| Description: |
The human gastrointestinal tract is inhabited by trillions microbial cells that mostly form a symbiotic relationship with the host. Bacteria have been studied best with regard to the function and effects in the intestinal tract. Bacteria can promote development of colorectal cancer (CRC), but also inflammatory bowel disease (IBD). The focus of recent studies has shifted to the contribution of bacteria-derived metabolites, the intermediate or end products of metabolic reactions, on the intestinal tract. In this work, we aimed to further delineate to contribution of microbiota-derived metabolites on the intestinal diseases IBD and CRC. First, in chapter 2, the role of microbiota-derived metabolites in colorectal cancer is comprehensively assessed. Here, the focus is on the impact of established contributors, including secondary bile acids, short-chain fatty acids, trimethylamine-N-oxide, indoles and colibactin. A loss of epithelial barrier integrity is a hallmark of IBD. Therefore, we utilized a screen in chapter 3 using the released factors by bacteria after a two-day culture, which were added to intestinal organoids. Here, we identified the bacterial species Fusobacterium nucleatum and Fusobacterium varium to release a compound that is toxic to intestinal organoids. Butyrate is a short-chain fatty acid that has been reported to be secreted by Fusobacterium species, which was confirmed to be released by our strains. Lastly, both Fusobacterium-released metabolites and butyrate induced autophagy in intestinal epithelial cells, indicating that this prolonged autophagy could result in toxicity to the organoids. All in all, this chapter identified Fusobacterium species to secrete butyrate which promoted autophagy and organoid cytotoxicity. Fusobacterium nucleatum is not only associated with IBD, but also with CRC. Thus, in chapter 4 we wondered whether Fusobacterium species secrete metabolites that could promote development of colorectal cancer. A pro-inflammatory compound activating ALPK1 signaling was identified to ... |