Antibiotic Treatment of Clostridium difficile Carrier Mice Triggers a Supershedder State, Spore-Mediated Transmission, and Severe Disease in Immunocompromised Hosts

Abstract

Clostridium difficile persists in hospitals by exploiting an infection cycle that is dependent on humans shedding highly resistant and infectious spores. Here we show that human virulent C. difficile can asymptomatically colonize the intestines of immunocompetent mice, establishing a carrier state that persists for many months. C. difficile carrier mice consistently shed low levels of spores but, surprisingly, do not transmit infection to cohabiting mice. However, antibiotic treatment of carriers triggers a highly contagious supershedder state, characterized by a dramatic reduction in the intestinal microbiota species diversity, C. difficile overgrowth, and excretion of high levels of spores. Stopping antibiotic treatment normally leads to recovery of the intestinal microbiota species diversity and suppresses C. difficile levels, although some mice persist in the supershedding state for extended periods. Spore-mediated transmission to immunocompetent mice treated with antibiotics results in self-limiting mucosal inflammation of the large intestine. In contrast, transmission to mice whose innate immune responses are compromised (Myd88 ؊/؊ ) leads to a severe intestinal disease that is often fatal. Thus, mice can be used to investigate distinct stages of the C. difficile infection cycle and can serve as a valuable surrogate for studying the spore-mediated transmission and interactions between C. difficile and the host and its microbiota, and the results obtained should guide infection control measures.

Crossing the scale from within-host infection dynamics to between-host transmission fitness: a discussion of current assumptions and knowledge

“…Several studies of transmission in animal hosts have also shown a scaling of transmission fitness with pathogen load, e.g. Salmonella and Clostridium difficile transmission in mice [61,62] and Escherichia coli in cattle [63]. All these examples suggest that for some diseases and under some scenarios, infectiousness might be directly determined by pathogen load.…”

The interplay between microbiome dynamics and pathogen dynamics in a murine model ofClostridium difficileInfection

“…22 In some cases this can lead to the development of colitis. 23,24 In this present study, we utilized antibiotic-treated mice to demonstrate that altering the community structure of the indigenous gut microbiota is associated with both the loss of colonization resistance against C. difficile and differences in the severity of disease.…”

Both, toxin A and toxin B, are important inClostridium difficileinfection.

“…The mouse model is well established to study colonisation but has recently also been developed as an infection model. 29 The piglet model has also been described as mimicking CDI well. 30 Throughout these studies, it should be borne in mind that while extremely useful, animals are only a model of human disease.…”