Indole-3-carbinol alleviates Klebsiella pneumoniae-induced sepsis by modulating mitochondrial fragmentation of macrophages

The gut–lung axis shapes host defense, yet the role of commensal metabolites in preserving macrophage mitochondrial function during gram-negative sepsis remains unclear. We investigated whether indole-3-carbinol (I3C) promotes macrophage mitochondrial bioenergetic fitness and mitigates disease severity in a murine model of Klebsiella pneumoniae sepsis. Infection reduced Lactobacillaceae abundance and decreased systemic I3C levels. Oral I3C supplementation restored I3C levels, alleviated lung injury, and improved survival and organ function. However, these benefits were abolished following clodronate-mediated macrophage depletion. Alveolar macrophage transcriptomics and bioenergetics revealed that I3C restores oxidative phosphorylation and limits Drp1-dependent mitochondrial fission via activation of the aryl hydrocarbon receptor (AhR). In patients, low serum I3C levels correlated with higher proinflammatory cytokines, organ failure scores, and shock risk. Our findings indicate that I3C functions as an AhR agonist that preserves macrophage bioenergetic capacity, dampens cytokine storms, and mitigates K. pneumoniae–induced sepsis—supporting I3C as a host-directed therapeutic candidate.