Shared by Dr. David Cook, MS, PhD
C. diff. Research and Development Community:
Review of: Konigsknecht MJ, CM Theriot, IL Bergin, CA Schumacher, PD Schloss and VB Young. 2015. Infection and Immunity. Dynamics and establishment of Clostridium difficile infection in the murine gastrointestinal tract. Vol 83 (3): pages 934-41.
In this paper from Vince Young’s lab at the University of Michigan Medical School, Konigsknecht et al measure the early events associated with C. difficile infection in a mouse model. Investigators followed the germination, growth, toxin production and histopathology following infection with C. difficile strain VPI 10463 subsequent to a 5 day antibiotic treatment of cefoperazone in the drinking water. Strengths of the work include the sampling every 6 hours of the mouse GI tract–including stomach, small intestine, cecum and colon–over the first 36 hours post-infection. In this brief time span, the investigators observe evidence of bacterial germination and growth, initially in the cecum and large intestine but later spreading to all regions of the small intestine and stomach, with concomitant pathologic effects and mortality. Both spores and toxin are detectable by 24 hours post-infection, consistent with the observation that the transcriptional program associated with sporulation is also likely involved in toxin production. This observation suggests that disease caused by toxin requires a minimal titer in the GI tract, and is consistent with the observation in humans that some individuals are colonized by low levels of C. difficile without evidence of clinical symptoms.
By 30-36 hours post-infection, the levels of vegetative organisms and spores are comparable in stomach and cecum-colon, with lower amounts in the small intestine.Despite the (unexpectedly) high levels of C. difficile observed in stomach and small intestine, tissue damage in the mouse is confined to the cecum and colon, consistent with the site of C. difficile pathology in humans. The authors demonstrate that bile acid profiles are shifted away from detectable secondary bile acids. In addition, microbiota diversity is dramatically decreased in the colon, primarily as a result of the antibiotic regimen, to favor an abundance of Lactobacillus. Both of these observations are consistent with previously published results from the Young lab (Theriot et al, 2014. Nature Communications).
These results further refine our understanding of infection in the mouse model and will enable other researchers to make more precise use of the model in developing new therapies. It should be noted, however, that there are important differences between C. difficile infection and disease in mice and in humans. In the mouse, C. difficile infection leads to rapid mortality. In humans, disease is slower, more chronic due to relapse, and is fatal only in a minority of cases. The microbiome changes are also different. Depending on the antibiotic used, mice can become dominated by a single microbe unlike humans. In the present case, mice were completely dominated by Lactobacillus, a normal commensal in the mouse but one that is mostly absent in humans. The observation in the Konigsknecht study that C. difficile grows in the stomach of mice is also at odds with our understanding of C. difficile infection in humans. Despite these caveats, this is an important work that furthers the science behind understanding C. difficile infection.