Spatial Organization of the Microbiota - Impact of Direct Bacterial Interaction with the Colonic Crypt Epithelium and Long-lived Stem Cells

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Our microbiota is a complex community and within the recent years, our understanding of its composition has dramatically improved. Inflammatory, dietary and malignant conditions are associated with quantitative changes of the microbial composition in the gut. While these quantitative differences are well established, little is known about the exact distribution and changes of the spatial organization of the microbiota. Recent work has demonstrated that dietary and inflammatory changes might be associated in translocation of luminal bacteria towards the gut epithelium but the exact conditions and the impact of this translocation are still not known.We hypothesize that development of chronic pathological conditions in the gut are promoted by pathological translocation of luminal bacteria towards the gut epithelium. Direct attachment of commensal luminal bacteria to specialized epithelial gut cells in the crypt and in particular to stem cells in the crypt base may result in direct epithelial damage as well as indirect injuries through induction of severe immunological responses.We will apply visualization technologies as well as new computational analysis systems to study the relation of the bacteria to the host epithelial anatomy in healthy intestinal tissue and in samples from patients with inflammatory bowel diseases and colorectal malignancies. To unravel the conditions that promote translocation of bacteria towards the epithelium and to study the impact of direct interaction of certain bacterial strains with the epithelial stem cells, we will use stem cell reporter mice as well as a new primary epithelial culture system. In mice, the impact of inflammation and dietary changes for spatial reorganization of the microbiota and responses, mediated specifically by the stem cells will be studied. Furthermore, colonization of mice with specific bacterial strains that have the ability to attach to the gut epithelium will be performed. Using primary epithelial human and murine colonic epithelial stem cell-derived in vitro systems, we will study direct effects of certain bacteria and their virulence factors on different subpopulations of epithelial cells including long-lived stem cells. This system will also be modulated to study how specific host factors affect the intestinal mucosal barrier properties.