Neuropod cells differentiate between sugars and sweeteners and guide our preference for sugar

The intestine has sensory cells and communicates with the brain. These two facts are not new. At the end of the 1860s, the idea was already germinating in the minds of certain histologists. After observing such entities on the tongue, this was the case in thesmall intestine. In 1902, scientists discovered the first hormone secreted by intestinal cells: secretin. Almost 40 years later, we witnessed the birth of intestinal endocrinology. However, it will be necessary to wait another fifty years for the taste receptors present at the level of certain cells of the intestine to be highlighted. Even more recently, in 2015, scientists have discovered that certain secretory cells of the intestine are connected by a synaptic architecture to certain nerves.

We now know that these cells generate electrical activity in response to external stimuli, typically the presence of nutrients. These cells are therefore distinguished from sensory cells that secrete hormones only by their ability to form synapses. To distinguish them, we use the term neuropod cells. Also, since the advent of sweeteners, we know that our appetite is preferentially directed towards sugar and that the chemistry that takes place within the language is not sufficient to explain this state of affairs. In a recent study published in Nature Neuroscience, American scientists demonstrate that in mice and probably in humans, this preference is caused by the neuropod cells secreting cholecystokinin (CCK).

Some previous results

We have the ability to identify the glucose through our intestinal cells. However, when glucose no longer passes through the small intestine thanks to an experimental device, this ability disappears. It therefore seems that the identification of glucose takes place within this anatomical portion. For some years now, it has been known that it is, among other things, the CCK neuropod cells which are responsible for this identification. They are mainly located in the duodenum, the most upstream part of the intestine. They manage to inform the brain of the presence of glucose within milliseconds through ion channels and of secretions hormonal.

On the strength of these previous results, the scientists who discovered neuropod cells put forward a new hypothesis: what if these cells could explain the fact that we prefer caloric sugars to sweeteners ? In order to test it, the investigators carried out a series of experiments essential to the demonstration of the hypothesis in question.

Neuropod cells are necessary for the transmission of nerve impulses

To start, the researchers injected sugars (sucrose, glucose, fructose, galactose), sugar analogues (α-methylglucopyranoside, maltodextrin) and sweeteners (sucralose, acesulfame K, saccharin) in the mouse duodenum. Using a well-known method, the patch clamp, they were able to measure the electric currents resulting from these injections at the level of the vagus nerve, the nerve to which the CCK neuropod cells are attached. With some variations, we see a stimulation electricity within the vagus nerve regardless of the substance used. These results confirm that this portion of the intestine is indeed responsible for the reward signals transmitted to the brain after theingestion sugars, sugar analogues, or sweeteners.

The next step consisted in demonstrating that the activations observed were indeed caused by the CCK neuropod cells. Using a genetically modified mouse model expressing a sequence ofDNA coding for a protein photosensitive transmembrane, the researchers were able to turn ON/OFF the CCK neuropod cells at will. This transmembrane protein has a special feature: it forms an ion channel specific to ions chlorides (Cl-) and its activation depends on the presence of a wave length very specific light (532 nm).

The experimenters therefore repeated the initial experiment in these genetically modified mice with a optical fiber transplanted into their gut. In one condition, they sent a non-specific wavelength (473 nm), which had no impact on the transmembrane protein and therefore should not change the electrical current measured in the vagus nerve. This is what they observed. On the other hand, when they sent a specific wavelength (532 nm) activating the transmembrane protein and allowing the passage of chloride ions, this must have resulted in a hyperpolarization of the membrane preventing the depolarization of the CCK neuropod cells, which is necessary for the transmission of the electrical signal to the nerves related of the vagus nerve. And this is what they observe: in this condition, the electrical current measured at the level of the vagus nerve is similar to the resting potential. In other words, nothing happens.

In order to be sure, the scientists wanted to do some tests in vitro. They cultivated neurons isolated afferents and measured the electrical current in these cells after the addition of sugars, sugar analogues or sweeteners. Results: no substance causes action potential. But when afferent neurons are cultured with CCK neuropod cells, an electric current is observed. Taken together, these results demonstrate that CCK neuropod cells are absolutely necessary for electrical signaling between the light small intestine and the vagus nerve.

Neuropod cells distinguish sugar from sweeteners

The focus now is on whether the pathways that sugars and sweeteners take to cause vagus nerve stimulation are the same or different. Consistent with their hypothesis, the researchers believe they are different. If this were not the case, it is difficult to see how the CCK neuropod cells could be responsible for the preference towards sugar. To do this, they repeated their experiment in mice and organoids made using human cells by blocking with various molecules pharmacological certain receptors of interest that are expressed on the surface of CCK neuropod cells. They demonstrated that glucose from sucrose was taken up by the SGLT 1 receptor (for Sodium Glucose Like carry 1) while sweeteners are taken up by the taste receptor T1R3 (for Taste receptor type 1 member 3). Their results show that the distinction which does not take place at the level of the tongue, sucrose and sweeteners binder to T1R2/T1R3 receptors, takes place in the duodenum by CCK neuropod cells.

Thanks to this distinction, neuropod cells can transmit different signals to afferent nerves from the vagus nerve depending on what they detect. Indeed, subsequently, scientists show that different neurotransmitters are released depending on the detected substance. In the case of glucose, a release of glutamate while in the case sweeteners, we observe a release ofATP. This therefore demonstrates that CCK neuropod cells inform different populations of vagus nerve afferent neurons with different neurotransmitters depending on the nutritional stimulus they sense. The experiment also demonstrated that the transmission of information from sweeteners was independent of CCK secretion.

Why do we prefer sugars to sweeteners?

After all these adventures, the scientists will finally try to answer the question by using a similar experimental device in conscious mice. Indeed, the challenge is still to turn ON/OFF the CCK neuropod cells while recording the food preferences of the mice. But a major problem arose: the optical fiber which delivered the light in the first experiments risks perforating theepithelium intestinal. Our experimenters had to show some ingenuity. Their team has developed a specific flexible optical fiber for theoptogenetics intestinal. In order to validate the effectiveness of their device, they looked at whether the inactivation of CCK neuropod cells eliminated the effects appetite suppressants normal CCK secretion. To do this, they force-fed the mice with fat under two conditions: either leaving the neuropod cells active (473 nm) or deactivating them (532 nm). The food intake of the control mice was drastically reduced, unlike the mice whose neuropod cells had been deactivated. The device was indeed effective.

The final experiment consisted of exposing the mice to solutions enriched with sugar or sweetener until they showed a stable and marked preference for sugar. While control mice showed a sugar preference of 90.8%, mice whose CCK neuropod cells were OFF showed a preference of only 58.9%. But that does not mean that the preference is no longer effective. Indeed, in subsequent experiments, the scientists demonstrated that without deactivating the neuropod cells, the mice regained their preference towards sugar. This suggests that turning off neuropod cells impairs the ability to discriminate between sugar and sweeteners without lastingly impacting sugar preference. Finally, by activating CCK neuropod cells using another light-dependent transmembrane protein forming an ion-specific ion channel hydrogen (H+), the researchers demonstrated that the consumption of sweeteners in these mice increased significantly. This definitively shows that the inadvertent deactivation or activation of CCK neuropod cells has a considerable impact on the distinction and ultimately on the preference between sugars and sweeteners.

While this study is robust and interesting, we must keep in mind that it partially explains our preferences. Indeed, there still remains an explanatory gap between mice making a decision in a cage and humans choosing in an infinitely complex environment with influences that are certainly biological, but also psychological, economic and social.