Fecal microbiota transplantation provokes systemic host immune changes that drive the clearance of lethal disseminated pathogens

• Published in: The Journal of immunology (1950) 2017-05, Vol.198 (1_Supplement), p.199-199.19
• Main Authors: Kim, Sangman Michael, DeFazio, Jennifer, Hyoju, Sanjiv, Krezalek, Monika, Khodarev, Nikolai, Sangwan, Naseer, Gilbert, Jack, Zaborina, Olga, Jabri, Bana, Alverdy, John
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.198.Supp.199.19

After several iterations across medical disciplines, fecal microbiota transplantation (FMT) is now widely and effectively used to treat recurrent C. difficile infection. FMT normalizes the composition of the gut microbiota and is widely thought to mediate its protective effects by displacing pathogens in the context of the gut. We have previously shown that the microbiome of patients with severe sepsis consists of a low-diversity pathobiome dominated by multi-drug resistant pathogens. To test the hypothesis that treatment with FMT would protect against sepsis, we employed a gut-derived sepsis model that involves inoculation of a pathogen community (PC) into the gut of surgically-stressed mice. Septic mice receiving FMT derived from healthy mice via enema exhibited a dramatic increase in survival accompanied by restoration of gut microbial diversity. Intriguingly, we observed that treatment with FMT led to alterations to the host transcriptome in extra-intestinal tissues. Given the systemic effects of FMT administration, we next investigated whether FMT could influence survival in a model in which the PC was acutely disseminated via i.p. injection. Remarkably, administration of FMT in the gut markedly increased survival and drove the systemic clearance of pathogens. This suggests that the effects of FMT are not merely mediated by gut-confined colonization resistance, but also through the modulation of systemic host physiology in a way that is detrimental to pathogens. Comparative transcriptomics suggested that in both models the FMT rescue effect depends on the upregulation of the IRF3/Type I IFN signaling pathways, and using knockout mice we demonstrated that IRF3 is required for FMT-mediated protection and pathogen clearance.