An unexpected benefit from E. coli: how enterobactin benefits host health

Abstract

Iron plays many critical roles in human biology, such as aiding the transport of oxygen and mediating redox reactions. Iron is essential for life, yet little is known about how iron is taken up into mitochondria to impact the labile iron pool. Iron deficiency is one of the most prevalent human nutrient-deficiency diseases in the world and is a major cause of anemia that affects >25% of the world's population, but unfortunately the current treatment (oral iron supplementation) is inefficient and has many side effects. A greater understanding of iron uptake, and discovery of molecules that aid in this process, may lead to more effective treatments for iron deficiency. In this study, we uncovered a unique and surprising role for an Escherichia coli-produced siderophore enterobactin (Ent) that facilitates iron uptake by the host, observed in both C. elegans and mammalian cells. Although siderophores are well-known Fe⁺³ scavengers, this activity has previously been described to only benefit iron acquisition by bacteria, not the host. This unexpected function is dependent on the binding of Ent to the host's ATP synthase α-subunit but is independent of other subunits of the ATP synthase. This finding marks a major shift regarding the role of this siderophore in the "iron tug-of-war" paradigm, which is often used to describe the fight between the bacteria and the host for this essential micronutrient. Instead, this study presents E. coli as a commensal "friend" that provides a molecule that supports the host's iron homeostasis. This work reveals a novel, beneficial role of a bacteria-generated molecule in aiding the host's iron homeostasis, and points to surprising new benefits from commensal bacteria.

Keywords: C. elegans; commensal; holobiont; iron deficiency; microbiome; microbiota; siderophore.

Figure 1. FIGURE 1: A cartoon depiction of the feeding assay used in this study.

The phenotypic outcome of each feeding condition is listed below each plate. (A) Heat-killed E. coli is not sufficient to support worm growth, nor is a trace amount of live E. coli, but when they are combined, worm growth is supported. (B) E. coli mutants deficient in enterobactin (Ent) synthesis did not support worm growth and reduced host iron. (C) Supplementation of Ent to Ent-deficient E. coli rescued worm growth and iron. (D) Feeding abundant Ent-deficient E. coli to worms resulted in a mild growth delay and low iron. The small circles represent trace, live E. coli (green: wild type, pink: Ent^-). The pink shape in (D) represents a lawn of abundant Ent^- E. coli.

Figure 2. FIGURE 2: A cartoon diagram of the interaction between ATP synthase α-subunit from the host, enterobactin from E. coli, and Fe⁺³ from the environment.

Together, this complex brings iron to the host mitochondria.