Abstract :
[en] The human gastrointestinal tract (GIT) microbiome plays essential roles in maintaining human health. A variety of diseases including colorectal cancer (CRC) are associated with microbial dysbiosis. Administration of microbial isolates associated with health benefits (e.g. prebiotics) together with specific dietary components (e.g., probiotics) may find application as supportive therapeutic options in the treatment and management of CRC. Although microbiome-modulating therapeutics hold great promise, such approaches are presently not formally integrated into treatment plans.
To obtain better understanding of combined pre- and probiotic regimens in relation to CRC, the present study was dedicated to investigate the effects of selected prebiotics on the proliferation of CRC primary cells and conventional CRC-cell lines, the effects of prebiotics on the growth and metabolism of selected probiotic strains, and the combinatorial/synbiotic effects of selected pre- and probiotics on CRC proliferation. In addition, this work established the in vitro gut-on-a chip HuMiX model with a simulated high-fibre medium for co-culturing human and microbial cells in HuMiX. Furthermore, the anti-carcinogenic combinatorial effects of dietary fiber (e.g., prebiotics), and GIT bacteria (e.g., probiotics) were evaluated using human GIT transcriptomes and metabolomes in HuMiX. An integrated in vitro and in silico modeling approach was finally established to decipher the complex cross-talk between gut bacteria, dietary components and human host cells.
My results demonstrate that in stark contrast to the individual pre- or probiotic treatments, the synbiotic regimen of the probiotic Lactobacillus rhamnosus GG and dietary fiber results in the down-regulation of genes involved in pro-carcinogenic pathways and drug resistance (e.g., ABC transporters) and reduced levels of the oncometabolite lactate. Distinct ratios of organic and short-chain fatty acids are produced during the simulated regimens. Treatment of primary CRC-derived cells with a molecular cocktail reflecting the synbiotic regimen attenuated self-renewal capacity. The developped integrated in vitro and in silico modelling approach provides mechanistic insights into the interplay between pre- and probiotics and elucidation of the microbiota-host relationship. In summary, my dissertation work illustrates the potential of HuMiX to be used for nutritional studies and more precisely for studying the underlying mechanisms of the effects that dietary components (e.g., dietary fiber) and probiotics have on CRC-derived cells. Thereby, this dissertation work highlights the potential for formulating efficacious dietary supplements including synbiotics in the context of therapeutic regimens for microbiome-linked diseases in the future.
