Non-antibiotic drugs break colonization resistance against pathogenic Gammaproteobacteria

Introduction: Drugs have been shown to be a critical determinant of inter-individual differences in the composition of the human gut microbiome, which is true not only for antibiotics but also for non-antibiotic drugs. We hypothesized that by altering the composition of the microbiome, non-antibiotic drugs open niches and facilitate pathogen colonization in a similar way to antibiotics.

Methods: We compared the susceptibility of commensal and pathogenic bacteria to non-antibiotic drugs and found that pathogens have higher drug resistance, which could favor their expansion after treatment. Drugs were selected that inhibited a broad spectrum of commensals while sparing pathogenic Gammaproteobacteria. We then developed the synthetic model community Com20 to screen for drug-microbiome interactions that increase the risk of enteropathogenic infections. To increase microbial complexity, we performed the same experiments with human stool-derived microbial communities. For drug candidates with particularly strong phenotypes, we tested their ability to disrupt colonization resistance and increase the infection risk for Salmonella Typhimurium (S. Tm) in gnotobiotic and SPF mice.

Results and Conclusion: Approximately 35% of the >50 drugs from different therapeutic classes we tested increased the abundance of S. Tm in synthetic and human stool-derived communities. This was due to direct effects of non-antibiotics on individual commensals, altered microbial interactions within communities and the potential of S. Tm to exploit different metabolic niches. Non-antibiotic drugs that favored S. Tm expansion in vitro also promoted other enteric pathogens and increased S. Tm loads in gnotobiotic and conventional mice. Our work allows the systematic evaluation and identification of non-antibiotic drugs that break colonization resistance and increase the risk of infection with enteropathogenic bacteria. These findings may inform future strategies to control pathogen proliferation and to assess individual microbiota-drug-pathogen risks.