title: 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.
authors: Microbial Pathogenesis Laboratory1 and Pathogen Genomics, Hinxton, United Kingdom. tl2@sanger.ac.uk
authors: Trevor D
authors: TD
authors: Lawley
authors: Simon
authors: S
authors: Clare
authors: Alan W
authors: AW
authors: Walker
authors: David
authors: D
authors: Goulding
authors: Richard A
authors: RA
authors: Stabler
authors: Nicholas
authors: N
authors: Croucher
authors: Piero
authors: P
authors: Mastroeni
authors: Paul
authors: P
authors: Scott
authors: Claire
authors: C
authors: Raisen
authors: Lynda
authors: L
authors: Mottram
authors: Neil F
authors: NF
authors: Fairweather
authors: Brendan W
authors: BW
authors: Wren
authors: Julian
authors: J
authors: Parkhill
authors: Gordon
authors: G
authors: Dougan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002353:Carrier State / Q000382:microbiology*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000472:pathogenicity; D004761:Enterocolitis, Pseudomembranous / Q000635:transmission*; D005260:Female; D016867:Immunocompromised Host; D007422:Intestines / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D013171:Spores, Bacterial / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88