A Neural Circuit for Gut-Induced Sugar Preference

Glucose is an essential source of energy in humans. Over the past decades, consumption of sugar has increased greatly and constitutes a large part of the global energy intake [1]. Currently, overconsumption of sugar is a serious problem around the world and contributes to the high incidence of obesity, type 2 diabetes mellitus, hypertension, and all-cause mortality [1]. As a result, there is an unmet clinical need to clarify the mechanisms of sugar preference and craving and to find means of limiting sugar overconsumption.

Dedicated brain circuits motivate its consumption, one being the oral sweet-taste circuit [2] (Fig. 1). In this circuit, taste information travels from taste receptor cells in the oral cavity to the primary gustatory cortex (insular cortex). The member 2 and 3 of taste 1 receptor (T1R2/T1R3) in the oral cavity send information to three nerves: the chorda tympani (cranial nerve VII), glossopharyngeal (cranial nerve IX), and superior laryngeal (cranial nerve X) [3]; then, it is transferred to the nucleus of the solitary tract, the parabrachial nucleus, the thalamus, and finally to the insular cortex [3]. This circuit recognizes sweet-tasting compounds and generates attraction behaviors to the sugar [2, 3]. In fact, even in the absence of an oral sweet-taste pathway, animals still have a strong attraction to sugar (sugar preference). In 1968, Holman first reported that post-oral nutrient actions induced by saccharin solution enhance food preferences in rats [4]. Recently, increasing numbers of studies have reported that gastrointestinal infusion conditions sugar preferences [5, 6]. The vagus nerve heavily innervates the gut and is a key connection between gut and brain. It senses both gastrointestinal stretching and gut hormones and sends the nutrient sensory information from the gut lumen to the brain stem. Many studies have shown that the gut-vagus-brain axis regulates feeding behaviors, including satiation, reward, and addiction [7, 8]. However, the role of this axis in sugar preference is unclear. Recently, Tan’s team, for the first time systematically elucidated the gut sugar-specific pathway mediated by the gut-vagus-brain axis at the circuit level [9]. It was characterized by behavioral tests, immunohistochemistry, functional imaging, genetically silenced, and chemogenetic-activation experiments. They used taste-knockout mice incapable of tasting sugar or sweetener, and found that they learnt to recognize and choose sugar rather than sweetener, indicating a positive post-ingestion effect. Notably, both a non-metabolizable glucose analogue and sugar could create sugar preference, suggesting that the preference for sugar does not rely on the caloric content. Immunohistochemical analysis led to the identification of neurons in the caudal nucleus of the solitary tract (cNST) activated by sugar rather than by sweetener. By combining the targeted recombination in active populations system and adeno-associated virus injection of tetanus toxin light chain, synaptic transmission in the cNST was inhibited, and thus the formation of sugar preference was prevented. How is the information transferred from gut to brain? A gut-brain axis via the vagus nerve was proposed based on previous studies. With transection and silencing of vagal neurons, the development of sugar preference was prevented, that showing the gut-brain axis is the key pathway for transmitting information from gut to brain. Using a vagal ganglion functional imaging platform, the authors directly monitored the responses of the gut-vagus-brain axis to sugar versus sweetener. They found a significant calcium response in ganglion neurons to glucose rather than sweetener. Next, to further demonstrate that neurons in the nodose ganglion sense sugar, they injected a tracer into GCaMP-expressing mice and found that neurons in the ganglion were labeled by the tracer in the gut. Although sweet-taste receptors are expressed in the enteroendocrine cells of the gut, mice with double-knockout of T1R2 and T1R3 still exhibited normal sugar preference behavior, showing that other receptors may be the sensor. Then, they focused on sodium-glucose-linked transporter-1 (SGLT1), the principal glucose transporter in the gut. Pharmacological inhibition of SGLT1 receptors abolished the glucose-dependent neuronal responses, suggesting that SGLT1 receptors could be the sensor that functions as a conduit between the gut and the vagus nerve. Can the selective activation of this circuit be used to generate preferences for stimuli that were previously disliked? The authors used chemogenetics to activate ensembles of neurons and examined their physiological and behavioral consequences. As expected, co-opting this circuit by chemogenetic activation created preferences for otherwise less-preferred stimuli.

Fig. 1.

The oral sweet-taste pathway (left) and the gut-brain axis (right) mediate the sugar-specific pathway. Cartoon of sugar-specific pathways showing that activation of sodium-glucose-linked transporter-1 (SGLT1) sends the glucose signal to vagal neurons in the gut. Then, the vagus nerve transfers the information to the brain and activates the caudal nucleus of the solitary tract (cNST). Meanwhile, the oral sweet-taste circuit shows that taste receptor cells in the oral cavity sense the sweet signal. Then cranial nerves VII, IX, and X transfer the signal to the nucleus of the solitary tract, the parabrachial nucleus, the thalamus, and finally to the insular cortex.

This multidisciplinary work discovered and characterized a new pathway by which the gut-to-brain axis mediates sugar preference independent of the sweet taste pathway. It provides mechanistic insights into how sugar in the gut drives the brain to consume sugar rather than artificial sweetener. More importantly, it opens up a few exciting new avenues for further exploring brain circuits dedicated to seeking, recognizing, and motivating the consumption of sugar and other nutrition and provides new target and strategy for preventing obesity and diabetes by suppressing the overconsumption of sugar.

Many questions remain from this clarification of a neural basis for sugar preference. First, neurons in the cNST were activated by signals from sweet receptors in the abdominal cavity as well as gut SGLT1 receptors. Further study analyzing interactions in the cNST showing how these signals come together to drive sugar consumption, preference, and craving would provide further insight into sugar-specific and sweet-taste pathways. Second, it is well known that cNST functions as a nexus of interoceptive signals conveying information from the body to the brain. Previous study has shown that sucrose infusion into the duodenum induces activation in the striatal, anterior cingulate cortical, and hippocampal areas associated with reward processing [6], which suggests that the reward cortices receiving projections from the cNST are also involved in the sugar preference pathway. Third, an obvious fundamental question is whether the gut-to-brain axis for sugar preference is operational in higher primates and humans, and whether this pathway plays a role in regulating protein and fat metabolism. Last, targeting the gut-brain axis, such as the SGLT1 receptor, vagus nerve, and neurons in the cNST may be a future research direction worth pursuing for the control of sugar overconsumption. Preclinical and clinical studies defining the translational aspects are keenly awaited.

Conflict of interest

The authors declare that they have no conflict of interest.