Letter

Precision editing of the gut microbiota ameliorates colitis

  • Nature volume 553, pages 208211 (11 January 2018)
  • doi:10.1038/nature25172
  • Download Citation
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Abstract

Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis1,2,3,4,5,6,7,8, characterized by changes in gut microbial communities that include an expansion of facultative anaerobic bacteria of the Enterobacteriaceae family (phylum Proteobacteria). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum-cofactor-dependent microbial respiratory pathways that are operational only during episodes of inflammation. By contrast, we found that tungstate treatment caused minimal changes in the microbiota composition under homeostatic conditions. Notably, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in mouse models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the inflamed gut.

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European Nucleotide Archive

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Acknowledgements

This work was supported by NIH grants AI112445 (A.J.B.), AI118807 (S.E.W.), AI128151 (S.E.W.), DK070855 (L.V.H.), DK102436 (B.A.D.) and 5K12HD-068369 (L.S.-D.), Welch Foundation grants I-1858 (S.E.W.) and I-1874 (L.V.H.), American Cancer Society Research Scholar Grant MPC-130347 (S.E.W.) and a Crohn’s and Colitis Foundation of America postdoctoral fellowship no. 454921 (W.Z.). Work in the L.V.H. laboratory is supported by the Howard Hughes Medical Institute. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the funders. We thank B. Sartor for the E. coli NC101 strain.

Author information

Author notes

    • R. Paul Wilson

    Present address: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.

    • Wenhan Zhu
    •  & Maria G. Winter

    These authors contributed equally to this work.

Affiliations

  1. Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA

    • Wenhan Zhu
    • , Maria G. Winter
    • , Luisella Spiga
    • , Elizabeth R. Hughes
    • , Lisa Büttner
    • , Caroline C. Gillis
    • , Andrew Y. Koh
    •  & Sebastian E. Winter
  2. Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, One Shields Avenue, Davis, California 95616, USA

    • Mariana X. Byndloss
    • , Everton de Lima Romão
    • , Christopher A. Lopez
    •  & Andreas J. Bäumler
  3. Department of Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA

    • Breck A. Duerkop
    • , Cassie L. Behrendt
    •  & Lora V. Hooper
  4. Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA

    • Luis Sifuentes-Dominguez
    •  & Andrew Y. Koh
  5. Department of Internal Medicine, Division of Digestive & Liver Diseases, University of Texas Southwestern Medical Center 75390, 5323 Harry Hines Boulevard, Dallas, Texas, USA

    • Kayci Huff-Hardy
    •  & Ezra Burstein
  6. Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, 1801 North Broad Street, Philadelphia, Pennsylvania 19122, USA

    • R. Paul Wilson
    •  & Çagla Tükel
  7. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA

    • Lora V. Hooper

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Contributions

W.Z., M.G.W., L.S., L.B., E.d.L.R., R.P.W., E.R.H, C.A.L. and C.C.G. performed and analysed nitrate reductase activity, in vitro bacterial competitive growth, NF-κB induction, DSS cytotoxity experiments and experiments involving conventionally raised C57BL/6 mice. M.G.W., L.S. and E.R.H. performed Il10−/− mouse experiments. W.Z. and M.G.W. performed inflammation analysis. C.L.B., M.G.W., L.S. and W.Z. performed germ-free-mouse experiments. B.A.D. and W.Z. analysed 16S and metagenomic data. M.X.B. analysed the histopathology. L.S.-D. and K.H.-H. contributed to humanized mouse experiments. L.S. and S.E.W. performed metabolite quantification. W.Z., Ç.T., A.Y.K., E.B., L.V.H., A.J.B. and S.E.W. designed the experiments, interpreted the data and wrote the manuscript with contributions from all authors.

Competing interests

A patent application has been filed on behalf of A.J.B. and S.E.W. and The Regents Of The University Of California based on some of the results reported in this letter (Application number, US 14/964,487). All other authors declare no competing financial interests.

Corresponding authors

Correspondence to Andreas J. Bäumler or Sebastian E. Winter.

Reviewer Information Nature thanks C. Elson, M. Fischbach and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    This file contains information regarding the bacterial strains used in this study.

  2. 2.

    Supplementary Table 2

    This file contains information regarding primers used in this study.

  3. 3.

    Supplementary Table 3

    This file contains information regarding the plasmids used in this study.

  4. 4.

    Supplementary Table 4

    This file contains relevant information regarding the human samples used in this study.

  5. 5.

    Supplementary Table 5

    This file contains information regarding the statistical methods used as well as the details of statistics (such as exact p value) in each figure of the manuscript.

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