Hepcidin sustains Kupffer cell immune defense against bloodstream bacterial infection via gut-derived metabolites in mice
Yihang Pan, Lihua Shen, Zehua Wu, Xueke Wang, Xiwang Liu, Yan Zhang, Qinyu Luo, Sijin Liu, Xiangming Fang, Qiang Shu, Qixing Chen
Yihang Pan, Lihua Shen, Zehua Wu, Xueke Wang, Xiwang Liu, Yan Zhang, Qinyu Luo, Sijin Liu, Xiangming Fang, Qiang Shu, Qixing Chen
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Research Article Immunology Infectious disease

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

Abstract

Bloodstream bacterial infections cause one-third of deaths from bacterial infections, and eradication of circulating bacteria is essential to prevent disseminated infections. 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–derived 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 Lactobacillus intestinalis and a concomitant reduction in the gut-to-liver shuttling of its metabolite IPA. IPA supplementation or L. intestinalis 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 L. intestinalis 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.

Authors

Yihang Pan, Lihua Shen, Zehua Wu, Xueke Wang, Xiwang Liu, Yan Zhang, Qinyu Luo, Sijin Liu, Xiangming Fang, Qiang Shu, Qixing Chen

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Figure 2

Hepcidin deficiency impairs KCs to clear invading bacteria.

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Hepcidin deficiency impairs KCs to clear invading bacteria. (A) Represen...
(A) Representative intravital microscopy (IVM) images showing KCs (red) capturing circulating E. coli–GFP (yellow) in Hamp1–/– and WT mice. Scale bars: 20 μm. (B) Number of E. coli–GFP captured per KC. n = 6 per group; data are presented as mean ± SEM. (C) Representative IVM images of KCs (red) in Hamp1–/– and WT mice. Scale bars: 50 μm. (D) Total number of KCs (per field of view) in Hamp1–/– and WT mice. n = 8 per group; data are presented as mean ± SEM. (E) Flow cytometry analysis of liver CD45+F4/80+CD11bint cells of Hamp1–/– and WT mice with t-distributed stochastic neighbor embedding dimension reduction. (F) Quantitative analysis of subsets of KCs (KC1 and KC2) in liver CD45+F4/80+CD11bint cells of Hamp1–/– and WT mice. n = 7–8 per group; data are presented as mean ± SEM. (G–J) IVM images (G) combined with 3-dimensional reconstruction (H) to analyze KC volume (I) and surface area (J) in Hamp1–/– and WT mice. Scale bars: 20 μm. n = 6 per group; data are presented as mean ± SEM. *P < 0.05, ****P < 0.0001, by 2-tailed Student’s t test. Data presented are from 6 (A and B), 8 (C and D), 4 (E and F), and 6 (G–J) independent experiments. Each symbol represents an individual mouse (A–F). Symbols represent individual KCs from 6 mice with 5 fields of view per mouse (I and J).