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Updated: Dec 21, 2025
Cefoperazone-treated Mouse Model of Clinically-relevant Clostridium difficile Strain R20291
Published on: December 10, 2016
Outbreaks of Typhlocolitis Caused by Hypervirulent Group ST1 Clostridioides difficile in Highly Immunocompromised
Kathleen G L Ma1, Kvin Lertpiriyapong2, Alessandra Piersigilli3
1Tri-Institutional Training Program in Laboratory Animal Medicine and Science, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, New York.
Abstract:
Clostridioides difficile is an enteric pathogen that can cause significant clinical disease in both humans and animals. However, clinical disease arises most commonly after treatment with broad-spectrum antibiotics. The organism's ability to cause naturally occurring disease in mice is rare, and little is known about its clinical significance in highly immunocompromised mice. We report on 2 outbreaks of diarrhea associated with C. difficile in mice. In outbreak 1, 182 of approximately 2, 400 NOD.Cg-Prkdc/SzJ (NSG) and related strains of mice became clinically ill after cessation of a 14-d course of 0.12% amoxicillin feed to control an increase in clinical signs associated with Corynebacterium bovis infection. Most mice had been engrafted with human tumors; the remainder were experimentally naïve. Affected animals exhibited 1 of 3 clinical syndromes: 1) peracute death; 2) severe diarrhea leading to euthanasia or death; or 3) mild to moderate diarrhea followed by recovery. A given cage could contain both affected and unaffected mice. Outbreak 2 involved a small breeding colony (approximately 50 mice) of NOD. CB17-Prkdc/NCrCrl (NOD-scid) mice that had not received antibiotics or experimental manipulations. In both outbreaks, C. difficile was isolated, and toxins A and B were detected in intestinal content or feces. Histopathologic lesions highly suggestive of C. difficile enterotoxemia included fibrinonecrotizing and neutrophilic typhlocolitis with characteristic 'volcano' erosions or pseudomembrane formation. Genomic analysis of 4 isolates (3 from outbreak 1 and 1 from outbreak 2) revealed that these isolates were closely related to a pathogenic human isolate, CD 196. To our knowledge, this report is the first to describe naturally occurring outbreaks of C. difficile-associated typhlocolitis with significant morbidity and mortality in highly immunocompromised strains of mice.
Insights
Naturally occurring Clostridioides difficile outbreaks caused significant illness and death in highly immunocompromised mice, even without antibiotic use. This highlights the pathogen
Area of Science:
- Microbiology
- Immunology
- Veterinary Pathology
Background:
- Clostridioides difficile is an enteric pathogen causing disease in humans and animals, often linked to antibiotic use.
- Naturally occurring C. difficile disease is rare in mice, with limited understanding of its impact in immunocompromised models.
- Highly immunocompromised mice, such as NSG and NOD-scid strains, are frequently used in research.
Purpose of the Study:
- To report and characterize two distinct outbreaks of naturally occurring Clostridioides difficile-associated diarrhea in highly immunocompromised mice.
- To investigate the clinical presentation, pathological findings, and genomic relatedness of C. difficile isolates from these outbreaks.
- To assess the significance of C. difficile as a cause of morbidity and mortality in immunocompromised mouse models.
Main Methods:
- Clinical observation and documentation of disease signs in affected mouse colonies.
- Isolation and detection of C. difficile toxins A and B from fecal and intestinal samples.
- Histopathological examination of affected tissues to identify characteristic lesions of typhlocolitis.
- Genomic analysis of C. difficile isolates to determine their relationship to known pathogenic strains.
Main Results:
- Two outbreaks of C. difficile-associated diarrhea occurred in NSG and NOD-scid mice, resulting in significant morbidity and mortality.
- Clinical signs included peracute death, severe diarrhea, and milder forms with recovery.
- Histopathology revealed fibrinonecrotizing and neutrophilic typhlocolitis with pseudomembrane formation, consistent with C. difficile enterotoxemia.
- Genomic analysis showed isolates were closely related to the pathogenic human strain CD 196.
Conclusions:
- Naturally occurring Clostridioides difficile outbreaks can cause severe disease and mortality in highly immunocompromised mice, independent of antibiotic administration.
- These findings underscore the importance of C. difficile surveillance in research settings involving immunocompromised animal models.
- The study provides the first description of naturally occurring C. difficile-associated typhlocolitis with significant impact in these susceptible mouse strains.
