Most people in the USA manage their health by taking at least one prescription drug, and drugs classified as non-antibiotics can adversely affect the gut microbiome and disrupt intestinal homeostasis1,2. Here we identify medications that are associated with an increased risk of gastrointestinal infections across a population cohort of more than one million individuals monitored over 15 years. Notably, the cardiac glycoside digoxin and other drugs identified in this epidemiological study are sufficient to alter the composition of the microbiome and the risk of infection with Salmonella enterica subsp. enterica serovar Typhimurium (S. Tm) in mice. The effect of digoxin treatment on S. Tm infection is transmissible through the microbiome, and characterization of this interaction highlights a digoxin-responsive β-defensin that alters the microbiome composition and consequent immune surveillance of the invading pathogen. Combining epidemiological and experimental approaches thus provides an opportunity to uncover drug-host-microbiome-pathogen interactions that increase the risk of infections in humans.
© 2025. The Author(s), under exclusive licence to Springer Nature Limited.