Microbes suppress genetic disorders of hyper-activated Ras by inhibiting iron-mediated growth factor modulation in C. elegans

Gut bacteria play crucial roles in promoting host health, but their ability to suppress the effects of genetic defects remains unclear. Ras(gain-of-function, gf) mutations are involved in various developmental disorders, thus identifying bacterial-activity changes capable of repressing the effects of hyper-activated Ras is important. Here, we screened mutations of all non-essential E. coli genes and identified 151 E. coli mutants that mitigate let-60/Ras(gf)-induced vulval developmental abnormalities in C. elegans. Interestingly, bacteria with mutations in genes involved in iron acquisition suppress host Ras(gf)-induced vulval defects through elevating 2,3-dihydroxybenzoic acid, a bacterial siderophore that sequesters iron. Consequently, host mitochondrial iron availability is decreased, which prompts the nuclear accumulation of the chromatin modifier LIN-65 and then downregulates lin-3/EGF transcription to repress Ras(gf)-induced vulval defects. Our findings identify a mechanism for coordinating Ras growth signaling with iron availability, through which gut bacteria suppress host Ras(gf)-induced defects and exemplify the potential of modifying gut bacterial activity to improve genetic diseases.