Antibiotic-induced dysbiosis predicts mortality in an animal model of Clostridium difficile infection

• Published in: bioRxiv
• Main Authors: Burdet, Charles, Sayah-Jeanne, Sakina, Nguyen, Thu Thuy, Hugon, Perrine, Fr d rique Sablier-Gallis, Saint-Lu, Nathalie, Corbel, Tanguy, St phanie Ferreira, Pulse, Mark, Weiss, William J, Andremont, Antoine, France Mentr, De Gunzburg, Jean
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 07.05.2018
• Subjects: Animal models; Animals; Antibiotics; Charcoal; Clindamycin; Colonization; Diversity indices; Dysbacteriosis; Intestinal microflora; Intestine; Microbiota; Mortality; Moxifloxacin; rRNA 16S; Survival
• DOI: 10.1101/315382

Background: Antibiotic disruption of the intestinal microbiota favors colonization by Clostridium difficile. Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis, and quantified the link between this intensity and mortality. Methods: We administered either moxifloxacin (n=70) or clindamycin (n=60) to hamsters by subcutaneous injection from day 1 (D1) to D5, and challenged them with a C. difficile toxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0 and D3 using diversity indices determined from 16S rRNA gene profiling. Survival was monitored until D16. We analyzed the relationship between fecal antibiotic concentrations and dysbiosis at the time of C. difficile challenge and studied their capacity to predict subsequent death of the animals. Results: Increasing doses of DAV131A reduced fecal concentrations of both antibiotics, lowered dysbiosis and increased survival from 0% to 100%. Mortality was related to the level of dysbiosis (p<10-5 for the change of Shannon index in moxifloxacin-treated animals and p<10-9 in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the ROC curve of 0.89 [95%CI, 0.82;0.95] and 0.95 [0.90;0.98], respectively. Conclusions Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency to the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in a similar manner with the two antibiotics.