Norvaisas, P; (2019) Interaction between host, microbiota, diet and drugs in C. elegans and E. coli. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The microbiota regulates many aspects of human health. However, despite great advances in its research, it has proven hard to establish the causal relationship between the effects of the microbiota, drugs and diet on the host physiology. This thesis encompasses the first systematic study of an anticancer drug 5-fluorouracil and antidiabetic drug metformin in terms of their interactions with bacterial metabolism and diet. Metformin and 5-fluorouracil are chemically and pharmacologically distinct drugs which interact with the microbiota via different mechanisms. We have developed novel high-throughput screening approaches and applied multi-omics and computational systems biology methods to elucidate the interplay of multiple factors regulating efficacy of these drugs in the C. elegans and E. coli host-bacteria model. We show that bacteria can either enhance or suppress the efficacy of 5-fluorouracil through direct drug conversion, which depends on bacterial vitamin B6, B9, and ribonucleotide metabolism, as well as through disturbances in bacterial deoxyribonucleotide pools. Importantly, we have discovered a novel drug-bacteria interaction mechanism. We show that metformin's effects are controlled by the bacterial nutrient sensing transcription factor Crp and notably regulated by diet. Crp activation in metformin treatment rewires bacterial metabolism and leads to agmatine accumulation, which we identified as the key metabolic link between metformin's effects on the bacteria and the host. We also describe metformin induced bacterial phenotype changes, which may explain some of its effects on the gut microbiota and document metformin resistance mechanisms and its possible targets in bacteria. Overall, our findings reveal a key role of bacteria in integrating environmental factors such as drugs and diet to regulate host physiology. Our study establishes an experimental platform for further investigation of complex host-microbe-drug-diet interactions in animal models and highlights the possibility of modulating the microbiota for host health benefits.

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