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Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection

Nature Medicine volume 22, pages 1330–1334 (2016)Cite this article

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An Erratum to this article was published on 06 December 2016

This article has been updated

Abstract

Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and is an urgent public health concern worldwide1. Over the past decade, incidence, severity and costs associated with C. difficile infection (CDI) have increased dramatically2. CDI is most commonly initiated by antibiotic-mediated disruption of the gut microbiota; however, non-antibiotic-associated CDI cases are well documented and on the rise3,4. This suggests that unexplored environmental, nutrient and host factors probably influence CDI. Here we show that excess dietary zinc (Zn) substantially alters the gut microbiota and, in turn, reduces the minimum amount of antibiotics needed to confer susceptibility to CDI. In mice colonized with C. difficile, excess dietary Zn severely exacerbated C. difficile–associated disease by increasing toxin activity and altering the host immune response. In addition, we show that the Zn-binding S100 protein calprotectin has antimicrobial effects against C. difficile and is an essential component of the innate immune response to CDI. Taken together, these data suggest that nutrient Zn levels have a key role in determining susceptibility to CDI and severity of disease, and that calprotectin-mediated metal limitation is an important factor in the host immune response to C. difficile.

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Figure 1: Increased dietary Zn alters tissue Zn levels and dramatically alters the gut microbiota.
Figure 2: Excess dietary Zn exacerbates C. difficile–associated disease.
Figure 3: Excess dietary Zn decreases the threshold of antibiotics needed to confer susceptibility to CDI.
Figure 4: Calprotectin is essential for combating CDI.

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  • 20 October 2016

    In the version of this article initially published online, the low-zinc diet was incorrectly described as 0 mg per kg body weight (mg/kg) Zn and should be described as 'low-Zn diet; 0 mg Zn per kg of diet (mg/kg)'. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We thank P. Schloss and J. Sorg for critical feedback on this study, and D. Aronoff and S. Walk for providing C. difficile strains. This research was supported by the US Department of Veterans Affairs (Merit Review Award no. 1I01BX002482; E.P.S.), the US National Institutes of Health (NIH) (grant no. R01 AI101171 (E.P.S.) and P41 GM103391-05 (R.M.C.)) and the Vanderbilt Digestive Disease Research Center (VDDRC) (grant no. P30DK058404; E.P.S.). J.P.Z. was supported by NIH–NIDDK grant no. T32DK007673 and NIH–NIAID grant no. F32AI120553. J.L.M. was supported by NIH–NIGMS grant no. T32GM065086. M.R.N. was supported by the Thrasher Research Fund Early Career Award.

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Authors and Affiliations

  1. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Joseph P Zackular, Ashley T Jordan, Lillian J Juttukonda, Michael J Noto, Yaofang Zhang, Lorraine B Ware, M Kay Washington & Eric P Skaar

  2. Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA

    Jessica L Moore, Walter J Chazin & Richard M Caprioli

  3. Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee, USA

    Jessica L Moore & Richard M Caprioli

  4. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Michael J Noto, Matthew W Semler & Lorraine B Ware

  5. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Maribeth R Nicholson

  6. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

    Jonathan D Crews

  7. Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA

    Walter J Chazin & Richard M Caprioli

  8. Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA

    Walter J Chazin

  9. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA

    Richard M Caprioli

  10. US Department of Veterans Affairs, Tennessee Valley Healthcare Systems, Nashville, Tennessee, USA

    Eric P Skaar

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Contributions

J.P.Z. and E.P.S. designed experiments and wrote the manuscript with input from the co-authors; J.P.Z. performed animal experiments, the corresponding assays and analyses with assistance from A.T.J.; J.P.Z. performed microbiota community analyses; L.J.J. designed altered metal diets; J.L.M. and R.M.C. performed MALDI–MS imaging and corresponding analyses; Y.Z. and R.M.C. performed ICP–MS; M.K.W. performed histological analyses; W.J.C. assisted in calprotectin assays; M.R.N. and J.D.C. enlisted pediatric patients and collected fecal samples; M.W.S., M.J.N. and L.B.W. collected adult serum and aided in the analyses of calprotectin experiments.

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Correspondence to Eric P Skaar.

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Zackular, J., Moore, J., Jordan, A. et al. Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection. Nat Med 22, 1330–1334 (2016). https://doi.org/10.1038/nm.4174

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