Impact of microbiota on the intestinal macrophage compartment

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The pathogenesis of inflammatory bowel diseases (IBD) is incompletely understood. Remarkably the genome wide association studies explain only about one fourth of the disease cases. In parallel the incidence IBD has been increasing steadily since the Second World War, suggesting that environmental factors and ensuing changes in the intestinal microbiota contribute to this development. It may be concluded that intestinal microbiota play a crucial role in the homeostasis of the intestinal mucosa. Macrophage subpopulations strongly determine the balance of the mucosal immune system. While in health regulatory M2 subtypes are predominant, the inflammatory M1 subtype has primarily been found in intestinal inflammation such as inflammatory bowel diseases. With the present project we aim to define the role of microbiota in the development of macrophage subtypes in the intestinal compartment. Whether such effects are restricted to the neonatal phase or can also occur in the adult phase will be elucidated by comparing mice that stay germfree or are associated with microbiota directly after birth or at five weeks of age. To be able to define the functional relevance of microbiota-mediated changes in the intestinal macrophage compartment for IBD, various models of chronic intestinal inflammation will be included. Ultimately, single bacteria or bacterial compounds will be identified that have the potential to modulate the macrophage compartment to the regulatory subtype and thus maintain homeostasis. In parallel, a human in-vitro system with in vitro-polarized macrophages or intestinal macrophages from patients and controls will be used to transfer the findings from the mouse system to the human situation. This translational system will in addition make it possible to assess the functional impact of disease-associated mutations on the microbiota-dependent effects on macrophage subtypes.These studies will characterize the role of defined microbiota in the development of the macrophage development in the intestinal mucosa. The obtained results are expected to help in the development of future therapeutic strategies for the treatment of IBD.