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 inNature microbiology Vol. 7; no. 10; pp. 1605 - 1620
Main Authors Spanogiannopoulos, Peter, Kyaw, Than S., Guthrie, Ben G. H., Bradley, Patrick H., Lee, Joyce V., Melamed, Jonathan, Malig, Ysabella Noelle Amora, Lam, Kathy N., Gempis, Daryll, Sandy, Moriah, Kidder, Wesley, Van Blarigan, Erin L., Atreya, Chloe E., Venook, Alan, Gerona, Roy R., Goga, Andrei, Pollard, Katherine S., Turnbaugh, Peter J.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.10.2022
Nature Publishing Group
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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.
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