Cefoperazone-treated mice as an experimental platform to assess differential virulence of<i>Clostridium difficile</i>strains

Theriot, Casey M.; Koumpouras, Charles C.; Carlson, Paul E.; Bergin, Ingrid I.; Aronoff, David M.; Young, Vincent B.

doi:10.4161/gmic.19142

Cited by 176 publications

(287 citation statements)

References 43 publications

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“…It is interesting that a large amount of C. difficile in the small intestine at 30 h postchallenge (between 10 5 and 10 6 CFU/g) does not result in disease, whereas 10 7 CFU of C. difficile/g in the cecum results in an increased amount of detectable cytotoxic activity and significant histopathological signs of disease. These data further support that the cecum is the site for optimal C. difficile growth, toxin production, and disease after antibiotic treatment (7,15,23).…”

Section: Discussionsupporting

confidence: 59%

“…There were no significant histological alterations in the stomach or small intestine at any time point. As we reported previously (15), infected animals developed a severe colitis characterized by edema, neutrophilic inflammation, and various degrees of epithelial erosion (Fig. 4).…”

Section: Resultsmentioning

confidence: 60%

“…Each tissue was scored separately and without knowledge of which other tissues belonged to that animal. Histological lesions were categorically scored from 0 (normal) to 4 (most severe) for edema, inflammation, and epithelial damage using previously established scoring criteria (15). Individual parameter scores were summed for a summary histological score with a maximum value of 12.…”

Section: Methodsmentioning

confidence: 99%

“…Vero cell cytotoxicity assays were performed as described previously (15). Briefly, Vero cells were seeded in a 96-well flatbottom microtiter plate at a density of 10 5 cells/well.…”

Section: Methodsmentioning

confidence: 99%

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Dynamics and Establishment of Clostridium difficile Infection in the Murine Gastrointestinal Tract

et al. 2015

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Clostridium difficile infection (CDI) following antibiotic therapy is a major public health threat. While antibiotic disruption of the indigenous microbiota underlies the majority of cases of CDI, the early dynamics of infection in the disturbed intestinal ecosystem are poorly characterized. This study defines the dynamics of infection with C. difficile strain VPI 10463 throughout the gastrointestinal (GI) tract using a murine model of infection. After inducing susceptibility to C. difficile colonization via antibiotic administration, we followed the dynamics of spore germination, colonization, sporulation, toxin activity, and disease progression throughout the GI tract. C. difficile spores were able to germinate within 6 h postchallenge, resulting in the establishment of vegetative bacteria in the distal GI tract. Spores and cytotoxin activity were detected by 24 h postchallenge, and histopathologic colitis developed by 30 h. Within 36 h, all infected mice succumbed to infection. We correlated the establishment of infection with changes in the microbiota and bile acid profile of the small and large intestines. Antibiotic administration resulted in significant changes to the microbiota in the small and large intestines, as well as a significant shift in the abundance of primary and secondary bile acids. Ex vivo analysis suggested the small intestine as the site of spore germination. This study provides an integrated understanding of the timing and location of the events surrounding C. difficile colonization and identifies potential targets for the development of new therapeutic strategies.C lostridium difficile infection (CDI) is the most common cause of health care-associated infectious diarrhea and colitis. CDI results in upwards of 14,000 deaths annually and $4.8 billion in excess health care costs in the United States (1). C. difficile is a Gram-positive, anaerobic, spore-forming bacterium that produces toxins that inactivate Rho family GTPases, resulting in a loss of epithelial barrier function, mucosal inflammation, and intestinal damage (2). Individuals infected with C. difficile exhibit clinical manifestations that can range from mild diarrhea to toxic megacolon and death (2).CDI is initiated by transmission of the environmentally stable spore form of the pathogen. To establish infection, the spore must germinate following interactions with small molecule germinants, which are primarily bile acids (3). After germination, a productive infection will result in vegetative growth of the pathogen, which then produces toxin, resulting in colitis. Thus, CDI results when C. difficile spores encounter an intestinal environment that supports all of the aspects of C. difficile physiology. The use of antibiotics is a primary risk factor for developing CDI due to loss of the protective effects of the gut microbiota, deemed colonization resistance (4-6).The loss of colonization resistance against CDI results in an environment that allows for C. difficile germination and growth. How the gut microbiota mediates coloniza...

