Role of colonic enteroendocrine cells in metabolic control

营养物质的消化和吸收是胃肠道的基本功能。当肠内容物到达结肠时，这个器官主要负责水和电解质的再吸收。尽管如此，通过结肠微生物群的代谢活动，不可消化的肠道内容物被发酵，导致许多小代谢物的通量，这些代谢物被微生物和宿主利用。事实上，现在估计细菌代谢贡献了到达宿主的热量的6-10%。因此，感知和响应源自结肠的代谢通量的机制似乎对代谢稳态至关重要。在这方面，胃肠道上皮含有肠内分泌细胞（EECs），它们产生多种激素，帮助协调胃肠道生理，以及各种远端器官的代谢反应。考虑到大多数消化和吸收过程的位置是小肠，结肠产生几种控制宿主代谢和食欲的激素（例如，Glp-1, Glp-2, Insl5）是有趣的。利用小鼠结肠EEC缺乏模型（EECCol），我们发现这些细胞对宿主代谢稳态至关重要。我们发现这些老鼠会肥胖，这主要是由于贪食。此外，它还与肠道菌群的变化（生态失调）有关。我们假设结肠EECs的空间分布反映了微生物对不可消化营养物质代谢产生的大量热量通量。本项目的目的是评估结肠EECs如何调节宿主代谢，其基本假设是它们作为源自结肠的代谢通量的近端传感器。为实现这一目标，我们提出以下目标：

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.