Pan Yihang, Shen Lihua, Wu Zehua, Wang Xueke, Liu Xiwang, Zhang Yan, Luo Qinyu, Liu Sijin, Fang Xiangming, Shu Qiang, Chen Qixing
Department of Clinical Research Center.
Department of Gastroenterology, and.
J Clin Invest. 2025 Jul 3;135(17). doi: 10.1172/JCI189607. eCollection 2025 Sep 2.
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.
血流细菌感染导致三分之一的细菌感染死亡，清除循环中的细菌对于预防播散性感染至关重要。在此，我们发现，系统性铁稳态的主要调节因子铁调素通过调节肠道共生菌衍生的色氨酸衍生物吲哚-3-丙酸（IPA），影响库普弗细胞（KC）对血流细菌感染的免疫防御。铁调素缺乏会损害KC对细菌的捕获，并通过KC的形态变化加剧全身细菌播散。肠道微生物群耗竭和粪便微生物群移植表明，肠道微生物群介导了KC体积的改变。从机制上讲，铁调素缺乏导致产生IPA的共生肠乳酸杆菌丰度降低，其代谢产物IPA从肠道到肝脏的穿梭随之减少。补充IPA或定殖肠乳酸杆菌可恢复铁调素缺乏小鼠的KC体积和肝脏对血流细菌感染的免疫防御。此外，菌血症患者的铁调素水平与抗生素使用天数和住院时间相关。总的来说，我们的研究结果突出了铁调素在通过肠道共生菌肠乳酸杆菌及其色氨酸衍生物IPA维持KC介导的肝脏对血流细菌感染的防御中以前未被认识的作用。更重要的是，我们表明，通过受IPA启发的疗法恢复肠道微生物群与肝脏之间的串扰，可能为增强宿主对铁调素水平低且细菌感染风险高的人群中血流细菌感染的防御提供一种有前景的策略。
