Unravelling the functional dynamics between the human gut microbiome and intestinal inflammatory responses

Summary

There is a scientific and societal need for human cell-based models that can be used for the safety assessment of chemicals. The intestine is the most important location for the uptake of orally exposed chemicals and thus one of the organs for which reliable cell models are required within toxicological sciences. The interaction between ingested chemicals, compounds produced by intestinal bacteria and intestinal cells is an important aspect of the functioning of the intestine and therefore for the cell-based models. The first part of this thesis focusses on this interaction of chemicals and intestinal microbial fragments and compounds that interact with the intestinal cells via so called Toll Like Receptors that can activate the intestinal innate immune system. Human cell based models of increasing biological complexity have been evaluated for their responses. In the second part of thesis studies the interactions of the intestinal cells with short-chain fatty acids that are produced by the intestinal microbiota and used by the intestinal cells. Lastly existing data sets on gene expression of different established and novel cell-based intestinal models such as gut-on-a-chip models have been compared. Overall, both existing and novel intestinal models are critically assessed to help define their use in replacing animal studies.