Nutrient competition predicts gut microbiome restructuring under drug perturbations

Human gut bacteria are routinely exposed to stresses, and community-level responses are difficult to predict. To interrogate these effects, we screened stool-derived in vitro communities with 707 clinically relevant drugs. Across ∼5,000 community-drug conditions, compositional and metabolomic responses were shaped by nutrient competition, with certain species expanding due to the suppression of competitors. Most compositional changes arose from strain extinction and were reversed by reintroducing extinct species, although certain drugs promoted alternative states long after treatment. Despite strong selection pressures, resistance emergence was infrequent. Responses to drugs were qualitatively conserved across communities, while nutrient competition quantitatively tuned species abundances, consistent with consumer-resource model predictions. Together, nutrient competition provides a predictive framework to anticipate and potentially mitigate drug side effects on the gut microbiota.