Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits


Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy1,2. How antibiotic-mediated elimination of commensal bacteria promotes infection by antibiotic-resistant bacteria is a fertile area for speculation with few defined mechanisms. Here we demonstrate that antibiotic treatment of mice notably downregulates intestinal expression of RegIIIγ (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIIIγ markedly decreases in vivo killing of VRE in the intestine of antibiotic-treated mice. Stimulation of intestinal Toll-like receptor 4 by oral administration of lipopolysaccharide re-induces RegIIIγ, thereby boosting innate immune resistance of antibiotic-treated mice against VRE. Compromised mucosal innate immune defence, as induced by broad-spectrum antibiotic therapy, can be corrected by selectively stimulating mucosal epithelial Toll-like receptors, providing a potential therapeutic approach to reduce colonization and infection by antibiotic-resistant microbes.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: MyD88-mediated signalling in non-haematopoietic cells is required for RegIIIγ-mediated clearance of VRE.
Figure 2: RegIIIγ expression is downregulated in antibiotic-treated mice, correlating with decreased clearance of VRE.
Figure 3: Administration of LPS to antibiotic-treated mice restores RegIIIγ levels and enhances luminal VRE killing.
Figure 4: Delayed LPS treatment of mice receiving antibiotics restores RegIIIγ levels and enhances luminal VRE killing.


  1. Rice, L. B. Emergence of vancomycin-resistant enterococci. Emerg. Infect. Dis. 7, 183–187 (2001)

    CAS  Article  Google Scholar 

  2. Rice, L. B. Antimicrobial resistance in gram-positive bacteria. Am. J. Infect. Control 34, S11–S19 (2006)

    Article  Google Scholar 

  3. Murray, B. E. Vancomycin-resistant enterococcal infections. N. Engl. J. Med. 342, 710–721 (2000)

    CAS  Article  Google Scholar 

  4. Richards, M. J., Edwards, J. R., Culver, D. H. & Gaynes, R. P. Nosocomial infections in combined medical-surgical intensive care units in the United States. Infect. Control Hosp. Epidemiol. 21, 510–515 (2000)

    CAS  Article  Google Scholar 

  5. Wenzel, R. P. & Edmond, M. B. Managing antibiotic resistance. N. Engl. J. Med. 343, 1961–1963 (2000)

    CAS  Article  Google Scholar 

  6. Donskey, C. J. The role of the intestinal tract as a reservoir and source for transmission of nosocomial pathogens. Clin. Infect. Dis. 39, 219–226 (2004)

    Article  Google Scholar 

  7. Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006)

    ADS  CAS  Article  Google Scholar 

  8. Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immunol. 4, 269–273 (2003)

    CAS  Article  Google Scholar 

  9. Brandl, K., Plitas, G., Schnabl, B., DeMatteo, R. P. & Pamer, E. G. MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204, 1891–1900 (2007)

    CAS  Article  Google Scholar 

  10. Cash, H. L., Whitham, C. V. & Hooper, L. V. Refolding, purification, and characterization of human and murine RegIII proteins expressed in Escherichia coli . Protein Expr. Purif. 48, 151–159 (2006)

    CAS  Article  Google Scholar 

  11. Donskey, C. J. et al. Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N. Engl. J. Med. 343, 1925–1932 (2000)

    CAS  Article  Google Scholar 

  12. Miyazaki, S. et al. Development of systemic bacteraemia after oral inoculation of vancomycin-resistant enterococci in mice. J. Med. Microbiol. 50, 695–701 (2001)

    CAS  Article  Google Scholar 

  13. Stiefel, U., Pultz, N. J., Helfand, M. S. & Donskey, C. J. Increased susceptibility to vancomycin-resistant Enterococcus intestinal colonization persists after completion of anti-anaerobic antibiotic treatment in mice. Infect. Control Hosp. Epidemiol. 25, 373–379 (2004)

    Article  Google Scholar 

  14. Wells, C. L., Jechorek, R. P. & Erlandsen, S. L. Evidence for the translocation of Enterococcus faecalis across the mouse intestinal tract. J. Infect. Dis. 162, 82–90 (1990)

    CAS  Article  Google Scholar 

  15. Wells, C. L., Jechorek, R. P., Maddaus, M. A. & Simmons, R. L. Effects of clindamycin and metronidazole on the intestinal colonization and translocation of enterococci in mice. Antimicrob. Agents Chemother. 32, 1769–1775 (1988)

    CAS  Article  Google Scholar 

  16. Sonnenburg, J. L., Chen, C. T. & Gordon, J. I. Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host. PLoS Biol. 4, e413 (2006)

    Article  Google Scholar 

  17. Pultz, N. J., Stiefel, U., Subramanyan, S., Helfand, M. S. & Donskey, C. J. Mechanisms by which anaerobic microbiota inhibit the establishment in mice of intestinal colonization by vancomycin-resistant Enterococcus . J. Infect. Dis. 191, 949–956 (2005)

    Article  Google Scholar 

  18. Kelly, C. P., Pothoulakis, C. & LaMont, J. T. Clostridium difficile colitis. N. Engl. J. Med. 330, 257–262 (1994)

    CAS  Article  Google Scholar 

  19. Kanzler, H., Barrat, F. J., Hessel, E. M. & Coffman, R. L. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nature Med. 13, 552–559 (2007)

    CAS  Article  Google Scholar 

  20. Abreu, M. T., Fukata, M. & Arditi, M. TLR signaling in the gut in health and disease. J. Immunol. 174, 4453–4460 (2005)

    CAS  Article  Google Scholar 

  21. Lotz, M., Menard, S. & Hornef, M. Innate immune recognition on the intestinal mucosa. Int. J. Med. Microbiol. 297, 379–392 (2007)

    CAS  Article  Google Scholar 

  22. Cario, E. et al. Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J. Immunol. 164, 966–972 (2000)

    CAS  Article  Google Scholar 

  23. Hornef, M. W., Frisan, T., Vandewalle, A., Normark, S. & Richter-Dahlfors, A. Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells. J. Exp. Med. 195, 559–570 (2002)

    CAS  Article  Google Scholar 

  24. Ortega-Cava, C. F. et al. Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J. Immunol. 170, 3977–3985 (2003)

    CAS  Article  Google Scholar 

  25. Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. & Stappenbeck, T. S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl Acad. Sci. USA 102, 99–104 (2005)

    ADS  CAS  Article  Google Scholar 

  26. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004)

    CAS  Article  Google Scholar 

  27. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007)

    ADS  CAS  Article  Google Scholar 

  28. Hammett-Stabler, C. A. & Johns, T. Laboratory guidelines for monitoring of antimicrobial drugs. Clin. Chem. 44, 1129–1140 (1998)

    CAS  PubMed  Google Scholar 

Download references


The authors thank L.V. Hooper for providing polyclonal RegIIIγ antiserum, I. Leiner for technical assistance, and W. Falk, B. Salzberger and all members of the Pamer laboratory for discussions. This research was supported by the Alexander von Humboldt Foundation through a Feodor Lynen postdoctoral fellowship to KB and NIH grant AI39031 and AI42135 to EGP.

Author Contributions K.B., G.P., R.P.D. and E.G.P. designed the research. K.B., G.P., C.N.M., C.U., T.J., B.S. and M.F. performed the research. K.B. and E.G.P. analysed the data and wrote the paper.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Eric G. Pamer.

Supplementary information

Supplementary Information

The file contains Supplementary Figures S1-S8 with Legends. (PDF 271 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Brandl, K., Plitas, G., Mihu, C. et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455, 804–807 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing