Change in Bacterial Diversity of Fecal Microbiota Drives Mortality in a Hamster Model of Antibiotic-induced Clostridium difficile Colitis

Abstract

Background C. difficile (C diff) infection results from antibiotic-induced changes in colonic microbiota. DAV131A, an oral adsorbent-based product, can sequester antibiotic (AB) residues in the gut and reduce mortality in a hamster model of moxifloxacin (MXF) or clindamycin (CM) induced C diffcolitis. We studied the link between changes of the bacterial diversity within the fecal microbiota and mortality in this model.MethodsMale Syrian hamsters were administered 30 mg/kg MXF or 5 mg/kg CM subcutaneously once a day for 5 days (D1 to D5) and orally infected at D3 with 104C diffspores. They were orally administered various doses of DAV131A (0, and 200 to 900 mg/kg twice a day), from D1 to D8. Survival was monitored up to D16 and feces were collected (D1 and D3) to characterize the microbiota by 16S rRNA gene profiling. Changes of various α- (Shannon, Observed OTUs and Chao1) and β- (Bray-Curtis dissimilarity and [un]weighted UniFrac) diversity indices between D1 and D3 were obtained for each animal. We analyzed links between (i) DAV131A dose and changes of bacterial diversity and (ii) changes of bacterial diversity and mortality using non parametric tests and logistic regression.ResultsData from 70 and 60 animals were available in the MXF and CM studies, among which 10 and 28 died, respectively. Increasing doses of DAV131A reduced mortality from 100% to 0% and reduced changes in bacterial diversity of the fecal microbiota. Very strong predictors of mortality were changes in Shannon and unweighted UniFrac indices, which were markedly less affected in hamsters who survived (see table below median (min; max) according to vital status and area under the ROC curve, AUROC). Died Survived p AUROC [95% CI] MXF n 1060 Shannon -1.7 (-3.0; -1.0)-1.0 (-1.9; 0.1)<10-40.91 [0.80; 0.99] Unweighted UniFrac 0.61 (0.56; 0.76)0.51 (0.37; 0.65)<10-60.95 [0.89; 0.99] CM n 2832 Shannon -2.2 (-4.3; -0.4)-1.1 (-2.6; 0.0)<10-70.88 [0.78; 0.96] Unweighted UniFrac 0.71 (0.59; 0.84)0.60 (0.49; 0.68)<10-100.94 [0.87; 0.98]ConclusionThe extent of AB-induced changes in gut bacterial diversity correlated with increased mortality in a hamster model of C diff colitis. Higher doses of DAV131A protected fecal microbiota disruption and hence mortality.Disclosures C. Burdet, Da Volterra: Consultant and Research Contractor, Consulting fee; N. Saint-Lu, Da Volterra: Employee, Salary; S. Sayah-Jeanne, Da Volterra: Employee, Salary; P. Hugon, Da Volterra: Employee, Salary; F. Sablier-Gallis, Da Volterra: Employee, Salary; S. Ferreira, Genoscreen: Employee, Salary; A. Andremont, Da Volterra: Consultant, Consulting fee; F. Mentré, Da Volterra: Consultant and Research Contractor, Consulting fee; J. De Gunzburg, Da Volterra: Consultant and Shareholder, Consulting fee