Head dopaminergic and serotonergic neurons monitor alterations in gut bacterial activity through a gut-brain-gut axis

The brain is suggested to monitor gut microbial changes to critically maintain health, whereas the particular bacterial alterations and the mechanisms involved are largely unclear. Here, through a genome-wide screen, we identified 29 E. coli genes whose inactivation can be surveilled by C. elegans head dopaminergic and serotonergic neurons through increasing host neuronal dopamine and serotonin biosynthesis. Mechanistically, we found that these head neurons respond to the E. coli lack of respiratory chain genes by detecting the bacteria-caused reductions in host labile iron levels that impair intestinal mitochondria, and the intestine-expressed mitochondrial stress sensor ATFS-1 is critically involved. Furthermore, this neuronal response in turn promotes intestinal ferritin-1 expression to counteract bacteria-caused labile iron reduction and thereby maintaining mitochondrial function. Our findings systematically identify bacterial activity changes that elevate brain dopamine and serotonin levels and unveil an unexpected gut-brain-gut axis in which the head neurons inspect bacterial activity-mediated changes in host iron metabolism and mitochondrial function, enlightening crucial roles and mechanisms of brain in surveilling microbial activity alterations.