gut bacteria, with resistance emerging independently across diverse species and enduring for over 10 weeks. Antimicrobial resistance (AMR) is a global health concern linked to millions of deaths each year. It is widely driven by excessive and inappropriate antibiotic use.
Past efforts to study AMR have largely relied on in vitro experiments and animal models, which fall short in replicating the full complexity of human microbial environments. In the study titled "Brief antibiotic use drives human gut bacteria towards low-cost resistance," published in Nature , researchers performed a longitudinal metagenomic study to explain how resistance evolves in vivo. Sixty healthy adults received ciprofloxacin, 500 mg twice daily, for five days.
Over a 20-week period, participants collected 16 stool samples, yielding 960 samples for analysis. Shotgun metagenomic sequencing was performed on all samples, generating an average of 18.8 million reads per sample.
A computational tool named PolyPanner was developed to identify true polymorphic sites across time. Researchers reconstructed 5,665 genomes representing commensal bacterial populations and identified 2.3 million genetic variants.
Among these, 513 populations exhibited selective sweeps, clear evidence of adaptive evolution. A high concentration of mutations occurred in gyrA, a gene associated with fluoroquinolone resistance. Among the 513 evolving populations, sweeping genetic changes frequently occurred in gyrA, a gene central to fluoroquinolone resistance.
Sixty-three populations across 34 participants exhibited gyrA mutations, which typically arose independently within individuals. Nearly 10% of initially susceptible bacterial populations acquired resistance through these mutations. Once established, gyrA sweeps persisted beyond 10 weeks and were predicted to remain detectable for up to a year.
Additional resistance-associated mutations occurred in other genes, though these events were less common and appeared in fewer species. Resistance was more likely to emerge in populations that were abundant before treatment and experienced significant declines during exposure, identifying a condition correlated with higher odds of evolutionary change. Resistance mutations did not come with fitness costs, allowing resistant strains to retain a dominant population after treatment concluded.
Targeted sequencing showed no evidence of resistance reversion. Mutations in gyrA accounted for only part of the observed resistance, suggesting additional mechanisms. Based on the results, even short-term antibiotic use can lead to resistance mutations that persist in the human gut for months after treatment ends.
Mutations arise independently across bacterial species and do not incur a measurable fitness cost, allowing resistant strains to remain prevalent. Gut microbes proved capable of evolving resistance without prior infection. Commensal populations may therefore act as reservoirs for resistance traits that could transfer to pathogenic bacteria through horizontal gene transfer beyond the interaction with antibiotics.
Because resistance evolved predictably based on population size, it allows for the possibility of predicting resistance outcomes if the starting population is known in advance of treatment. Experiments with differing admixes of starting populations and treatment types are needed to fully expand this predictive modeling. Monitoring microbial composition and abundance before and during treatment could help guide more precise antibiotic use, reduce long-term risks associated with resistance and improve overall stewardship of antibiotic use.
More information: Eitan Yaffe et al, Brief antibiotic use drives human gut bacteria towards low-cost resistance, Nature (2025). DOI: 10.1038/s41586-025-08781-x © 2025 Science X Network.
