Enterobactin, a substance that a gut bacterium uses to obtain iron, acts as a signal that disrupts two enzymes in roundworm neurons and extends the animal’s lifespan
Enterobactin, a substance that a gut bacterium uses to obtain iron, acts as a signal that disrupts two enzymes in roundworm neurons and extends the animal’s lifespan
Filipe Cabreiro’s laboratory at the University of Cologne inactivated nearly 4000 genes in Escherichia coli one at a time and recorded how each change affected the behaviour of the roundworm Caenorhabditis elegans. Worms fed bacteria that produced excess enterobactin, an iron-binding molecule, moved more, maintained their muscles better with age and lived longer. The preprint was posted on bioRxiv on 8 October 2026.
In 2018, another group showed that enterobactin carries iron into worm mitochondria, helping larvae grow. Cabreiro and his team proposed that the same molecule might also regulate behaviour, health and longevity in adult worms. In their screen, genes involved in iron metabolism had the strongest effects on behaviour: worms fed bacteria with an inactivated fepD gene, which brings captured iron back into the bacterium, moved noticeably faster than usual.
Without fepD, the bacterium adjusts its metabolism and produces much more enterobactin to obtain iron. When the researchers inactivated genes required for enterobactin synthesis, the effect disappeared; when they added its precursors, the effect returned. Enterobactin is the strongest iron-binding molecule known in nature. Its iron-binding affinity is expressed as a 1 followed by 52 zeros, with 27 more zeros than the corresponding value for EDTA, a synthetic metal-binding compound.
To identify the mechanism, the researchers tested which proteins enterobactin binds to. Its strongest binding was to the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). Modelling indicated that the molecule occupies the same pocket in GCDH that normally holds the electron carrier FAD and destabilizes the structures of two of the enzyme’s electron-transfer partners. In humans, mutations in this gene cause glutaric acidemia type 1, a disease involving movement disorders. The authors explicitly connect their finding in worms to this disease: the same part of the mitochondrial machinery is vulnerable both to a mutation in humans and to the action of a bacterial substance.
Disrupting electron transfer raises reactive oxygen species levels in neurons. This increase acts as a signal that activates a protective programme, restoring the cell’s protein balance and extending the animal’s lifespan, rather than causing damage. In worms, damage to Complex I or Complex IV in electron transfer had already been shown to trigger a similar response, with two mutually incompatible protective programmes involved. Enterobactin added a third route, originating in bacteria. The antioxidant vitamin C abolished both the increase in movement speed and the lifespan extension; SOD-2 knockout enhanced both effects in the presence of enterobactin, while the pro-oxidant paraquat reproduced them on its own.
NMDA receptors seemed likely to relay the signal because they become overactive in people with the same disease. Blocking them unexpectedly enhanced enterobactin’s effect, indicating that the signal travels through another pathway. The mediator proved to be the PDFR-1 receptor, previously shown to regulate arousal and searching behaviour in worms. Loss of either this receptor or its neuropeptide partner abolished all of enterobactin’s effects on movement, muscles and longevity.
Cabreiro describes the finding this way: enterobactin is a by-product of bacteria competing for the iron they need, and it happens to engage an evolutionarily ancient neuronal pathway in the host and take control of it. The authors call such substances “neuromanipulators”, bacterial molecules that adjust host behaviour to support the bacterium’s own survival while also changing how quickly the host ages.