Abstract
ABSTRACTClostridium difficile is a spore-forming anaerobic bacterium that causes colitis in patients with disrupted colonic microbiota. While some individuals are asymptomatic C. difficile carriers, symptomatic disease ranges from mild diarrhea to potentially lethal toxic megacolon. The wide disease spectrum has been attributed to the infected host’s age, underlying diseases, immune status, and microbiome composition. However, strain-specific differences in C. difficile virulence have also been implicated in determining colitis severity. Because patients infected with C. difficile are unique in terms of medical history, microbiome composition, and immune competence, determining the relative contribution of C. difficile virulence to disease severity has been challenging, and conclusions regarding the virulence of specific strains have been inconsistent. To address this, we used a mouse model to test 33 clinical C. difficile strains isolated from patients with disease severities ranging from asymptomatic carriage to severe colitis, and we determined their relative in vivo virulence in genetically identical, antibiotic-pretreated mice. We found that murine infections with C. difficile clade 2 strains (including multilocus sequence type 1/ribotype 027) were associated with higher lethality and that C. difficile strains associated with greater human disease severity caused more severe disease in mice. While toxin production was not strongly correlated with in vivo colonic pathology, the ability of C. difficile strains to grow in the presence of secondary bile acids was associated with greater disease severity. Whole-genome sequencing and identification of core and accessory genes identified a subset of accessory genes that distinguish high-virulence from lower-virulence C. difficile strains.
Highlights
Clostridium difficile is a spore-forming anaerobic bacterium that causes colitis in patients with disrupted colonic microbiota
We found that that clinical isolates belonging to C. difficile’s clade 2 resulted in higher lethality in mice but that these differences in virulence were not attributable to the amount of toxin production or differences in toxin gene sequence
We obtained a diverse array of C. difficile clinical isolates from patients hospitalized at Memorial Sloan Kettering Cancer Center (MSKCC) (n ϭ 21) and Washington University’s (WU) academic medical center affiliate, Barnes-Jewish Hospital (BJH; n ϭ 12) and classified the isolates by using MLST [24, 25]
Summary
Clostridium difficile is a spore-forming anaerobic bacterium that causes colitis in patients with disrupted colonic microbiota. We used a mouse model to test 33 clinical C. difficile strains isolated from patients with disease severities ranging from asymptomatic carriage to severe colitis, and we determined their relative in vivo virulence in genetically identical, antibiotic-pretreated mice. The relative virulence of different clinical C. difficile strains, postulated to determine disease severity in patients, has been more difficult to consistently associate with mild versus severe colitis. Patients with C. difficile infection have a range of other diseases (comorbidities), variable states of immune function, and generally have received diverse combinations of microbiota-disrupting antibiotics [8, 16,17,18,19,20] These complex clinical variables make it difficult to distinguish the role of strain differences in the severity of colitis
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