Bacterial Metabolism Affects the C. elegans Response to Cancer Chemotherapeutics.

The human microbiota greatly affects physiology and disease; however, the contribution of bacteria to the response to chemotherapeutic drugs remains poorly understood. Caenorhabditis elegans and its bacterial diet provide a powerful system to study host-bacteria interactions. Here, we use this system to study how bacteria affect the C. elegans response to chemotherapeutics. We find that different bacterial species can increase the response to one drug yet decrease the effect of another. We perform genetic screens in two bacterial species using three chemotherapeutic drugs: 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (FUDR), and camptothecin (CPT). We find numerous bacterial nucleotide metabolism genes that affect drug efficacy in C. elegans. Surprisingly, we find that 5-FU and FUDR act through bacterial ribonucleotide metabolism to elicit their cytotoxic effects in C. elegans rather than by thymineless death or DNA damage. Our study provides a blueprint for characterizing the role of bacteria in the host response to chemotherapeutics.

Interspecies systems biology uncovers metabolites affecting C. elegans gene expression and life history traits.

Diet greatly influences gene expression and physiology. In mammals, elucidating the effects and mechanisms of individual nutrients is challenging due to the complexity of both the animal and its diet. Here, we used an interspecies systems biology approach with Caenorhabditis elegans and two of its bacterial diets, Escherichia coli and Comamonas aquatica, to identify metabolites that affect the animal's gene expression and physiology. We identify vitamin B12 as the major dilutable metabolite provided by Comamonas aq. that regulates gene expression, accelerates development, and reduces fertility but does not affect lifespan. We find that vitamin B12 has a dual role in the animal: it affects development and fertility via the methionine/S-Adenosylmethionine (SAM) cycle and breaks down the short-chain fatty acid propionic acid, preventing its toxic buildup. Our interspecies systems biology approach provides a paradigm for understanding complex interactions between diet and physiology.

Complex expression dynamics and robustness in C. elegans insulin networks.

Gene families expand by gene duplication, and resulting paralogs diverge through mutation. Functional diversification can include neofunctionalization as well as subfunctionalization of ancestral functions. In addition, redundancy in which multiple genes fulfill overlapping functions is often maintained. Here, we use the family of 40 Caenorhabditis elegans insulins to gain insight into the balance between specificity and redundancy. The insulin/insulin-like growth factor (IIS) pathway comprises a single receptor, DAF-2. To date, no single insulin-like peptide recapitulates all DAF-2-associated phenotypes, likely due to redundancy between insulin-like genes. To provide a first-level annotation of potential patterns of redundancy, we comprehensively delineate the spatiotemporal and conditional expression of all 40 insulins in living animals. We observe extensive dynamics in expression that can explain the lack of simple patterns of pairwise redundancy. We propose a model in which gene families evolve to attain differential alliances in different tissues and in response to a range of environmental stresses.