Dietary acquisition and intestinal absorption in the mammals is the only way by which its systemic iron requirement is fulfilled. We harbor a diverse group of microbial population in our intestines that also rely on host diet for their iron. It is unclear if and how the gut microbiota compete with the host iron absorption pathways. Germ free (GF) and control mice fed with iron-sufficient (350 ppm), moderately iron-containing (35 ppm) and iron-deficient (<5ppm) diets for 2 weeks demonstrated a significant resistance to iron deficiency anemia in the GF compared to the controls. This provides the first evidence of a reciprocal competition between host and commensals for limiting dietary iron. Interestingly, commensals possess an active mechanism that is inhibitory to the host iron transport system. Using a high throughput microbial screen, we demonstrate that gut microbiota produce metabolites that suppresses iron absorptive mechanisms. Specifically, we identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of the master transcription factor for intestinal iron absorption, HIF-2a. This suggested that probiotic based therapies could be utilized in iron overload disorders. Both DAP and reuterin effectively ameliorated systemic iron overload in a mouse model, suggesting these microbiota derived novel HIF-2a inhibitors could be strong candidates for the treatment of various forms of iron overload disorders in human.
