Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis

Nupur K. Das, Andrew J. Schwartz, Gabrielle Barthel, Naohiro Inohara, Qing Liu, Amanda Sankar, David R. Hill, Xiaoya Ma, Olivia Lamberg, Matthew K. Schnizlein, Juan L. Arqués, Jason R. Spence, Gabriel Nunez, Andrew D. Patterson, Duxin Sun, Vincent B. Young, Yatrik M. Shah

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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. Das et al. show that gut microbiota regulate host iron metabolism. Lactobacillus species are the major bacterial players involved in sensing intestinal iron levels and attenuating host iron absorption. The authors further show that mammalian iron disorders can be therapeutically targeted by modulating microbial species or their metabolites.

Original languageEnglish (US)
Pages (from-to)115-130.e6
JournalCell Metabolism
Volume31
Issue number1
DOIs
StatePublished - Jan 7 2020

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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