The role of vagus nerve in food-gut-brain axis. Vagal nerve manipulation as minimally invasive and reversible procedure for obesity treatment

The research question addressed in this project was “Can manipulation of abdominal vagal function and integrity be a new approach in obesity treatment?”. The hypothesis was that the vagus nerve can be the target in altering eating behaviour and energy expenditure, leading to the control of body weight. Results were as follows: 1) Truncal vagotomy: A detailed analysis of energy expenditure (EE) (total EE, resting EE and active EE) in rats subjected to vagotomy and other bariatric procedures (including gastric bypass, sleeve gastrectomy, duodenal switch and ileal transposition) have been performed, and the results have been published. 2) VNS/VBLOC: A series of VNS/VBLOC algorithms have been tested according to the effects of electric currents with different frequencies and different durations/intervals of electronic stimulation on eating behaviour over a time period of 24-48 hours. VBLOC reduced body weight by 10%, which was associated with reduced food intake, increased expression of anorexigenic neuropeptides in brainstem and hippocampus, and increased expression of hypothalamic orexigenic neuropeptides. 3) Botox: Botulinum toxin type A treatment has been tested in animals. The treatment reduced body weight by 20-30% in normal chow-fed rats, diet-induced obese (DIO) rats and DIO rats that had underwent sleeve gastrectomy. The body weight loss was associated with reduced food intake, increased energy expenditure, and increased expression of hypothalamic orexigenic neuropeptides. 4) Comparison experiments: In comparison to controls, % total weight loss (TWL) was 13% after Roux-en-Y-gastric bypass (RYGB), 16% after Omega-Loop gastric bypass (OmegaGB), 11% after sleeve gastrectomy (SG), 10% after VBLOC, and 17% after Botox. Truncal vagotomy per se was without TWL, but prevented Botox-induced %TWL. Gastric empting time (GET) was unchanged after Botox. Food intake was reduced after VBLOC or Botox. Energy expenditure was increased after Botox or OmergaGB. Meal duration (min/meal) and satiety ratio (min/g) were increased after Botox. Rate of eating (g/min) was decreased after OmegaGB. Intermeal interval (min) was increased after VBLOC. There were no mortality and surgical complications after Botox, VBLOC, and/or VTPP. However, the mortality rates were 8-36% after RYGB, GB or SG due to the experience curve effect and surgical complications. In conclusion, the study hypothesis has been tested in animal models. Throughout this project, the food-gut-brain axis has been explored as a target for new, minimally invasive obesity treatments, including vagus nerve stimulation/blocking (VNSB) and gastric Botox injections. The underlying mechanisms behind these new treatments and of currently used bariatric and metabolic surgeries such as gastric bypass, duodenal switch, sleeve gastrectomy, and ileal interposition have been studied (a figure cannot be inserted in this eRapport). The results obtained in this project has improved our understanding of the physiological mechanisms of bariatric surgery and led to the development of new, minimally invasive obesity treatments, namely blocking the gastric vagus nerve, by VNSB or Botox injection, can be used as non- or minimally invasive obesity treatment. Novel findings and methodology have not been published yet due to IPR. Priority patent application was filed on the 16th of July, 2014 (GB1412588.4). It is our intention to publish all the results and methods after the patent applicaiton is approved. Based on the results of this project, a clinical phase II trial of Botox-treatment of obesity has been started at St. Olavs Hospital (REK-ref: 2013/1597, SLV-ref: 12/13405-4)(http://clinicaltrials.gov/show/NCT02035397).