Non-antibiotic drugs can alter the composition of the gut microbiome, with largely undefined implications for human health. Here we compared the susceptibility of commensal and pathogenic bacteria to non-antibiotic drugs and found that pathogens show higher drug resistance, which could favor their expansion after treatment. We then developed a model system to screen for drug-microbiome interactions that increase the risk of enteropathogenic infections. Approximately 35% of the >50 drugs we tested increased the abundance of Salmonella Typhimurium in synthetic and human stool-derived microbial communities. This was due to direct effects of non-antibiotics on individual commensals, altered microbial interactions within communities and the potential of Salmonella to exploit different metabolic niches. Non-antibiotic drugs that favored Salmonella expansion in vitro also promoted other enteric pathogens and increased Salmonella loads in gnotobiotic and conventional mice. These findings may inform future strategies to control pathogen proliferation and to assess individual microbiota-drug-pathogen risks for infection.

Non-antibiotic drugs break colonization resistance against pathogenic Gammaproteobacteria