Contribution of Nutrient Delivery Rate to Gut-Brain Axis Signaling in Obesity and Bariatric Surgery

PROJECT SUMMARY/ABSTRACT Mechanisms underlying sustained weight loss after bariatric surgery remain unclear, though rapid nutrient delivery is a major candidate driving decreases in caloric intake via the gut-brain axis. Preclinical models have demonstrated the importance of the gut-brain axis in modulating short- and long-term feeding and taste preferences through gut-brain neural connections and the endocrine gut peptide response. Our clinical preliminary data demonstrates that rapid intestinal nutrient infusion (bypassing the stomach) in non-surgical patients with obesity can mimic the augmented gut-brain endocrine response (e.g. GLP-1) of bariatric surgery. Our overarching hypothesis is that bariatric surgery induces a chronic state of rapid nutrient delivery leading to hypersecretion of gut peptides known to signal satiety, slow GI motility, and decrease nutrient-rich food preference. This sustained and altered enteral delivery modifies nutrient-stimulated, gut endocrine and gut- brain signaling, which changes feeding behavior and leads to weight loss. In the following project, we will (Aim 1) test the hypothesis that rapid nutrient delivery is associated with augmented GLP-1 and brain fMRI responses. Human subjects being evaluated for bariatric surgery will undergo non-invasive placement of an enteral feeding tube for a variable rate glucose infusion into the small intestine, with concurrent measurement of the rapid brain signaling response using functional magnetic resonance imaging (fMRI) and gut peptide endocrine response. Additionally, we will (Aim 2) test the hypothesis that Roux-en-Y Gastric Bypass (RYGB) is associated with faster nutrient absorption compared to Sleeve Gastrectomy (SG). Preoperative and postoperative measurements of intestinal nutrient uptake will be made with non-metabolizable glucose and amino acid tracers, with measurement of the corresponding gut peptide endocrine responses to understand the putative differences in postoperative absorption of sleeve and gastric bypass. This career development plan is highly innovative, combining enteral nutrient infusion with fMRI to begin to (1) establish rapid intestinal nutrient delivery as a primary driver of the gut endocrine response of bariatric surgery, (2) determine the degree to which the most common bariatric operations increase nutrient absorption, and (3) identify brain regions that are rapidly responsive (within seconds) to enteral nutrient presence similar to preclinical rodent studies. Understanding gut-brain axis physiology and how it is altered by bariatric surgery may lead to identification of novel therapeutic strategies and simpler surgical or endoscopic treatments for obesity. The training plan associated with this career development award allows the PI to gain the necessary training in patient-oriented research and focuses long-term research efforts in studying the gut-brain axis in obesity and bariatric surgery.