Bacterial siderophore suppresses host genetic disorders of hyperactivated Ras by limiting iron deficiency that inhibits growth factor expression.

Gut bacteria promote host health, but their ability to suppress genetic disorders remains unclear. Ras (gain-of-function, gf) mutations are among the most deleterious genetic alterations, highlighting the importance of identifying bacteria-mediated mechanisms that mitigate hyperactivated Ras effects. Here, we screened all non-essential E. coli gene mutations and identified 151 mutants that mitigate let-60/ras(gf)-induced vulval developmental abnormalities in C. elegans. Notably, 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, triggering nuclear accumulation of the chromatin modifier LIN-65. LIN-65 and histone methyltransferase MET-2 then orchestrate the downregulation of lin-3/EGF transcription to repress ras(gf)-driven 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 disorders.