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Section: Discussionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

“…Vero cell cytotoxicity assays were performed as described previously (15). Briefly, Vero cells were seeded in a 96-well flatbottom microtiter plate at a density of 10 5 cells/well.…”

Section: Methodsmentioning

confidence: 99%

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Dynamics and Establishment of Clostridium difficile Infection in the Murine Gastrointestinal Tract

et al. 2015

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“…A model of CDI recurrence was developed from our previously described mouse CDI model (11,17,18). In all three experiments (n ϭ 82), mice received 0.5 mg of cefoperazone (MP Biochemicals, catalog no.…”

Section: Animals and Housingmentioning

confidence: 99%

Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease

et al. 2015

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dRecurrent Clostridium difficile infection (CDI) is of particular concern among health care-associated infections. The role of the microbiota in disease recovery is apparent given the success of fecal microbiota transplantation (FMT) for recurrent CDI. Here, we present a murine model of CDI relapse to further define the microbiota recovery following FMT. Cefoperazone-treated mice were infected with C. difficile 630 spores and treated with vancomycin after development of clinical disease. Vancomycin treatment suppressed both C. difficile colonization and cytotoxin titers. However, C. difficile counts increased within 7 days of completing treatment, accompanied by relapse of clinical signs. The administration of FMT immediately after vancomycin cleared C. difficile and decreased cytotoxicity within 1 week. The effects of FMT on the gut microbiota community were detectable in recipients 1-day posttransplant. Conversely, mice not treated with FMT remained persistently colonized with high levels of C. difficile, and the gut microbiota in these mice persisted at low diversity. These results suggest that full recovery of colonization resistance against C. difficile requires the restoration of a specific community structure. R ecently, the Centers for Disease Control identified Clostridium difficile as an urgent nosocomial threat. In particular, recurrent C. difficile infection (CDI) is a major concern (1). Up to 30% of patients experience recurrent symptoms following cessation of antibiotic therapy, and subsequent recurrences are more likely after a primary recurrence incidence (2, 3). A healthy, diverse gastrointestinal microbial community, termed the gut microbiota, is important in resistance against the development of CDI. The normal gut microbiota provides colonization resistance (the ability to resist pathogen colonization) against C. difficile (4). In both human studies and animal models, perturbation of the indigenous gut microbiota by antibiotic administration has been correlated to a susceptible community structure, ultimately leading to CDI (5-8). Although it is clear that antibiotic use is correlated with the majority of CDI cases (9), the standard therapy for CDI is the administration of an antibiotic regimen with activity against C. difficile (typically vancomycin or metronidazole). Paradoxically, this may further perturb the intestinal microbial community (10, 11). Therefore, it is important to understand the impact of antibiotic treatment for CDI on recovery of the gut microbiota and colonization resistance.In a murine model of persistent CDI, we have previously shown that the use of sequential antibiotics can delay recovery of bacterial diversity (11). Previous studies have suggested that patients who develop recurrence have a less diverse community than patients who have stable recovery (12). The idea that restoration of the gut microbiota is necessary to prevent or mitigate recurrence is supported by an ϳ90% success rate of fecal microbiota transplantation (FMT) (13), and significant recovery of diver...

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Characterization of the Effects of Candida Gastrointestinal Colonization on Clostridioides difficile Infection in a Murine Model

Romo

Kumamoto

2022

Methods in Molecular Biology

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Cefoperazone-treated mice as an experimental platform to assess differential virulence ofClostridium difficilestrains

Cited by 176 publications

References 43 publications

Dynamics and Establishment of Clostridium difficile Infection in the Murine Gastrointestinal Tract

Dynamics and Establishment of Clostridium difficile Infection in the Murine Gastrointestinal Tract

Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease

Characterization of the Effects of Candida Gastrointestinal Colonization on Clostridioides difficile Infection in a Murine Model

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