Dieescting the effects of sweet tastants in the human gut-brain axis

The importance of nutrient induced gut-brain signalling in the regulation of human food intake has become increasingly apparent as the obesity epidemic progresses. Much of the caloric excess consumed comes from dietary sugars, but our knowledge about the mechanisms mediating the physiological and appetitive effects of sweet tastants in the gut-brain axis is far from complete. The comparative effects of natural sugars vs. artificial non-nutritive sweeteners are also poorly understood. Research in animal and cellular models has suggested a key role in the gut for the sweet taste receptors previously well described in the mechanisms of oral taste. The work presented in this thesis sought to answer key questions initially based on the hypothesis that gut sweet taste receptors also play a key role in the human gut-brain axis. The key aims were to elucidate i) whether sweet taste receptors in the gut contribute to the effects of sweet tastants in the human gut-brain axis, and ii) whether oral sweet taste modulates gut physiology and/or gut-brain signalling. Fifty-eight (36 males and 22 females) young (23.3 + 3.4 years) participants were recruited into four studies. All were healthy and generally lean (BMI 22.3 + 1.9). Key methodologies used included gastric emptying, appetite and satiety scores, food intake, blood hormone and glycaemic responses, and functional brain imaging.In chapter 3, a sweet taste receptor antagonist, lactisole, was used as a tool to investigate the role of gut sweet taste receptors in mediating the responses to glucose. However, lactisole had no impact on gastric emptying (a proxy measure of gut-brain signalling), blood glucose, gut hormones, appetite ratings or food intake. The data outlined in chapter four revealed that ingesting non-nutritive sweeteners, (aspartame, saccharin, and acesulfame-k) in combination with glucose did not enhance glycaemic responses or affect appetite ratings. However, the studies presented in chapter five demonstrated that the pattern and rate of gastric emptying of glucose very clearly differed depending on whether it was given orally or administered intragastrically. The interaction between oral and gastrointestinal sweet stimuli on brain activation was therefore investigated using functional brain imaging, and demonstrated that an oral pre-taste of glucose had a marked impact on subsequent brain responses to an intragastric glucose load. Effects were observed in homeostatic and non-homeostatic regions.These data offer little evidence that gut sweet taste receptors are important in humans: a non-taste pathway appears more likely to mediate the effects of glucose. However gut-brain signalling is markedly affected by oral sweet taste receptors. This has direct relevance for a better understanding of healthy human nutrition. Future studies need to investigate these interactions in more detail, using a wider panel of nutrients and tastants in health and disease.