Author: Alyce Martin
Martin, Alyce, 2018 The Role of Enterochromaffin Cells as Sensors in the Gastrointestinal Lumen, Flinders University, College of Medicine and Public Health
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Enterochromaffin (EC) cells are a specialised type of enteroendocrine cell within the mucosal lining of the gastrointestinal tract that synthesise and secrete almost all serotonin (5-HT) in the body. EC cell-derived 5-HT is a pleiotropic bioamine, with a wide range of physiological roles, including platelet aggregation, GI motility, bone density regulation, liver regeneration and inflammation. A growing body of evidence also highlights the role of 5-HT in the regulation of glucose homeostasis and energy metabolism, via effects on hepatic gluconeogenesis, mobilization of hepatic free fatty acids and the browning of white adipose tissue. The broad physiological effects of EC cell-derived 5-HT have direct implications for metabolic disorders such as type 2 diabetes (T2D) and obesity, where energy homeostasis is significantly perturbed.
The gut microbiome has been demonstrated to regulate metabolism, and a dynamic relationship exists whereby microbial metabolites such as short chain fatty acids (SCFAs) can increase EC cell 5-HT synthesis. Evidence also suggests an increase in 5-HT following nutrient ingestion. Details related to how EC cells respond to ingested nutrients and the microbiome are scarce, however, and despite their role in regulating a number of important physiological functions, primary EC cell biology has been inadequately studied.
The aims of this work were, firstly, to isolate primary EC cells from the duodenum and colon of mice and interrogate their nutrient sensing capacity of primary EC cells under low- and high-fat diet conditions, and to evaluate whether this nutrient sensing capacity is region-dependent. This work then aimed to determine whether luminal nutrients, particularly sugars and SCFAs, acutely increase 5-HT release. Finally, this work aimed to develop a mouse model of microbial dysbiosis and depleted gut 5-HT, to determine whether the gut microbiome alters host metabolism through a gut 5-HT-dependent pathway.
This study has demonstrated the novel finding that regional subpopulations of EC cells exist, with respect to their size, nutrient sensing capacity and response to a number of nutrient stimuli. In particular, duodenal and colonic EC cells have the capacity to detect a number of sugars and sweet tastants, through hexose transporters and taste receptors, respectively, as well as free fatty acids within the GI lumen. In addition, the capacity of EC cells to detect these nutrients is dependent on the region of the gut they exist in, and can be influenced by dietary changes. In addition, this work has found that in an acute setting, sugars such as glucose, fructose and sucrose, differentially increase the release of 5-HT from duodenal and colonic EC cells, while SCFAs do not. Findings in this study also demonstrate that gut 5-HT acts as a signalling nexus between the gut microbiome and host metabolism, by affecting blood glucose control and adiposity. Finally, this work provides the first evidence of existence of a bi-directional relationship between the gut microbiome and gut 5-HT. This study has, therefore, demonstrated that EC cells are important, region-specific sensory cells that can detect and respond to changes in the luminal environment of the GI tract, and that this can have significant consequences for regulating host metabolism and potentially human health.
Keywords: enteroendocrine, serotonin, metabolism, obesity, gastrointestinal, endocrine, gut hormone, microbiome
Subject: Medical Science thesis
Thesis type: Doctor of Philosophy
Completed: 2018
School: College of Medicine and Public Health
Supervisor: Professor Damien Keating