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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  1. 1.

    et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007)

  2. 2.

    et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129 (2007)

  3. 3.

    et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292–300 (2010)

  4. 4.

    et al. Intestinal microbial ecology in premature infants assessed with non-culture-based techniques. J. Pediatr. 156, 20–25 (2010)

  5. 5.

    et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci. Transl. Med. 5, 193ra91 (2013)

  6. 6.

    et al. Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-γ-dependent elimination of Paneth cells. Nat. Immunol. 14, 136–142 (2013)

  7. 7.

    , & The dynamics of gut-associated microbial communities during inflammation. EMBO Rep. 14, 319–327 (2013)

  8. 8.

    , & Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol. 33, 496–503 (2015)

  9. 9.

    et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007)

  10. 10.

    et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011)

  11. 11.

    et al. Microbial respiration and formate oxidation as metabolic signatures of inflammation-associated dysbiosis. Cell Host Microbe 21, 208–219 (2017)

  12. 12.

    et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013)

  13. 13.

    et al. Properties of the periplasmic nitrate reductases from Paracoccus pantotrophus and Escherichia coli after growth in tungsten-supplemented media. FEMS Microbiol. Lett. 220, 261–269 (2003)

  14. 14.

    , , & The role of the resident intestinal flora in acute and chronic dextran sulfate sodium-induced colitis in mice. Eur. J. Gastroenterol. Hepatol. 12, 267–273 (2000)

  15. 15.

    et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 108, 1617–1621 (1995)

  16. 16.

    et al. An antibiotic regimen for the treatment of active Crohn’s disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am. J. Gastroenterol. 91, 328–332 (1996)

  17. 17.

    et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007)

  18. 18.

    , , & The role of pathogenic microbes and commensal bacteria in irritable bowel syndrome. Dig. Dis. 27 (Suppl 1), 85–89 (2009)

  19. 19.

    et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012)

  20. 20.

    et al. Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium. Nat. Microbiol. 2, 16215 (2016)

  21. 21.

    et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 53, 1617–1623 (2004)

  22. 22.

    et al. Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature 540, 280–283 (2016)

  23. 23.

    ., & Molecular Cloning 2nd edn (Cold Spring Harbor Laboratory Press, 1989)

  24. 24.

    ., & Advanced Bacterial Genetics (Cold Spring Harbor Laboratory Press, 1980)

  25. 25.

    , , & The alternative electron acceptor tetrathionate supports B12-dependent anaerobic growth of Salmonella enterica serovar Typhimurium on ethanolamine or 1,2-propanediol. J. Bacteriol. 183, 2463–2475 (2001)

  26. 26.

    et al. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335–336 (2010)

  27. 27.

    , & FisHiCal: an R package for iterative FISH-based calibration of Hi-C data. Bioinformatics 30, 3120–3122 (2014)

  28. 28.

    & Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics 22, 1658–1659 (2006)

  29. 29.

    , , , & CD-HIT: accelerated for clustering the next-generation sequencing data. Bioinformatics 28, 3150–3152 (2012)

  30. 30.

    et al. Enteric salmonellosis disrupts the microbial ecology of the murine gastrointestinal tract. Infect. Immun. 76, 907–915 (2008)

  31. 31.

    et al. Contribution of flagellin pattern recognition to intestinal inflammation during Salmonella enterica serotype Typhimurium infection. Infect. Immun. 77, 1904–1916 (2009)

  32. 32.

    et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010)

  33. 33.

    , , & Improvement of phylum- and class-specific primers for real-time PCR quantification of bacterial taxa. J. Microbiol. Methods 86, 351–356 (2011)

  34. 34.

    & Identification and expression of genes narL and narX of the nar (nitrate reductase) locus in Escherichia coli K-12. J. Bacteriol. 170, 1589–1597 (1988)

  35. 35.

    , , & Nuclear retention of IκBα protects it from signal-induced degradation and inhibits nuclear factor κB transcriptional activation. J. Biol. Chem. 274, 9108–9115 (1999)

  36. 36.

    et al. A Salmonella virulence factor activates the NOD1/NOD2 signaling pathway. MBio 20, e00266–11 (2011)

  37. 37.

    et al. Escherichia coli isolated from a Crohn’s disease patient adheres, invades, and induces inflammatory responses in polarized intestinal epithelial cells. Int. J. Med. Microbiol. 298, 397–409 (2008)

  38. 38.

    et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology 128, 891–906 (2005)

  39. 39.

    , , & Multipartite regulation of rctB, the replication initiator gene of Vibrio cholerae chromosome II. J. Bacteriol. 187, 7167–7175 (2005)

  40. 40.

    , & A broad host range mobilization system for in vivo genetic engineering: transposon mutagenesis in gram negative bacteria. Nat. Biotechnol. 1, 784–791 (1983)

  41. 41.

    et al. The use of real-time reverse transcriptase PCR for the quantification of cytokine gene expression. J. Biomol. Tech. 14, 33–43 (2003)

  42. 42.

    et al. T cells help to amplify inflammatory responses induced by Salmonella enterica serotype Typhimurium in the intestinal mucosa. Infect. Immun. 76, 2008–2017 (2008)

  43. 43.

    et al. The Vi-capsule prevents Toll-like receptor 4 recognition of Salmonella. Cell. Microbiol. 10, 876–890 (2008)

  44. 44.

    & Construction of versatile low-copy-number vectors for cloning, sequencing and gene expression in Escherichia coli. Gene 100, 195–199 (1991)

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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.


  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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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.

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    Supplementary Table 1

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

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    Supplementary Table 3

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

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    Supplementary Table 4

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

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    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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