In recent years, much attention has been paid to the cellular and organismal responses to dietary restriction, however less attention has been paid to responses to dietary composition, which can also have profound effects on physiology. We sought to elucidate the mechanisms connecting dietary composition, metabolic gene regulation, and physiological responses.
In its natural environment, C. elegans encounters diverse bacterial diets. Compared to a diet of E. coli OP50, a diet of Comamonas aquatica accelerates C. elegans developmental rate, reduces fecundity and shortens lifespan. These physiological responses are accompanied by gene expression changes. Taking advantage of this natural, genetically tractable predator-prey system, we performed genetic screens i) in C. elegans to identify regulators of diet-responsive genes, and ii) in E. coli and Comamonas to determine dietary factors driving transcriptional and physiological responses in C. elegans. We identified a C. elegans transcriptional program that regulates metabolic genes in response to vitamin B12 content in the bacterial diet, and find that vitamin B12 supplementation accelerates development.
Interestingly, several B12-responsive metabolic genes of unknown function are transcriptionally activated when B12 levels are low and flux through the canonical B12-dependent propionate breakdown pathway is impaired. Mutation of these genes renders animals sensitive to propionate-induced toxicity on low B12-diets. We hypothesize that these genes form an alternate, B12-independent, beta-oxidation-like propionate breakdown shunt in C. elegans. In support of this hypothesis, metabolomics revealed a unique intermediate from the putative shunt, and this metabolite accumulates when we mutate a predicted downstream enzyme. We propose that C. elegans has evolved an adaptive response to low-B12 content bacterial diets, in which novel propionate breakdown genes are transcriptionally unregulated to compensate for reduced canonical propionate breakdown pathway function.
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