Enterobactin carries iron into C. elegans and mammalian intestinal cells by a mechanism independent of divalent metal transporter DMT1.

The diverse microbiota of the intestine is expected to benefit the host, yet the beneficial metabolites derived from the microbiota are still poorly understood. Enterobactin (Ent) is a well-known secreted iron-scavenging siderophore made by bacteria to fetch iron from the host or environment. Little was known about a positive role of Ent until a recent discovery in the nematode C. elegans indicated a beneficial role of Ent in promoting mitochondrial iron level in the animal intestine. To solidify this new paradigm, we further tested this role in C. elegans and multiple mammalian cell models and its relationship with the primary iron transporter DMT1/SMF-3 and several other iron-related genes. Here we show that ferric enterobactin (FeEnt) supplementation promotes whole organism development in C. elegans, increases iron uptake in caco-2 human intestinal epithelial cells, and supports iron-dependent differentiation of murine erythroid progenitor cells, indicating that the FeEnt complex can effectively enter these cells and be bioavailable. Our data in multiple models demonstrate that FeEnt-mediated iron transport is independent of all tested iron transporters. In addition, FeEnt supplementation robustly suppresses the developmental defects of a hif-1 mutant under low iron condition, suggesting the critical role in iron homeostasis for this well-known hypoxia regulator. These results suggest that FeEnt can effectively enter animal cells and their mitochondria through a previously unknown mechanism that may be leveraged as a therapeutic ferric iron carrier for the treatment of DMT1- or HIF-1-related iron deficiency and anemia.