Impact of Donor Microbiota on the Efficacy of Fecal Microbiota Transplantation in a Mouse Model of Lethal Bacterial Infection

Authors:
Andrew Benjamin, Ellen Cohn, Jessica Cao, John Alverdy, Olga Zaborina, Rebecca Meltzer, Robert Keskey

Body of Abstract:
Background: A western diet (WD) that is high in fat and low in fiber negatively affects the composition and function of the gut microbiota and has been implicated in a number of poor outcomes following both surgical and infectious stress. We have demonstrated that mice consuming WD experience alterations in their gut microbiota with decreased diversity and reduced metabolite production that are associated with increased mortality when compared to a low fat, high fiber, standard chow diet (SD). Furthermore, we demonstrated that a fecal microbiota transplant (FMT) from an SD FMT donor can rescue an SD recipient from lethal bacterial peritonitis. However, it remains unclear the extent to which the quality of the donor and recipient microbiota impact the efficacy of FMT rescue from lethal infection.

Hypothesis: We hypothesized that dietary induced changes to the FMT donor microbiota impact the ability of FMT to rescue mice from lethal infection, independent of the microbiota of the recipient.

Methods: C57BL/6 male mice were maintained on the following diets varying in fat and fiber composition for 6 weeks prior to the experiment: a standard diet (SD, 18% fat and 18% fiber), western diet (WD, 60% fat and no fiber), and high fat/high fiber diet (HFHF, 45% fat and 30% fiber). An FMT was prepared by sacrificing a healthy littermate and resuspending the cecal contents in sterile saline, using donors from each diet (SD-FMT, WD-FMT, and HFHF-FMT). Infection-related survival was assessed using an established murine model of lethal bacterial infection with intraperitoneal (IP) injection of Serratia marcescens (Sm). Approximately 1mL of FMT was delivered to each mouse via enema at the time of IP Sm and mice were monitored for 24 hours to determine survival. Cecal contents and serum were collected for 16S rRNA sequencing and metabolomics at time of sacrifice.

Results: An SD-FMT delivered to an SD recipient significantly increased gut tryptophan, short chain fatty acids, and indole metabolites without impacting microbiota composition. SD-FMT was associated with significantly reduced disease severity, as seen by lower sepsis scores and higher temperatures, and improved survival in both SD (100% survival with FMT vs 20% without) and WD (75% survival with FMT vs 25% without) recipients (n=5 per group, p=0.011). WD-FMT failed to rescue both SD and WD recipients (n=5 per group, p=0.7). The addition of dietary fiber to a high fat diet (HFHF-FMT) alone was not sufficient to improve survival following IP Sm, indicating that both dietary fat and fiber content are important in shaping an FMT donor microbiota capable of rescuing mice from lethal infection.

Conclusions: FMT results in significant functional changes to the gut microbiota and can rescue mice from lethal bacteria peritonitis, in a manner which is dependent on the FMT donor microbiota, but independent of the recipient. High fat diet-induced changes to the FMT donor microbiota negate this rescue effect.