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

ABSTRACTClostridium difficilepersists 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. difficilecan asymptomatically colonize the intestines of immunocompetent mice, establishing a carrier state that persists for many months. C. difficilecarrier 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. difficileovergrowth, and excretion of high levels of spores. Stopping antibiotic treatment normally leads to recovery of the intestinal microbiota species diversity and suppresses C. difficilelevels, 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. difficileinfection cycle and can serve as a valuable surrogate for studying the spore-mediated transmission and interactions between C. difficileand the host and its microbiota, and the results obtained should guide infection control measures.