O01 - Replenishing the core gut microbiome via fecal microbiota transplant (FMT) can rescue mice from advanced-stage polymicrobial sepsis
Author(s):
Jennifer DeFazio, Sangman Kim, Scott Christley, Irma Fleming, Baddr Shakhsheer, Bana Jabri, Olga Zaborina, John Alverdy, University of Chicago
Background: During critical illness, the normal gut microbiota are replaced by virulent and multi-drug resistant (MDR) healthcare acquire pathogens (HAPs).
Hypothesis: The aim of this study was to test the hypothesis that replenishing the microbiota with a fecal microbiota transplant (FMT) could rescue mice with advanced stage polymicrobial sepsis due HAPs.
Methods: We developed a novel model of lethal polymicrobial gut-derived sepsis due to MDR-HAPs in mice. Mice underwent a 30% hepatectomy with intestinal inoculation of a well characterized MDR human pathogen community (HPC) from the stool of a patient dying of sepsis. 100% of mice developed clinically apparent severe sepsis by 24 hours confirmed by positive cultures of the HPC in the lung, liver, spleen and blood (n=24) with only 30% surviving to day 7. In reiterative experiments, when mice appeared frankly septic at 24 hours, they were assigned to receive either a fecal microbiota transplant (FMT- cecal contents of normal, healthy mice in H20) or an autoclaved (AC) FMT via enema. When moribund, mice were sacrificed and underwent 16S rRNA analysis of the gut microbiota on cecal contents and tissues. Filtered cecal lysates were inoculated onto bone marrow-derived dendritic cells (BMDCs) to assess the direct effect of the microbiota on immune function.
Results: FMT resulted in an 87% survival rate as compared to AC which resulted in only 17% survival (n=15/group, p<0.001). FMT mice appeared completely healthy on POD 7. 16S rRNA showed a shift of the microbiota at the initiation of sepsis and in all groups through POD 7 (p<0.05). There was also a significant decrease in Enterobacteriaceae and Enterococcus in FMT vs. AC (p<0.05). The presence of Coprobacteriaceae was associated with survival during FMT treatment (p<0.05). BMDC assays demonstrated differentially expressed cytokines between groups; IL-6 and IL-10 were increased in the FMT mice compared to AC mice (P<0.05). Finally, the BMDC assays performed on healthy appearing surviving mice on POD7 from both groups demonstrated that FMT microbiota induced cytokines at a low baseline level compared to AC microbiota which remained proinflammatory as judged by IL- 6, 10, 12, RANTES, and TNF (P<0.01).
Conclusions: Fecal Microbiota Transplant rescued mice from advanced stage polymicrobial sepsis due to MDR- HAPs possibly owing to its effect on both local and systemic immune function.