Combining metformin or semaglutide medical treatments to metabolic surgery in patients with obesity: is there a synergistic effect on the gut response ? – BARGAIN

Metabolic surgery (MS) is considered as very effective for the treatment of obesity and its associated co-morbidity, particularly type 2 diabetes (T2D). The post-operative hormonal response of the gut is a key factor in the improvement of the latter. However, a significant proportion of patients present weight regain and recurrent T2D in the medium and long term. Combination therapy could be an effective approach to increase the durability of weight loss and diabetes remission. Metformin and semaglutide used in the treatment of T2D could mimic some of the effects of MS on the hormonal response of the gut, particularly by stimulating the GLP-1 signaling pathway. We hypothesize that the combination of these antidiabetic drugs with MS could amplify the efficacy of both therapies in high-risk patients. The overarching goal of this research project is to gain fundamental insight into the physiological mechanisms that underlie the effect of metformin/semaglutide when combined to MS on glucose homeostasis and body weight regulation. We have formed a multidisciplinary team to unravel how such a combination impacts the gut responses using a translational approach that combines clinical and preclinical studies. In humans, we will work on two cohorts of subjects with obesity and a history of MS and treated with metformin (Task 1) or semaglutide (Task 2) to determine the postprandial gut response as well as the metabolic composition/activity of the microbiota. Task 1, the BAROMET study, is an ancillary protocol to the DiabOUT trial, and will include 20 patients from both the metformin and standard care groups, for a total of 40 participants. Task 2 will involve patients with a history of MS who will receive semaglutide. In both tasks, patients will undergo a standardized meal test to measure the postprandial gut and pancreatic hormones and provide stool samples for microbiota analysis during in-person visit at the hospital. In animals, we will work on bariatric surgery models in rats with and without diabetes treated with metformin or semaglutide to characterize glucose homeostasis and gut and pancreatic hormone secretion (Task 3) and characterize gut adaptation and function (Task 4). For Task 3, before and after surgery, and 3 weeks after the treatments, a meal test will be performed to determine changes in the gut and pancreatic hormones secretion and feces will be collected to characterize the gut microbiota. For task 4, following the sacrifice of the animals, the pancreas, gastrointestinal tract, and liver will undergo analysis to determine the endocrine cell number and sensibility and liver functions. The intestinal glucose absorption and metabolism as well as the number of enteroendocrine cells will also be assessed. The microbiota study in both humans and rats will be part of Task 5. This interdisciplinary project will allow a better understanding of the intestinal effect of antidiabetic drugs usually proposed in diabetic patients undergoing MS, and ultimately, determine the most appropriate therapeutic classes in this specific context of modified digestive anatomy.