Exploring the Potential of Gut Taste Receptors for the Treatment of Disordered Eating Behaviour

Background Individuals who suffer from disordered overeating often experience dysregulated food reward. As such, investigation of the mechanisms underlying food reward can contribute to our understanding of disordered eating behaviours. Emerging evidence highlights the role of post-ingestive gut–brain signalling in reinforcing food-related reward. The sodium-glucose cotransporter 1 (SGLT1) expressed in the small intestine is the receptor that is thought to initiate gut-brain signalling of sugar reward. Phlorizin, a naturally occurring SGLT1 inhibitor, offers a pharmacological tool to investigate gut-mediated reinforcement. Aims & Objectives This study aimed to investigate 1) whether pharmacological inhibition of intestinal SGLT1 with phlorizin can reduce intra-gastrically delivered glucose reinforcement in mice; 2) patterns of brain activation induced by oral versus post-ingestive glucose. Method Adult male C57BL/6J mice self-administered either oral or intra-gastric 8% glucose, under fixed and progressive ratio schedules. A subset of mice received either 0.04% phlorizin v/v in 5% DMSO v/v vehicle, or vehicle alone, via intragastric infusion paired to oral glucose delivery. Brains were subsequently processed for c-Fos immunostaining to identify neuronal activation in brain regions relating to taste and reward. Results Mice operantly responded for both oral and intra-gastric glucose, demonstrating that gut delivery of glucose is reinforcing. Despite this, analyses revealed no statistically significant differences between phlorizin and vehicle groups (p > 0.05) in mice self-administering intra-gastric glucose. Subsequent immunohistochemistry analysis revealed distinct activation patterns associated with oral and post-ingestive glucose. Oral glucose was associated with higher c-fos expression in the rostral nucleus solitary tract, nucleus accumbens, and granular insular cortex (p < 0.05) whereas intragastric glucose was associated with higher c-fos expression in the caudal nucleus solitary tract and lateral parabrachial nucleus (p < 0.05). Discussion & Conclusions Collectively, these findings show that intestinal SGLT1 inhibition at the concentration tested does not impact gut-mediated glucose reward, suggesting a non-SGLT1 mediated mechanism. Further, fos expression data suggests that oral glucose rewards may be predominantly processed in mesolimbic regions and taste cortex versus more brainstem areas by intragastric glucose.