Dietary Zinc Alters the Microbiota and Decreases Resistance to Clostridium difficile Infection

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 likely influence CDI. Here we show that excess dietary zinc (Zn) significantly alters the gut microbiota and in turn reduces the threshold of antibiotics needed to confer susceptibility to C. difficile infection. In mice colonized with C. difficile, excess dietary Zn severely exacerbates 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 is antimicrobial against C. difficile and an essential component of the innate immune response to CDI. Together, these data suggest that nutrient Zn levels play 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.