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Here, we found that hepcidin, the master regulator of systemic iron homeostasis, affected Kupffer cell (KC) immune defense against bloodstream bacterial infections by modulating the gut commensal bacteria\u2013derived tryptophan derivative indole-3-propionic acid (IPA). Hepcidin deficiency impaired bacterial capture by KCs and exacerbated systemic bacterial dissemination through morphological changes in KCs. Gut microbiota depletion and fecal microbiota transplantation revealed that the gut microbiota mediated the alteration of KCs volume. Mechanistically, hepcidin deficiency led to a decreased abundance of the IPA-producing commensal\n                    <jats:italic>Lactobacillus intestinalis<\/jats:italic>\n                    and a concomitant reduction in the gut-to-liver shuttling of its metabolite IPA. IPA supplementation or\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>intestinalis<\/jats:italic>\n                    colonization restored the KC volume and hepatic immune defense against bloodstream bacterial infection in hepcidin-deficient mice. Moreover, hepcidin levels in patients with bacteremia were associated with days of antibiotic usage and hospitalization. Collectively, our findings highlight a previously unappreciated role of hepcidin in sustaining KC-mediated hepatic defense against bloodstream bacterial infections through the gut commensal\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>intestinalis<\/jats:italic>\n                    and its tryptophan derivative IPA. More importantly, we show that restoring the crosstalk between the gut microbiota and liver through IPA-inspired therapies may offer a promising strategy for enhancing the host defense against bloodstream bacterial infections in those with low hepcidin levels and a high risk for bacterial infections.\n                  <\/jats:p>","DOI":"10.1172\/jci189607","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T15:05:23Z","timestamp":1751555123000},"source":"Crossref","is-referenced-by-count":8,"title":["Hepcidin sustains Kupffer cell immune defense against bloodstream bacterial infection via gut-derived metabolites in mice"],"prefix":"10.1172","volume":"135","author":[{"given":"Yihang","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Clinical Research Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, 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