Investigating the role of the gut metabolome in appetite regulation and obesity

Abstract

The rising incidence of obesity results from an innate predisposition to weight gain in an increasingly obesogenic environment. Long-term treatments are limited, with the only effective method being bariatric surgery.

Appetite regulation is considered a crucial factor in obesity progression and treatment evasion. Post-prandial satiation and satiety are mediated by a combination of sensory cues, gastric distension, and sensing of specific nutrients in the gastrointestinal tract by enteroendocrine cells. These then secrete anorexigenic peptide hormones in response to the caloric and macronutrient content of food. There is mounting evidence that the post-prandial satiety response is impaired in obesity as a result of blunted gut hormone secretion. Indeed, the therapeutic effects of bariatric surgery are thought to be in part mediated by restoring levels of these satiating hormones. Therefore, a promising avenue for treatment of obesity is to mimic the post-operative hormonal profile by increasing intrinsic gut peptide secretion.

This PhD project will further knowledge of nutrient-modulated gut hormone secretion. A combination of different targeted and untargeted metabolomic approaches were employed on intestinal content from different regions of the human gut, collected using nasointestinal tubes following the consumption of different meals. Gastric and duodenal content was analysed from healthy weight and obese participants following consumption of three meals (high-carbohydrate, high-protein and high-fat), and ileal and colonic content from individuals following a high-protein high-fibre meal. In addition, subjective appetite and plasma levels of gut and pancreatic peptides were measured.

This work enabled the study of the metabolic events leading up to gut hormone release and satiety in humans. It demonstrated associations between metabolic changes and circulating hormonal and metabolic markers, and deepens understanding in the role of nutrient sensing in appetite regulation, and how this might be perturbed in obesity. This will pave the way for the development of novel antiobesity strategies.