Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis

Cell Metab. 2020 Jan 7;31(1):115-130.e6. doi: 10.1016/j.cmet.2019.10.005. Epub 2019 Nov 7.

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.

Keywords: EPAS1; HIF; HIF-2a; anemia; ferritin; hemochromatosis; hypoxia; hypoxia-inducible factor; iron; metabolites; microbiota.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Line
  • Cell Proliferation / drug effects
  • Diamines / pharmacology
  • Dimerization
  • Duodenum / drug effects
  • Duodenum / microbiology
  • Feces / microbiology
  • Female
  • Ferritins / genetics
  • Ferritins / metabolism*
  • Gastrointestinal Microbiome* / physiology
  • Glyceraldehyde / analogs & derivatives
  • Glyceraldehyde / pharmacology
  • Homeostasis
  • Humans
  • Iron / metabolism*
  • Lactobacillus / genetics
  • Lactobacillus / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Organoids / drug effects
  • Organoids / microbiology
  • Probiotics / pharmacology
  • Propane / pharmacology
  • Signal Transduction / drug effects

Substances

  • Anti-Bacterial Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Diamines
  • endothelial PAS domain-containing protein 1
  • 3-hydroxypropionaldehyde
  • Glyceraldehyde
  • Ferritins
  • trimethylenediamine
  • Iron
  • Propane