A gut-brain-gut axis orchestrates host responses counteracting microbiome-induced iron insufficiency.

The brain monitors changes in the gut microbiome to maintain health, but the impact of specific bacterial alterations, as well as the underlying mechanisms, remains largely unclear. Here, we discovered an unexpected neuronal regulation of iron metabolism, mediating the neuronal surveillance of gut bacterial activity in C. elegans. Specifically, through a genome-wide screen, we identified 29 E. coli genes, mainly linked to metabolism regulation, whose inactivation could increase dopamine and serotonin biosynthesis in C. elegans head neurons. These neurons respond to the lack of respiratory chain genes in E. coli in the gut by perceiving intestinal mitochondrial impairment resulting from bacterial-induced reduction in host labile iron levels. Such neuronal responses subsequently promote intestinal ferritin-1 expression to counteract bacterially induced labile iron reduction, thus maintaining mitochondrial function. Our findings reveal how alterations in bacterial metabolism can elevate dopamine and serotonin levels in the host brain, demonstrating that the nervous system not only senses microbiome-caused changes in the gut but also feeds back to revert them.