Letter | Published:

Microcins mediate competition among Enterobacteriaceae in the inflamed gut

Nature volume 540, pages 280283 (08 December 2016) | Download Citation

Abstract

The Enterobacteriaceae are a family of Gram-negative bacteria that include commensal organisms as well as primary and opportunistic pathogens that are among the leading causes of morbidity and mortality worldwide. Although Enterobacteriaceae often comprise less than 1% of a healthy intestine’s microbiota1, some of these organisms can bloom in the inflamed gut2,3,4,5; expansion of enterobacteria is a hallmark of microbial imbalance known as dysbiosis6. Microcins are small secreted proteins that possess antimicrobial activity in vitro7,8, but whose role in vivo has been unclear. Here we demonstrate that microcins enable the probiotic bacterium Escherichia coli Nissle 1917 (EcN) to limit the expansion of competing Enterobacteriaceae (including pathogens and pathobionts) during intestinal inflammation. Microcin-producing EcN limits the growth of competitors in the inflamed intestine, including commensal E. coli, adherent–invasive E. coli and the related pathogen Salmonella enterica. Moreover, only therapeutic administration of the wild-type, microcin-producing EcN to mice previously infected with S. enterica substantially reduced intestinal colonization by the pathogen. Our work provides the first evidence that microcins mediate inter- and intraspecies competition among the Enterobacteriaceae in the inflamed gut. Moreover, we show that microcins can act as narrow-spectrum therapeutics to inhibit enteric pathogens and reduce enterobacterial blooms.

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Acknowledgements

We would like to acknowledge E. Nolan for critically reading the manuscript, J. Behnsen for setting up the Raffatellu laboratory germ-free mouse facility, and M. Valeri, A. Perez-Lopez, V. Diaz-Ochoa and E. Hoover for contributing to the maintenance of the germ-free facility. We would also like to thank W. Zhu and S. Winter for providing us with the protocol for cleaning up DNA stool samples from DSS, and M. Rolston at the UC Davis Host-Microbe Systems Biology Core for processing samples for Illumina MiSeq Analysis. We would like to acknowledge the students of the 2015 Summer course ‘Frontiers in Host–Microbe Interactions’, Marine Biology Laboratory, who helped with the generation of one dataset for the manuscript. Work in the laboratory of M.R. is supported by Public Health Service Grants AI083663, AI126277, AI101784, AI114625, AI105374, and DK058057. M.R. holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund.

Author information

Affiliations

  1. Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, California 92697, USA

    • Martina Sassone-Corsi
    • , Sean-Paul Nuccio
    • , Henry Liu
    • , Dulcemaria Hernandez
    • , Christine T. Vu
    • , Amy A. Takahashi
    •  & Manuela Raffatellu
  2. Institute for Immunology, University of California Irvine, Irvine, California 92697, USA

    • Martina Sassone-Corsi
    • , Sean-Paul Nuccio
    • , Robert A. Edwards
    •  & Manuela Raffatellu
  3. Department of Pathology and Laboratory Medicine, University of California, Irvine, California 92697, USA

    • Robert A. Edwards

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Contributions

M.S.-C. performed most bacterial growth assays and all animal experiments, and analysed the results. S.-P.N. analysed the microbiota data. R.A.E. scored histological sections. H.L., D.H., C.T.V., and A.A.T. assisted with mutant construction, bacterial growth assays, and animal experiments. M.S.-C. and M.R. were responsible for the overall study design. M.S.-C., S.-P.N. and M.R. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Manuela Raffatellu.

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DOI

https://doi.org/10.1038/nature20557

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