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. Over the past decade, incidence, severity and costs associated with C. difficile infection (CDI) have increased dramatically. 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. 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.
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Joseph P
JP
Zackular
Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.|Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee, USA.
Jessica L
JL
Moore
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Ashley T
AT
Jordan
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Lillian J
LJ
Juttukonda
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Michael J
MJ
Noto
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Maribeth R
MR
Nicholson
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Jonathan D
JD
Crews
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Matthew W
MW
Semler
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Yaofang
Y
Zhang
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Lorraine B
LB
Ware
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
M Kay
MK
Washington
Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.|Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA.|Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.
Walter J
WJ
Chazin
Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.|Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee, USA.|Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA.|Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
Richard M
RM
Caprioli
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Tennessee Valley Healthcare Systems, US Department of Veterans Affairs, Nashville, Tennessee, USA.
Eric P
EP
Skaar
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D002432:Cecum / Q000473:pathology; D002648:Child; D016360:Clostridioides difficile; D003015:Clostridium Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D015331:Cohort Studies; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004768:Enterotoxins; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D014131:Trace Elements / Q000494:pharmacology*; D055815:Young Adult; D015032:Zinc / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D040502:Calgranulin B; D016207:Cytokines; D004768:Enterotoxins; D012336:RNA, Ribosomal, 16S; C576329:S100A9 protein, mouse; D014131:Trace Elements; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D015032:Zinc
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