期刊
CELL METABOLISM
卷 31, 期 1, 页码 115-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2019.10.005
关键词
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资金
- NIH, United States [CA148828, DK095201, F31 DK11655]
- University of Michigan Center for Gastrointestinal Research, United States [DK034933]
- University of Michigan, United States-GI Spore [CA130810]
- Clinical and Translational Science Award (CTSA) from The Michigan Institute for Clinical & Health Research (MICHR), United States [UL1TR000433]
- Pennsylvania Department of Health, United States
- Spanish Ministry of Science Innovation and Universities, Spain [RTA2017-00002-00-00]
- University of Michigan, United States Microbiome Explorer Program
- NIAID, United States Novel Alternative Model Systems for Enteric Diseases (NAMSED) consortium [U19AI116482]
- NIAID, United States [U01AI124255]
- Crohn's & Colitis Foundation, United States Senior Research Award [410234]
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 2 alpha (HIF-2 alpha) 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-2 alpha 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.
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