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A Method to Assess Bacteriocin Effects on the Gut Microbiota of Mice
Published on: July 25, 2017
Enterobactin inhibits microbiota-dependent activation of AhR to promote bacterial sepsis in mice
Robert C Keskey1,2, Jason Xiao3, Sanjiv Hyoju4
1Section of General Surgery, Department of Surgery, University of Chicago, Chicago, IL, USA. rkeskey@uchicagomedicine.org.
Abstract:
Sepsis is a major cause of morbidity and mortality, but our understanding of the mechanisms underlying survival or susceptibility is limited. Here, as pathogens often subvert host defence mechanisms, we hypothesized that this might influence the outcome of sepsis. We used microbiota analysis, faecal microbiota transplantation, antibiotic treatment and caecal metabolite analysis to show that gut-microbiota-derived tryptophan metabolites including indoles increased host survival in a mouse model of Serratia marcescens sepsis. Infection in macrophage-specific aryl hydrocarbon receptor (AhR) knockout mice revealed that AhR activation induced transcriptional reprogramming in macrophages and increased bacterial clearance and host survival. However, culture supernatants from multiple bacterial pathogens inhibited AhR activation in vitro. We showed that the secreted siderophore, enterobactin, inhibited AhR activation in vitro and increased sepsis mortality in vivo. By contrast, oral or systemic tryptophan supplementation increased survival. These findings show that sepsis survival depends upon the interplay between pathogen inhibition and the activation of AhR by a microbiota-derived metabolite.
Insights
Gut microbiota metabolites, like indoles, enhance survival in sepsis by activating the aryl hydrocarbon receptor (AhR). Pathogen-secreted enterobactin inhibits AhR, increasing sepsis mortality, highlighting a critical host-microbe interaction for survival.
Area of Science:
- Microbiology
- Immunology
- Metabolomics
Background:
- Sepsis significantly contributes to mortality and morbidity, with limited understanding of survival mechanisms.
- Pathogen subversion of host defenses may critically influence sepsis outcomes.
- The role of host-microbiota interactions in sepsis pathogenesis is increasingly recognized.
Purpose of the Study:
- To investigate the influence of gut microbiota and their metabolites on host survival during sepsis.
- To elucidate the role of the aryl hydrocarbon receptor (AhR) pathway in sepsis.
- To identify pathogen-derived factors that may counteract host protective mechanisms.
Main Methods:
- Utilized a mouse model of Serratia marcescens sepsis.
- Employed microbiota analysis, fecal microbiota transplantation, and antibiotic treatment.
- Conducted caecal metabolite analysis, macrophage-specific AhR knockout studies, and in vitro assays.
Main Results:
- Gut microbiota-derived tryptophan metabolites, including indoles, enhanced host survival in a mouse sepsis model.
- Activation of the aryl hydrocarbon receptor (AhR) in macrophages increased bacterial clearance and survival.
- Bacterial pathogen culture supernatants, specifically the siderophore enterobactin, inhibited AhR activation and increased sepsis mortality.
- Oral or systemic tryptophan supplementation improved host survival.
Conclusions:
- Sepsis survival is critically dependent on the balance between pathogen-derived inhibitors and microbiota-derived activators of the AhR pathway.
- Tryptophan metabolites and AhR activation represent potential therapeutic targets for sepsis.
- Understanding host-microbe-metabolite interactions is crucial for developing novel sepsis treatments.
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