Nutrient competition predicts gut microbiome restructuring under drug perturbations

Handuo Shi; Daniel P Newton; Taylor H Nguyen; Sylvie Estrela; Juan Sanchez; Michael Tu; Po-Yi Ho; Qinglin Zeng; Brian C DeFelice; Justin L Sonnenburg; Kerwyn Casey Huang

doi:10.1016/j.cell.2025.10.038

Nutrient competition predicts gut microbiome restructuring under drug perturbations

Cell. 2025 Nov 26;188(24):6971-6986.e14. doi: 10.1016/j.cell.2025.10.038. Epub 2025 Nov 17.

Authors

Affiliations

¹ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: handuo@stanford.edu.
² Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
³ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁴ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Center for Interdisciplinary Studies, Westlake University, Hangzhou, China.
⁵ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; School of Life Sciences, Tsinghua University, Beijing, China.
⁶ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁷ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: kchuang@stanford.edu.

Abstract

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.

Keywords: antibiotics; chemical screen; competitive release; consumer-resource models; extinction and recovery; in vitro community; nutrient competition; resistance.

MeSH terms

Bacteria / classification
Bacteria / drug effects
Bacteria / metabolism
Feces / microbiology
Gastrointestinal Microbiome* / drug effects
Humans
Nutrients* / metabolism

Substances

Nutrients