Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Metab. 2020 Jan 7;31(1):115-130.e6. doi: 10.1016/j.cmet.2019.10.005. Epub 2019 Nov 7.
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.
铁是所有生物都需要的一种重要的微量元素。在肠道中争夺铁对于维持本地微生物种群和宿主健康至关重要。在铁限制的情况下，宿主和本地微生物之间的共生关系如何持续存在尚不清楚。在这里，我们证明了土著细菌拥有一种依赖于铁的机制，可以抑制宿主的铁运输和储存。通过对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）——肠道铁吸收的主要转录因子，并增加铁储存蛋白铁蛋白，从而导致宿主肠道铁吸收减少。我们确定了 1,3-二氨基丙烷（DAP）和雷替丁通过抑制异二聚体抑制 HIF-2α。DAP 和雷替丁有效地改善了全身铁过载。这项工作提供了肠道微生物群代谢串扰的证据，这对于全身铁平衡至关重要。
