Interplay between mitochondria and diet mediates pathogen and stress resistance in Caenorhabditis elegans

Diet is a crucial determinant of organismal biology; interactions between the host, its diet, and its microbiota are critical to determining the health of an organism. A variety of genetic and biochemical means were used to assay stress sensitivity in C. elegans reared on two standard laboratory diets: E. coli OP50, the most commonly used food for C. elegans, or E. coli HT115, which is typically used for RNAi-mediated gene knockdown. We demonstrated that the relatively subtle shift to a diet of E. coli HT115 had a dramatic impact on C. elegans's survival after exposure to pathogenic or abiotic stresses. Interestingly, this was independent of canonical host defense pathways. Instead the change arises from improvements in mitochondrial health, likely due to alleviation of a vitamin B12 deficiency exhibited by worms reared on an E. coli OP50 diet. Increasing B12 availability, by feeding on E. coli HT115, supplementing E. coli OP50 with exogenous vitamin B12, or overexpression of the B12 transporter, improved mitochondrial homeostasis and increased resistance. Loss of the methylmalonyl-CoA mutase gene mmcm-1/MUT, which requires vitamin B12 as a cofactor, abolished these improvements, establishing a genetic basis for the E. coli OP50-incurred sensitivity. Our study forges a mechanistic link between a dietary deficiency (nutrition/microbiota) and a physiological consequence (host sensitivity), using the host-microbiota-diet framework. Author summary Vitamin B12 deficiency affects 10-40% of US adults, causing a range of health issues ranging from anemia to neurological defects. Here we provide a mechanistic link between dietary B12 deficiency and mitochondrial dysfunction. Our data indicate that B12 supports clearance of propionate, an intermediate of branched chain amino acid metabolism. Excess propionate compromises mitochondrial homeostasis, increasing susceptibility to abiotic stresses and bacterial pathogenesis. Importantly, this deficiency is absent when worms are fed a diet of E. coli HT115. C. elegans reared on E. coli OP50 are predisposed to a variety of health defects, including increased sensitivity to bacterial pathogens and stresses; these subtle phenotypes may be difficult to recapitulate under conventional RNAi feeding conditions with HT115, introducing unexpected experimental confounds. These findings reinforce the importance of considering the host-microbiota-nutrient axis when using this model organism.