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<p>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 <i>Serratia marcescens</i> 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.</p>

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Enterobactin inhibits microbiota-dependent activation of AhR to promote bacterial sepsis in mice

  • 期刊论文

  • 发表日期：

    2025年1月8日

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  • Robert C. Keskey,
  • Jason Xiao,
  • Sanjiv Hyoju,
  • Adam Lam,
  • Daniel Kim,
  • Ashley M. Sidebottom,
  • Alexander Zaborin,
  • Anne Dijkstra,
  • Rebecca Meltzer,
  • Abhimanyu Thakur,
  • Kui Zhang,
  • Huanhuan Joyce Chen,
  • Natalia V. Beloborodova,
  • Alisa K. Pautova,
  • Krysta Wolfe,
  • Bhakti Patel,
  • Renee Thewissen,
  • Olga Zaborina,
  • John C. Alverdy

摘要

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.