A gut sensor for sugar preference

Abstract

Animals innately prefer caloric sugars over non-caloric sweeteners. Such preference depends on the sugar entering the intestine. [1][2][3][4] Although the brain is aware of the stimulus within seconds, [5][6][7][8] how the gut discerns the caloric sugar to guide choice is unknown. Recently, we discovered an intestinal transducer, known as the neuropod cell. 9,10 This cell synapses with the vagus to inform the brain about glucose in the gut in milliseconds. 10 Here, we demonstrate that neuropod cells distinguish a caloric sugar from a non-caloric sweetener using the electrogenic sodium glucose co-transporter 1 (SGLT1) or sweet taste receptors. Activation of neuropod cells by non-caloric sucralose leads to ATP release, whereas the entry of caloric sucrose via SGLT1 stimulates glutamate release. To interrogate the contribution of the neuropod cell to sugar preference, we developed a method to record animal preferences in real time while using optogenetics to silence or excite neuropod cells. We discovered that silencing these cells, or blocking their glutamatergic signaling, renders the animals unable to recognize the caloric sugar. And, exciting neuropod cells leads the animal to consume the non-caloric sweetener as if it were caloric. By transducing the precise identity of the stimuli entering the gut, neuropod cells guide an animal's internal preference toward the caloric sugar. Main TextThe cephalic senses guide our decision to eat. But what happens next, inside the gut, is essential for our eating preferences.As early as 1952, it was known that animals prefer the side of a T-maze if rewarded by nutrients delivered directly into the stomach. 1 Although the responses depend on the nutrient's caloric value, 7,8,11 how this value is signaled by the gut epithelium to drive preference is unknown. Of all macronutrients, sugars and available analogs have the most defined sensory properties. For instance, sucrose -a compound sugar made of D-glucose and fructose-contains both taste and calorie, whereas non-caloric sweeteners, like sucralose, carry only taste. Animals have an innate preference for sucrose over non-caloric sweeteners, even in the absence of taste. 3,12-14 Such preference depends on the sugar entering the intestine. 2,3,15,16 But slow acting intestinal hormones cannot account for the effect, 17 because the brain perceives stimuli from nutrients entering the small intestine within seconds. 6,8,10 Thus, a fast intestinal sensor must exist to steer the animal towards the caloric sugar.A gut sense for sweets. Intestinal signals arising from the lumen are relayed to the brain via the vagus nerve. 6,10,11 The vagus responds within seconds to an intraluminal stimulus of sucrose, 6,10,18 but the response to other sugars, including non-caloric sweeteners, is unclear. We therefore tested vagal firing responses to a panel of sugars: sucrose, D-glucose, fructose, galactose, maltodextrin, alpha-methylglucopyranoside (α-mgp), saccharin, acesulfame-K, and sucralose. All stimuli were perfused at physiological concentrati...

The specification and function of enteroendocrine cells in Drosophila and mammals: a comparative review

“…(Preprint) [123] and Tan H.E. et al [124] found that SGLT1 expressed in EECs transduced gut-brain sugar Accepted Article signals and mediated sugar preference.…”

The gut–brain axis: Identifying new therapeutic approaches for type 2 diabetes, obesity, and related disorders

“…This circuit requires glucose sensing by the glucose transporter SGLT1 and vagal signaling to Penk -expressing neurons in the NST. Similar work has focused on the gut side of a vagal sugar circuit [ 109 ] and gut-brain circuits have also been proposed for lipid preference [ 110 ]. Further elucidating these circuits could allow the development of a new class of diet products that activate both the taste system and gut-brain axis to help moderate the strong drive to consume sugar and other high-energy foods.…”

Protein Appetite at the Interface between Nutrient Sensing and Physiological Homeostasis

“…In one such study, specialized small intestinal enteroendocrine cells (neuropod cells) were shown to penetrate the lamina propria and synaptically oppose vagal afferent endings [172]. Optogenetic silencing of these neuropod cells in mice led to an inability to develop a preference for intestinal glucose versus the non-nutritive sweetener sucralose [173]. In another study, intestinal infusions of glucose and α-methyl-D-glucopyranoside (MDG), but not the non-nutritive sweetener acesulfame K (Ace K), supported preference learning and activated a bilateral subset of proenkephalin-expressing neurons in the caudal NTS (cNTS).…”