Influence of the gut microbiome on plasma metabolite patterns

The gut microbiome has become a burgeoning field of research and is proven to play a role in in many host physiological aspects, also contributing to the blood metabolome that is otherwise produced by tissues of the host organism. In order to increase the mechanistic understanding of how the microbiome influences its host health, there is a need to integrate knowledge of the composition of the gut microbiome with its functionality in terms of microbiota-mediated metabolic processes. The aim of this project was to obtain detailed insight in the mammalian-microbiome co-metabolism of endogenous metabolites and the extent to which the microbiome influences the plasma metabolome observed. This was achieved with the help of the MetaMap®Tox database in which the metabolome and toxicity data of more than 800 compounds are stored. To elucidate this interaction, metabolites produced by the gut microbiome in the blood of our animal model, Wistar rats, had to be determined. Therefore, antibiotics were used to modulate the microbial communities of Wistar-rats. After 28-day oral administration, metabolomics of plasma, feces, and cecum-content was done. Additionally, DNA was extracted from rat feces and the 16S subunit was sequenced to perform a core diversity analysis. Specific plasma metabolome patterns were established, and microbiome-related metabolites identified as key metabolites in MetaMap®Tox. Metabolites such as hippuric acid, indole derivates and glycerol appeared to be microbiome-derived or -associated plasma metabolites. In general, most changes were observed in metabolites belonging to the class of bile acids, complex lipids, fatty acids and related metabolites, as well as amino acids and related metabolites. Especially abrupt changes observed in the bile acid pool after antibiotic administration evidenced a strong influence of the microbiome on bile acid metabolism. In both feces and cecum-content, where almost all plasma metabolites could be determined as well, a treatment-related effect was observed, as well as only minimal, if any, differences between samples of male and female animals. The effects of the tested antibiotics, each possessing a different activity spectrum, could be separated from each other on the basis of the feces and cecum content metabolome. Largest changes were observed for the classes of lipids, bile acids and amino acids. It could also be shown that metabolome changes can be detected equally well in feces as in the cecum content, thus allowing to use a non invasive method for measurements of studies on metabolism by the gut microbiota. In conclusion, the functional microbial changes of the gut microbiome had to be assessed and the interactions between gut microbes and the host by applying metabolomics and taxonomic profiling had to be elucidated. The results of this thesis suggest that plasma and feces based metabolic profiling via a targeted analysis turned out to be a suitable tool to investigate the microbial functionality of the gut microbiome.