Intestinal nutrient sensing : a gut feeling for food

The alarming increase in obesity rates creates an urgent need for effective prevention and treatment strategies. The most effective treatment for obesity today is bariatric surgery. Bariatric surgery comprises a number of different procedures having in common that they induce weight loss and alter gut hormone release. Gut hormones are well known for their effects on food intake behavior and their role in weight loss after bariatric surgery is undeniable. In addition, the therapeutic use of GLP-1 (Glucagon-Like Peptide-1) analogues including liraglutide in type II diabetes and obesity is on the rise. This underlines why gut hormones are considered promising targets for the development of new treatment strategies against obesity and its comorbidities. The secretion of gut hormones, among which GLP-1, is influenced by nutrient ingestion. The interactions of dietary components or their breakdown products with receptors and transporters located on the enteroendocrine cells of the intestinal tract can induce their release, a process called intestinal nutrient sensing. In this thesis, we aimed to further elucidate intestinal nutrient sensing mechanisms on a cellular level. First, the regional expression of several gut nutrient sensing related genes along the intestinal tract was assessed in three commonly studied species, namely mouse, pig and man. Gene expression of receptors, transporters and peptides involved in nutrient sensing shows a distinctive distribution pattern along the small intestine, which is in the distal small intestine highly similar between the species. Subsequently, we sought to investigate if this expression was changed after a weight loss inducing bariatric procedure. By whole transcriptome analysis, we showed that upper gastrointestinal tissue expression of genes associated with nutrient sensing was hardly changed. In contrast, a considerable reduction in inflammatory pathways was observed. Next, we sought to investigate the effects of the non-caloric sweetener rebaudioside A. This Stevia rebaudiana-derived compound was approved on the European market in 2011. As there is still some controversy about the effects of sweeteners in general on GLP-1 release, we investigated the effects of this specific sweetener. Because of the short half-life of GLP-1, the effect of nutrient stimulation was mainly studied in ex vivo and in vitro models in which local intestinal hormone release could be determined. A two dimensional gut model using intestinal organoids derived from murine intestinal crypts was developed to study location-specific hormone secretion. Rebaudioside A was found to induce GLP-1 and PYY release ex vivo from porcine intestinal tissue and in two dimensional organoids. This induction of the release was specific for the intestinal location, with the ileum being most potently stimulated by rebaudioside A. Moreover, prolonged exposure to rebaudioside A increased enteroendocrine cell numbers in two dimensional organoids. When studying the underlying mechanism in enteroendocrine STC-1 cells, we concluded that rebaudioside A-induced GLP-1 release was independent of the sweet taste receptor. The studies presented in this thesis add to our understanding the role of receptors and other molecular structures that are likely to be involved in nutrient sensing and the modulation of gut hormone release. What we know now is that several factors play a role in gut hormone release. This includes not only the nature and dose of the active compound(s), but also the location and timing of its (their) interactions with receptors and other targets along the gastrointestinal tract. We have shown that rebaudioside A may be a potential compound to induce gut hormone release in vivo, especially when applied to the distal small intestine. Therefore, rebaudioside A may be a promising compound to influence food intake, possibly most potent when delivered in the ileum.