Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis

Nupur K Das1, Andrew J Schwartz1, Gabrielle Barthel1, Naohiro Inohara2, Qing Liu3, Amanda Sankar4, David R Hill5, Xiaoya Ma1, Olivia Lamberg1, Matthew K Schnizlein6, Juan L Arqués7, Jason R Spence8, Gabriel Nunez2, Andrew D Patterson3, Duxin Sun9, Vincent B Young10, Yatrik M Shah11

  1. Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  2. Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
  3. Department of Veterinary and Biomedical Sciences, the Pennsylvania State University, University Park, PA 16802, USA.
  4. Department of Pediatrics, Division of Hematology-Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
  5. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA.
  6. Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
  7. Departamento Tecnología de Alimentos, INIA, Carretera de La Coruña Km 7, Madrid 28040, Spain.
  8. Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA.
  9. College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
  10. Department of Internal Medicine, Division of Infectious Disease, University of Michigan, Ann Arbor, MI 48109, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
  11. Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: shahy@umich.edu.

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.

Presented By Nupur Das

Metabolism, Immunology & MicrobiologyNicholas Liao2020-01 (Jan)