Although the gut microbiome is generally symbiotic or commensal, some microbiome members become pathogenic under certain circumstances. However, the factors driving this pathogenic switch are largely unknown. Pathogenic bacteria can generate uracil that triggers host dual oxidase (DUOX) to produce antimicrobial reactive oxygen species (ROS). We show that pathogens generate uracil and ribose upon nucleoside catabolism of gut luminal uridine, which triggers not only host defenses but also inter-bacterial communication and pathogenesis in Drosophila. Uridine-derived uracil triggers DUOX-dependent ROS generation, whereas ribose induces bacterial quorum sensing (QS) and virulence gene expression. Genes implicated in nucleotide metabolism are found in pathogens but not commensal bacteria, and their genetic ablation blocks QS and the commensal-to-pathogen transition in vivo. Furthermore, commensal bacteria lack functional nucleoside catabolism, which is required to achieve gut-microbe symbiosis, but can become pathogenic by enabling nucleotide catabolism. These findings reveal molecular mechanisms governing the commensal-to-pathogen transition in different contexts of host-microbe interactions.
Bibliographical noteFunding Information:
This work was supported by grants from the National Creative Research Initiative programs of the National Research Foundation, South Korea (2015R1A3A2033475). E.-K.K. and K.-A.L. were supported by NRF-2017R1D1A1B03034197 and NRF-2019R1I1A1A01059606, respectively. E.-K.K. and W.-J.L. conceived and designed the experiments. E.-K.K. K.-A.L. M.K. K.-Y.J. and S.H.S. performed the experiments. E.-K.K. D.Y.H. D.H. Y.K. and W.-J.L. analyzed the data. E.-K.K and W.-J.L. wrote the manuscript. The authors declare no competing interests.
© 2020 Elsevier Inc.
- dual oxidase
- nucleoside hydrolase
- quorum sensing
- reactive oxygen species