The role of enteroendocrine cell differentiation in the success of bariatric surgery

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Project Abstract: One of the most prominent reasons to study the mechanisms underlying the success of bariatric surgery is to replicate surgery outcomes with non-invasive treatment(s). Vertical sleeve gastrectomy (VSG), one of the most frequently performed bariatric surgeries in the world, results in substantial weight loss and dramatic remission of T2DM within 1 year. The drastic postprandial increase in the levels of gut-secreted peptides, such as glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY), and cholecystokinin (CCK), after VSG has been hypothesized to be a critical mechanism of surgical success because of their roles in satiety and glucose homeostasis. The gut-peptides are made in the intestinal epithelium, and we (and others) see that VSG increases the number of GLP-1-secreting enteroendocrine cells (EEC). A key question we wish to address is what drives the EEC differentiation after VSG, whether this EEC differentiation limited to the GLP- 1-secreting cells or the other EECs, and whether this increase contributes to weight loss and improvements in glucose homeostasis seen with VSG. Our preliminary data demonstrate that VSG alters explicitly intestinal stem cell (ISC) expression of several genes that regulate intestinal secretory cell development including EEC differentiation. Using a novel intestinal organoid model (enteroids), we next demonstrated that specific subspecies of bile acids increase the GLP-1-secreting EECs. Hence, we hypothesize that the increased in bile acid secretion after VSG impacts the ISC fate towards EECs and this is critical to bariatric surgery outcomes. Here, we propose a combination of complementary in vitro and in vivo studies using human and mouse enteroids and mouse genetic manipulation with VSG surgery to test the following specific aims: 1) test hypothesis that bile acids drive EEC differentiation; 2) test hypothesis that modulation of ISC fate affects body weight and glucose homeostasis; 3) test hypothesis that increased EEC differentiation is necessary for VSG outcomes. This research plan is expected to make a significant contribution to the understanding of ISC homeostasis and to determine the origin of the surgery-induced increase in gut-peptides levels with the ultimate goal of developing an alternative strategy to bariatric surgery. During the grant period, Dr. Sandoval, who is an expert in endocrinology and bariatric surgery, will provide an exceptional research environment and resources at the University of Colorado Anschutz Medical Campus and also provide guidance in research strategy, grant writing, lab management, and networking and communication. Drs. Inge, Dempsey (CU), Samuelson, Spence (UM) and Sethupathy (Cornell University), who are experts in bariatric surgery, developmental and/or stem cell biology, will provide additional guidance and training activities as detailed in the Career development activity. Successfully achieved aims will lead me to a NIH-funded independent researcher studying the mechanism of VSG to reproduce its surgical benefits with a non-invasive strategy in the treatment the obesity and T2DM within a medical sciences department.