Bacterial metabolites alter the consequences of reduced insulin signaling in C. elegans via increasing the expression of the acid sphingomyelinase asm-3

Abstract Individuals consuming an identical diet often exhibit vast differences in their physiological response to the same nutrients. Studies of identical twins and genetically identical laboratory animals have both shown that much of this variability cannot be explained by differences in genetics. Differences in gut microbes and local microflora have emerged as a leading potential source of this variability, but mechanistic investigations of three-way host-microbe-diet interactions are difficult in most animals. Here, we find that dietary sugar availability suppresses the longevity, dauer formation and gene expression changes of daf-2 (insulin-like receptor) mutants fed Escherichia coli OP50, but not daf-2 mutants fed many other bacteria. To determine how sugar availability and bacteria intersect to affect C. elegans insulin signaling we conducted transposon mutagenesis screens and found that the effects of sugar availability on C. elegans insulin signaling depend on bacterial pyruvate dehydrogenase activity. We further found that reducing bacterial pyruvate dehydrogenase activity results in increased pyruvate and lactate accumulation and induced host expression of the acid sphingomyelinase asm-3 . Lastly, we find that asm-3 is required for the loss of pyruvate dehydrogenase activity to alter the phenotype of daf-2 mutants. Collectively, our findings establish a novel link between bacterial pyruvate metabolism and host insulin signaling that is mediated by altering the expression of a host acid sphingomyelinase.