Molecular regulation of intestinal epithelial cell (IEC) differentiation and function – A novel role for the transcription factor c-Maf

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Throughout the last years it has become increasingly clear that the intestinal epithelium has a remarkable capacity to dynamically adapt to environmental changes, such as alterations of the microbiota, in response to inflammation, injury or variations in energy supply and demand. This plasticity, which has been coined epithelial remodelling, is characterized by a coordinated reshaping of the intestinal epithelial structure and function to appropriately respond to changing environmental input and to eventually restore homeostasis. Especially, the critical importance of intestinal plasticity for maintaining energy balance of the whole organism has been highlighted, yet the molecular mechanisms and transcriptional mediators governing the nutritional remodelling of the intestinal epithelium have remained incompletely defined. Another aspect that has not been studied in detail yet is the impact of inflammation on intestinal epithelial cells and nutrient uptake. Recently, we and others identified c-Maf as a novel master transcriptional regulator of the small intestinal (SI) epithelium, which critically controls the differentiation and function of enterocytes, especially their capacity to sense and take up nutrients. Based on this work, we hypothesize that c-Maf also plays a key role in SI remodelling processes that are characterized by (temporary) changes in the intestinal nutrient uptake capacity. Thus, in this project, we aim to define how c-Maf-dependent nutritional adaption of the SI to different metabolic challenges (e.g. maternal lactation and SI inflammation) is characterized on the cellular and molecular level and how it determines host energy status and function. Furthermore, we seek to identify the underlying molecular mechanisms by which c-Maf controls enterocytes and the specific environmental signals that modulate its expression. Finally, the translational relevance of our work will be determined by investigating c-Maf expression and function in human enterocytes from healthy and inflamed SI tissue. In sum, this study will allow us to specifically define the molecular circuits that govern the nutritional remodelling of the SI epithelium, including pathological adaptations that are linked to intestinal inflammation. The anticipated results will provide an unprecedented resource of SI epithelial remodelling and carry novel implications for the modulation of the absorptive capacity of the gut.