Influence of the gut microbiome on plasma metabolite patterns

Abstract

General introduction Chapter 2 25 Gut microbiome-related metabolic changes in plasma of antibiotic-treated rats Chapter 3 55 Microbiome-related metabolite changes in gut tissue, cecum content and feces of rats treated with antibiotics Chapter 4 87 Impact of lincosamides antibiotics on the composition of the rat gut microbiota and the metabolite profile of plasma and feces Chapter 5 Analysis of metabolome changes in the bile acid pool in feces and plasma of antibiotic-treated rats Chapter 6 General discussion Chapter 7 Summary Appendix Acknowledgements, Curriculum Vitae, List of publications, Overview of completed training activities Although the fundamental role of the microbiome in the well-being of the host is clear, science is now dealing with a bigger challenge, i.e. understanding the mechanisms by which these processes of the tight microbial-host interaction are driven. Integrative approaches that not only assess the composition of the gut microbiome but also its functionality must be implemented to unravel the complex dynamics of these interactions [11]. There are high intra-and interspecies variabilities regarding the composition of the microbiome, however, there are also indications that the functionality in terms of gene activity and metabolic output of the microbes have a lower variability [20-22] which supports assessing functional microbial changes with metabolomics approaches. capacity of metabolites, or the first pass metabolism of xenobiotics can influence the host's metabolism or the toxicity of a compound, which may have implications for the host's health. However, since mechanistic studies are mostly performed in rodents, the results are difficult to extrapolate to humans and other species due to the interspecies differences in the composition of the microbiome. Furthermore, the microbiome is influenced by several factors such as a change in diet, the host condition, radiation, xenobiotics and genetics, which results in a high variability regarding the composition of the microbial community within species, but also between different species [14-16,61-63]. Hence, an essential first step is to identify host species-specific effects, e.g. to measure the endogenous metabolite profile, to identify key metabolites and to correlate them to bacterial species. New technologies such as the omics technologies enable a deep research of the complex interaction between microbiome and host, potentially having the power to elucidate its outstanding role in the developing organism. To understand its role in toxicology and pharmacology, it is essential to determine the microbiota's function, composition, community organization, and resulting host-microbiota interactions. Omics technologies, especially metabolomics, can be suitable tools to identify microbiome-derived orassociated metabolites and to reflect changes in the composition of the microbiota that could potentially lead to disease [18]. Analyzing the production of microbiota-derived metabolites is the first stage of a series of investigations that have th...

New approach methodologies (NAMs) for human-relevant biokinetics predictions

“…In contrast to tumor-derived cell lines, primary cells closely mimic the physiological state of cells in vivo but can on-mans only express one MDR1-encoded protein (P-glycoprotein, P-gp), and BCRP expression is high in rodent kidneys but low in humans (Chu et al, 2013). Differences in physiology may need to be accounted for as well when predicting absorption on the basis of NAMs, including differences in the small intestinal transit time (Sutton, 2004), the intestinal pH and radius (Dressman and Yamada, 1991), microbiome composition (Behr, 2019), and differences in the structure of the gastro-intestinal tract, e.g., no circular folds in the dog (Slatter, 2003) that affect the surface area. Differences in distribution in rat, mouse, dog and human have been associated with differences in protein binding and active transport into organs (Grover and Benet, 2009).…”