Role of colonic enteroendocrine cells in metabolic control

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Nutrient digestion and absorption are essential functions of the gastrointestinal (GI) tract. By the time the intestinal contents reach the colon, the organ is mostly responsible for water and electrolyte reabsorption. Nonetheless, through the metabolic activities of the colonic microbiota, non-digestible luminal contents are fermented resulting in the flux of many small metabolites that are utilized by both microbial organisms as well as by the host. In fact, it is now estimated that bacterial metabolism contributes ~6-10% of the calories that reach the host. Hence, mechanisms to sense and respond to the metabolic flux originating in the colon would seem essential to metabolic homeostasis. In this regard, the GI epithelium contains enteroendocrine cells (EECs), which produce a variety of hormones that help coordinate GI physiology, as well as metabolic responses in a variety of distant organs. Considering that the location of most digestive and absorptive processes is the small intestine, it is intriguing that the colon produces several hormones that control host metabolism and appetite (e.g., Glp-1, Glp-2, Insl5). Using a mouse model of colonic EEC deficiency (EECCol) we have uncovered that these cells are critical to host metabolic homeostasis. We find that these mice develop obesity, which is mostly due to hyperphagia. Moreover, it is associated with changes in intestinal microbiota (dysbiosis). We hypothesize that the spatial distribution of colonic EECs reflects the significant caloric flux derived from microbial metabolism of non-digestible nutrients. The purpose of this project is to evaluate how colonic EECs modulate host metabolism, with the underlying hypothesis that they act as proximal sensors of metabolic flux originating in the colon. To address this goal, we propose the following aims: Aim 1: How does dysbiosis contribute to the metabolic phenotype resulting from colonic EEC deficiency? Hyperphagia and obesity in EECCol mice can be prevented by treating their dysbiosis. Here we will test the hypothesis that bacterially derived metabolites are responsible for modulating appetite and body weight. Aim 2: How is colonic EEC deficiency able to affect microbiota composition? In this aim will test the hypothesis that host digestion and absorption of nutrients from the intestinal lumen is impacted by colonic EECs and that this in turn influences carbon sources and microbiota composition. Overall, the pursuit of this project will provide novel insights into the role of colonic EECs in the regulation of host metabolism and will fill key gaps in our understanding of how the intestinal microbiome regulates metabolic homeostasis more broadly.