Interactions between epithelial Stem Cells and Bacteria in gastrointestinal Homeostasis and Carcinogenesis

• Applicant: Professor Dr. Michael Sigal
• Subject Area: Gastroenterology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 415844804

The gastrointestinal epithelium creates a physical barrier separating the luminal microbiota from the host. In addition to its passive barrier function, it is the central interface of signal transduction between the luminal microbiota and the host.The close interaction between the epithelium and the microbiota is important for a variety of physiological processes. However, it also bears the risk of injury to the epithelium and disruption of its homeostasis by pathogens. Major gastrointestinal pathologies such as inflammatory bowel diseases and gastrointestinal cancers are associated with a loss of epithelial integrity, disruption of the mucosal barrier and increased epithelial colonization with bacteria. Since several bacterial species are able to induce severe genomic damage to epithelial cells upon close contact, it appears crucial to understand the processes that enable the required exposure of the epithelium to the microbiota but at the same time limit the interaction to reduce the risk of injury.Gastrointestinal epithelia are organized into clonal glands or crypts that have a similar organization throughout the gastrointestinal tract. The base of these invaginations contains long-lived stem cells that constantly give rise to and replace the short-lived differentiated cells at the mucosal surface, which are being shed into the lumen6. This enables a rapid turnover of surface cells, whereas the stem cells in the base are located away from the lumen where they are more protected. While interaction of bacteria with differentiated cells could lead to the described beneficial effects, mislocalization to the stem cell compartment could be the key event leading to a disruption of the homeostasis. On the one hand, direct interaction with bacteria could lead to cellular injury of stem cells, including genomic damage. On the other hand, these interactions could result in severe host responses aimed at limiting the colonization of stem cells. Accordingly, we have identified that Helicobacter pylori, a gastric pathogen and main risk factor for gastric cancer, is able to penetrate the crypt and directly colonize the stem cell compartment. This interaction results in induction of inflammatory responses, increased proliferation of the crypt and development of premalignant gastric lesions.We will characterize the relationships between epithelial stem cells and specific bacteria that chronically colonize the gastrointestinal tract and have pathogenic potential. We will study how bacteria, such as Helicobacter pylori in the stomach and PkS+ E. coli in the colon affect the stem cells by characterizing their transcriptome, genome and investigating their functional and competitive behavior. We will address, which factors control the localization of bacteria and how the host is equipped to prevent stem cell injury induced by bacteria. Moreover, the pathological consequences of stem cell infection will be investigated particularly in the context of cancer.

• DFG Programme: Independent Junior Research Groups