Shaping gut microbiota and immune system by the intestinal epithelial cells: from tissue homeostasis to diseases

Abstract

Intestinal homeostasis is a product of a complex and regulated network among diet, microbiota, gut epithelial cells and the immune system. The great challenge for the gastrointestinal tract is to respond to pathogens and to food antigen while it needs to keep its function, such as nutrient absorption, and to tolerate foreign antigens. Any disturb between these interactions unleashes an inflammatory process that has been associated with a plethora of diseases. Large efforts focusing the role of the interface between gut microbiota and immune system allowed us to understand to impact of gut microbiota in the developing of immune cells and how this contribute for the onset of several diseases, ranging from local inflammatory bowel disease to distant and systemic diseases such as cardiovascular, type 2 diabetes and metabolic syndrome. Despite that, less attention was given to the cross-talk among enteroendocrine cells (EECs), immune system and gut microbiota. EECs are cells scattered throughout the intestinal epithelium and can secrete more than twenty hormones, among them GIP and GLP, once they sense nutrients and microbiota metabolites. Thus, EECs may have a paracrine effect on surrounding immune cells within the gut, but also and endocrine effect. But how EECs interact with immune cells and gut microbiota and what are their impacts on intestinal and non-intestinal diseases are still unknown. Here, we hypothesized that EECs play an essential role in gut homeostasis, either by modulating immune cells and/or gut microbiota composition. To address this question, we will take an advantage to use sophisticated genetic mouse model to isolate an/or eliminating EECs by using cre-lox system or tamoxifen-inducible manner the context of inflammatory bowel diseases (colitis), during gut pathogen infection model and to tolerate antigen and generating regulatory T cells. We will further in vitro explore how the absence of these cells impacts the structure and function of the other cells, such as Goblet and Paneth cells. Finally, we will generate organoids in the absence of EECs cells to evaluate their impact in organoid formation structure and functioning regarding the secretion of mucus, antimicrobial peptide and what is the contribution of their secreted hormones in organoid generation. We believe that this project will expand the knowledge about the intricate interaction among all these components in the gastrointestinal tract, which in the future will contribute for new target for therapeutic purposes. (AU)