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High-throughput transcriptomics of 409 bacteria–drug pairs reveals drivers of gut microbiota perturbation

Nature Microbiology volume 9, pages 561–575 (2024)Cite this article

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Abstract

Many drugs can perturb the gut microbiome, potentially leading to negative health consequences. However, mechanisms of most microorganism–drug responses have not been elucidated at the genetic level. Using high-throughput bacterial transcriptomics, we systematically characterized the gene expression profiles of prevalent human gut bacteria exposed to the most frequently prescribed orally administered pharmaceuticals. Across >400 drug–microorganism pairs, significant and reproducible transcriptional responses were observed, including pathways involved in multidrug resistance, metabolite transport, tartrate metabolism and riboflavin biosynthesis. Importantly, we discovered that statin-mediated upregulation of the AcrAB-TolC efflux pump in Bacteroidales species enhances microbial sensitivity to vitamin A and secondary bile acids. Moreover, gut bacteria carrying acrAB-tolC genes are depleted in patients taking simvastatin, suggesting that drug–efflux interactions generate collateral toxicity that depletes pump-containing microorganisms from patient microbiomes. This study provides a resource to further understand the drivers of drug-mediated microbiota shifts for better informed clinical interventions.

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Fig. 1: Top-prescribed drugs elicit rich transcriptomic responses from prevalent gut bacterial species.
Fig. 2: Pathway enrichment analysis reveals modulation of conserved efflux pathways by top pharmaceutical compounds.
Fig. 3: Top pharmaceutical compounds impact gut bacterial metabolism, vitamin production and mitigation of toxic metabolites.
Fig. 4: Statin exposure alters Bacteroides sensitivity to common dietary metabolites via the AcrAB-TolC efflux pump.
Fig. 5: AcrAB-TolC is linked to gut microbiota shifts in statin-treated patient populations.
Fig. 6: Diverse patterns of transcriptional response among conspecific bacterial isolates.

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Data availability

All sequencing data generated in this study have been submitted to the NCBI BioProject database (http://www.ncbi.nlm.nih.gov/bioproject/) under accession number PRJNA925551.

Code availability

Scripts used to analyse sequencing data in this study can be accessed at https://github.com/wanglabcumc/microbial_RNAseq_processing.

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Acknowledgements

We thank members of the Wang laboratory for advice and comments on the paper. H.H.W. acknowledges relevant funding support from the NSF (MCB-2025515), NIH (2R01AI132403, 1R01DK118044, 1R01CA272898, 1R01EB031935, 1R21AI146817), ONR (N00014-18-1-2237, N00014-17-1-2353), AFRL (S-168-4X5-001), Burroughs Wellcome Fund (1016691), Irma T. Hirschl Trust and Schaefer Research Award. D.R. acknowledges relevant funding support from the Columbia Medical Scientist Training Program. R.U.S. was supported by a Fannie and John Hertz Foundation Fellowship and an NSF Graduate Research Fellowship (DGE-1644869). D.R.G. was supported by the Burroughs Wellcome Fund Postdoctoral Diversity Enrichment Program.

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  1. These authors contributed equally: Deirdre Ricaurte, Yiming Huang.

Authors and Affiliations

  1. Department of Systems Biology, Columbia University, New York, NY, USA

    Deirdre Ricaurte, Yiming Huang, Ravi U. Sheth, Diego Rivera Gelsinger, Andrew Kaufman & Harris H. Wang

  2. Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY, USA

    Deirdre Ricaurte, Yiming Huang & Ravi U. Sheth

  3. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

    Harris H. Wang

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Contributions

D.R., Y.H., R.U.S. and H.H.W. developed the initial concepts. D.R. and Y.H. performed experiments and analysed data with assistance from A.K., D.R.G. and R.U.S. and input from H.H.W. D.R., Y.H. and H.H.W. wrote the paper. All other authors discussed results and approved the paper.

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Correspondence to Harris H. Wang.

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Competing interests

H.H.W. is a scientific advisor of SNIPR Biome, Kingdom Supercultures, Fitbiomics, Arranta Bio, VecX Biomedicines and Genus PLC, and a scientific co-founder of Aclid, all of which are not involved in the study. R.U.S is a co-founder of Kingdom Supercultures. Y.H. and H.H.W. are cofounders of Foli Bio. The other authors declare no competing interests.

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Ricaurte, D., Huang, Y., Sheth, R.U. et al. High-throughput transcriptomics of 409 bacteria–drug pairs reveals drivers of gut microbiota perturbation. Nat Microbiol 9, 561–575 (2024). https://doi.org/10.1038/s41564-023-01581-x

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