Enteroendocrine cells: differentiation and function – EEC

Enteroendocrine cells (EECs) are rare cells found along the intestinal mucosa and represent the largest endocrine system in the human body. EECs sense nutrients and dietary metabolites generated by the gut microbiota in the intestinal lumen and, in response, secrete a variety of hormones that act locally or at distance. Enteroendocrine hormones emerged as important regulators of energy homeostasis via their control of intestinal absorption, food intake and insulin secretion. EECs arise from intestinal stem cells but the molecular mechanisms underlying the generation of the diversity of EECs and hormones are poorly understood. Furthermore, the role of the EEC system and of the interplay between EECs and the gut microbiota in intestinal energy metabolism and in the pathogenesis of metabolic diseases remain largely to be discovered. To gain insights into the origin, diversity and biological functions of EECs, we propose to solve the gene regulatory landscape dynamics during human EECs differentiation. Furthermore, we will search for and study the role of novel candidate genes in the implementation of the endocrine program, EECs subtypes specification and function. Next, we will conditionally ablate EECs in the mouse and evaluate the consequences on energy metabolism. In addition, we will study the impact on gut microbiota composition and examine its causal link with the metabolic defects observed in mice lacking enteroendocrine hormones. Finally, to further explore the role of EECs and link with pathology, we will determine the EEC transcriptomic signature, at the single cell level, in a human obese cohort. To achieve this, we will use human intestinal organoids and mouse models in combination with state-of-the-art omics technologies, systems biology and metabolic exploration. We expect that a better understanding - of the molecular mechanisms underlying EEC diversity and hormone production and - of the function of the EEC system and of its interactions with the gut microbiota - will fuel innovative strategies to manipulate them and foster the development of novel treatments for metabolic diseases such as obesity and diabetes.