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

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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.

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