Abstract
Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcare-associated pathogens. Here we report that sepsis in mice caused by a defined four-member pathogen community isolated from a patient with lethal sepsis is associated with the systemic suppression of key elements of the host transcriptome required for pathogen clearance and decreased butyrate expression. More specifically, these pathogens directly suppress interferon regulatory factor 3. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner. This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Taken together these results suggest that fecal microbiota transplantation may be a treatment option in sepsis associated with immunosuppression.
Highlights
Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcareassociated pathogens
We infected mice with a pathogen community (PC) isolated from the stool of a surgical patient who died of late-onset sepsis, consisting of three species of bacteria and one species of yeast (Candida albicans)[4] (Supplementary Table 1)
Bacterial lysates prepared from cecal contents of untreated mice (Microbiota) did not lead to a reduction in interferon regulatory factor 3 (IRF3), it did upregulate NFKBIA and TNF Alpha Induced Protein 3 (TNFAIP3) at the highest dose tested (Fig. 3c and Supplementary Fig. 3c). These results suggest that individual members of the PC have both distinct and complementary abilities to directly modulate NF-κB and IRF3 signaling with the net result being blockade of NF-κB and IRF3 signaling in both models of infection
Summary
Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcareassociated pathogens. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Colonization of critically ill patients with MDR pathogens is likely a result of the unusual selective pressures to which these patients and their microbiomes are exposed, including life support measures, prolonged antibiotic use, polypharmacy, and artificial feeding. These well-intentioned interventions can result in collapse of the microbiome, the dysregulation of which is increasingly being demonstrated to have a major adverse effect on the immune system. We demonstrate that a fecal microbiota transplant (FMT) can rescue mice from lethal sepsis due to a defined four-member pathogen community (PC) isolated from a critically ill patient by reversing the immunosuppressive effect of this PC
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