Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.

中文翻译：

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系统性铁稳态需要微生物代谢物信号传导。

铁是所有生物体所需的核心微量营养素。肠道中铁的竞争对于维持本地微生物种群和宿主健康至关重要。宿主和本地微生物之间的共生关系如何在铁限制期间持续存在尚不清楚。在这里，我们证明本地细菌具有抑制宿主铁运输和储存的铁依赖性机制。使用微生物代谢物的高通量筛选，我们发现肠道微生物群产生的代谢物抑制缺氧诱导因子 2α (HIF-2α) 是肠道铁吸收的主要转录因子，并增加铁储存蛋白铁蛋白，导致肠道菌群减少。宿主对铁的吸收。我们确定了 1, 3-二氨基丙烷 (DAP) 和罗伊素作为 HIF-2α 抑制剂，通过抑制异源二聚化。DAP 和罗伊氏素可有效改善全身铁过载。这项工作提供了肠道-微生物群代谢串扰的证据，这对全身铁稳态至关重要。