Hepcidin sustains Kupffer cell immune defense against bloodstream bacterial infection via gut-derived metabolites in mice.

Summary

Using murine models complemented by microbiota depletion, fecal transfer, and metabolite rescue, the authors show that hepcidin deficiency reduces an IPA-producing commensal (Lactobacillus intestinalis), lowers hepatic IPA shuttling, alters Kupffer cell volume/morphology, and impairs bacterial capture, leading to dissemination. Restoring IPA or L. intestinalis rescues Kupffer cell function. In bacteremic patients, hepcidin levels correlated with antibiotic days and length of hospitalization.

Key Findings

• Hepcidin deficiency impaired Kupffer cell bacterial capture and increased systemic dissemination via morphological changes in Kupffer cells.
• Gut microbiota mediated Kupffer cell volume; hepcidin deficiency reduced Lactobacillus intestinalis and gut-to-liver shuttling of its metabolite IPA.
• IPA supplementation or L. intestinalis colonization restored Kupffer cell volume and hepatic defense against bloodstream bacterial infection.
• In patients with bacteremia, hepcidin levels were associated with days of antibiotic use and hospitalization duration.

Clinical Implications

Identifying patients with low hepcidin who are at high risk for bloodstream infections could inform microbiome or metabolite (e.g., IPA) augmentation strategies to enhance hepatic immune clearance.

Limitations

• Primary evidence is from murine models; human validation is associative and not interventional.
• Pathogen spectrum and the safety/feasibility of IPA or microbiome-based therapies in humans remain to be established.

Future Directions

Prospective human studies to phenotype low-hepcidin states in bacteremia and early-phase trials testing IPA or L. intestinalis augmentation to enhance hepatic bacterial clearance.