Host and gut bacteria share metabolic pathways for anti-cancer drug metabolism
Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phy...
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Published in | Nature microbiology Vol. 7; no. 10; pp. 1605 - 1620 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.10.2022
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phyla. In both
Escherichia coli
and mammalian cells, fluoropyrimidines disrupt pyrimidine metabolism. Proteobacteria and Firmicutes metabolized 5-fluorouracil to its inactive metabolite dihydrofluorouracil, mimicking the major host mechanism for drug clearance. The
preTA
operon was necessary and sufficient for 5-fluorouracil inactivation by
E. coli
, exhibited high catalytic efficiency for the reductive reaction, decreased the bioavailability and efficacy of oral fluoropyrimidine treatment in mice and was prevalent in the gut microbiomes of colorectal cancer patients. The conservation of both the targets and enzymes for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug efficacy and side-effect profiles.
Anti-cancer fluoropyrimidine drugs have antibacterial effects on the gut microbiome, and these drugs can be metabolized by gut bacteria via conserved pathways also found in mammalian hosts. |
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Bibliography: | Equal contributions Author Contributions Statement P.J.T conceived of the project and was the primary supervisor for the study. R.R.G., A.G., and K.S.P. also supervised components of this work. P.S. led the in vitro screens and E. coli strain construction and established protocols for the pharmacokinetics and xenograft experiments. T.S.K. led the final pharmacokinetics, xenograft, transcriptomics, and amplicon sequencing data generation and analysis. B.G.H.G. led the biochemical characterization of PreTA. P.H.B. led the bioinformatic analysis of preTA operons across genomes and microbiomes. J.M., Y.N.A.M., T.S.K., B.G.H.G., and M.S. performed mass spectrometry. K.N.L. sequenced and analyzed the drug resistant E. coli mutants. J.V.L. assisted with the tumor xenograft measurements. C.E.A., A.V., and W.K. (GO Study PI) oversaw the conception and design of the GO Study and contributed patient samples. E.L.V.B. contributed to developing the study protocol and supervision of data collection for the GO Study. D.G. designed the GO Study Specimen Collection Kits and managed biospecimen collection, storage, and retrieval. P.S. wrote the initial draft. T.S.K. and P.J.T. revised the manuscript with input from all authors. |
ISSN: | 2058-5276 2058-5276 |
DOI: | 10.1038/s41564-022-01226-5 |