Bacterial pyruvate metabolism regulates host insulin sensitivity in C. elegans

Abstract

Two different individuals can consume an identical diet but experience different physiological outcomes. While there are many potential mechanistic reasons for this, one increasingly recognized reason is that differences in an animals microbiome can lead to differences in the processing of dietary nutrients. Thus, though a diet might start out the same, how it is experienced by a host is dependent on their microbiome. While exciting, mechanistic studies of diet-microbiome-host effects are often limited by the lack of high throughput laboratory techniques to identify and define interactions between dietary metabolites, microbial metabolism, and host biology. We hypothesized that the model organism Caenorhabditis elegans is an advantageous animal model for rapidly identifying and genetically dissecting interactions between dietary nutrients, microbial metabolism, and host physiology. Here, we used an established model of the effects of dietary glucose on insulin resistant mutant animals (daf-2/IR mutants) to study how differences in bacterial metabolism influence the consequences of dietary sugars on animal physiology. We found that the effect of dietary sugars on daf-2 mutant physiology is dependent on how the microbiome metabolizes dietary sugars. We found dietary sugar suppresses multiple daf-2 mutant phenotypes in the presence of some bacteria but has no effect in the presence of others. To determine how bacteria mediate the effects of dietary sugars on host physiology we screened 5,000 transposon mutations in the canonical C. elegans dietary bacteria, E. coli OP50 for effects on animal insulin signaling. From this, we found that the effects of exogenous sugars on the phenotype of daf-2 mutant animals is dependent on the function of pyruvate dehydrogenase in bacteria and that the loss of bacterial pyruvate dehydrogenase genes (ex. aceE) is sufficient to mimic the effects of dietary sugars on dauer formation, longevity, and gene expression in insulin signaling deficient animals. Collectively, our findings further support the growing body of evidence that the effects of dietary nutrients on animal physiology can be influenced by the gut microbiome. In addition, these studies demonstrate the advantages of the C. elegans model system for studying 3-way diet-microbiome-host interactions that are difficult to dissect in other model systems.