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

Summary

Gut-microbiota-derived indoles activate macrophage AhR to enhance bacterial clearance and survival in murine sepsis, while the pathogen siderophore enterobactin suppresses AhR signaling and worsens outcomes. Tryptophan supplementation restored survival, highlighting a microbiota–host–pathogen tug-of-war over AhR.

Key Findings

• Fecal microbiota transplantation and tryptophan metabolites (indoles) increased survival in Serratia marcescens sepsis.
• Macrophage-specific AhR deletion impaired bacterial clearance and survival, indicating a causal role for AhR.
• Culture supernatants from multiple pathogens inhibited AhR activation in vitro.
• Enterobactin, a secreted siderophore, inhibited AhR activation and increased sepsis mortality in vivo.
• Oral or systemic tryptophan supplementation improved survival.

Clinical Implications

While preclinical, the data suggest preserving microbiota-derived AhR agonists (e.g., through antimicrobial stewardship, nutrition) and exploring AhR agonists or strategies that neutralize siderophores. Translation to human sepsis requires careful clinical studies.

Limitations

• Findings are limited to murine models and selected pathogens; human applicability is unproven
• Specific dosing and timing of tryptophan may not translate directly to clinical practice

Future Directions

Test pharmacologic AhR agonists or siderophore-targeting strategies in diverse preclinical sepsis models, and evaluate AhR-related metabolite biomarkers and dietary modulation in human cohorts.