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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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.
The authors declare no competing financial interests.
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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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