Journal
NATURE MEDICINE
Volume 22, Issue 11, Pages 1330-1334Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4174
Keywords
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Funding
- US Department of Veterans Affairs (Merit Review Award) [1I01BX002482]
- US National Institutes of Health (NIH) [R01 AI101171, P41 GM103391-05]
- Vanderbilt Digestive Disease Research Center (VDDRC) [P30DK058404]
- NIH-NIDDK [T32DK007673]
- NIH-NIAID [F32AI120553]
- NIH-NIGMS [T32GM065086]
- Thrasher Research Fund Early Career Award
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Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and is an urgent public health concern worldwide(1). Over the past decade, incidence, severity and costs associated with C. difficile infection (CDI) have increased dramatically(2). 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 rise(3,4). 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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