Wait, What? How Your Gut Can Sense Sweetness

Artificial sweeteners like sucralose, a component of the brand name Splenda, are everywhere, and they're promoted by bodies like the American Diabetes Association. Here are some recipes promoted by the ADA to give you sweet without the sugar. Now, while sucralose or Splenda might not be worse for you than sucrose, regular table sugar, I'm not claiming that, the notion that you can just swap sucrose for sucralose and get free sweet and trick the body entirely is incorrect. And brilliant science from the lab of Diego Borges, which was recently featured on the popular Huberman Lab podcast, shows how your body outsmarts sweet. And now I'm going to show you by walking you through the data so that you can decide whether you think your physiology can be tricked by Splenda sweetened treats. Let's go. Welcome to my channel. Stay curious. Let me start by warming you up with a question. If you take mice and you put a flavor on their tongue, and at the same time you give an infusion of sucrose, normal table sugar, into their stomach so it passes through into their small intestine, what will happen is they'll learn to associate that flavor with the nutrients they're getting in their gastrointestinal system, and later on they'll seek out that flavor more. This is called flavor-nutrient conditioning. But here's the question: what if you did that same experiment, but instead of giving sucrose you gave sucralose, an artificial sweetener that doesn't provide calories, will the mice be conditioned to seek out more of that flavor? Pause and think about that. Hopefully you paused and thought about that, but the answer is no. Mice will not be conditioned in the same way to the sucralose, or the flavor associated with the sucralose, as they were with the flavor associated with sucrose. And what this is demonstrating is that there are post-oral, after-the-mouth sensors that can distinguish between sucrose and sucralose and have impacts on behavior, impact food choices down the line. That is a really important foundational principle. And with that, let's move on and talk about the paper I really wanna talk about, which is entitled "The preference for sugar over sweetener depends on a gut sensor cell" by Buchanan et al. and senior author Diego Borges in Nature Neuroscience. All right. Let's go. So the researchers started by taking sugars and sweeteners and infusing them into the gastrointestinal systems of mice to see if there's any response in the major nerve going from the gut to the brain, the vagus nerve. And indeed, they found that both sugars and sweeteners both could stimulate the vagus nerve. Specifically, sucrose and glucose and sucralose could all stimulate the vagus nerve. But here's the thing: sugars and sweeteners, they don't directly act on the vagus nerve. They find this out later, so that's a little bit of a spoiler alert scientifically speaking, but I'm giving it to you up front. Rather, they need a middle man to transmit the signal from the gut lumen over to the vagus nerve. A middleman or a middle cell. In this case, those middle cells are called the neuropod cells. Neuropod because they're gastrointestinal cells, but they're specialized to have a nerve-like property so they can synapse straight on to neurons and transmit a signal, in this case to the vagus nerve. So to prove that these neuropod cells were essential, they, they were the middleman, the middle cell transmitting the signal, the researchers used a technique, one of my favorites, called optogenetics. Opto meaning eye or alluding to light in genetics because what you do in this technique is you force different cells to express these channels on their surfaces. These channels are pumps that can move ions across the cell membrane and therefore activate or inhibit the cell's activity. Now these channels are light sensitive. So what you can do is express different combinations of channels in different cell types and stimulate or inhibit them with different light wavelengths to literally turn on and off cells. On and off cell circuits with light. Not like a light switch, but literally a light switch. How cool is that? That's optogenetics, and it's a pretty popular tool. So using 532 nanometer wavelength light, the researchers shut off the neuropod cells, and they found that by so doing, they could block the response in the vagus nerve to sweet sucrose or sucralose or glucose in the small intestine, in the gastrointestinal system. Otherwise put, by cutting out the middleman, the signal at the neuropod cell, they could block the transmission of sweet to the nervous system. And that's shown here, where on the y-axis you're looking at activity in the vagus nerve. And that little green dotted line is when you shut off the neuropod cells with green light. And you can see the signal transmitted from sweet to the nervous system goes away. The signal is blocked. So now the astute listener will be asking themself a question, which is, Nick, you said the body was smart and could distinguish between real sugar, glucose and sucrose, and artificial sweeteners like sucralose, but both are activating the vagus nerve and neuropod cells., as shown in the optogenetic experiment. So what gives? Where is the distinguishing occurring? To explain that, I want to provide you with an analogy. Imagine you're getting a phone call, okay? Phone call's coming in. Let's say for the sake of argument that you have the same ringtone for every person. Do you know who is calling you before you pick up the phone? The answer, of course, should be yes, because every phone call is coming from a particular phone number, and that phone number is linked to a caller ID. So you just look at the phone and you can tell who is calling you. And it's the same way in this system, whereby a sweet molecule has a particular receptor. That receptor activates a pathway that leads to the release of a particular transmitter onto the nervous system. So in this analogy, the sweet molecule receptor pair is like the phone number, and it's being communicated via a particular transmitter, the caller ID, to the nervous system. So hopefully that makes sense. So the researchers next wanted to determine what are the receptors for sucrose, glucose, versus sucralose. And what they found was that different populations of neuropod cells responded differentially to glucose versus sucralose, and that these populations of neuropod cells had different receptor expression patterns. So there are really two receptors in question here: the T1R3 sweet receptor and the sodium-glucose cotransporter, SGLT1. And what you can do is you can block these separately and see how that affects the signal from the sweet to the vagus nerve. So what you see here over on the left is sucrose in orange, and if you block SGLT1 with a molecule called floridzin, that's the blue line, the signal in the vagus nerve goes away, showing that SGLT1 is receiving signal from sucrose, versus if you block the T1R3 receptor with a component called gumerin, then you block the sucralose signal, but it doesn't work the other way around. So this is showing that the sucralose signal goes through the T1R3 pathway and the glucose signal, or the sucrose signal, goes through the SGLT1 pathway. So there are different receptors, different phone numbers you could say, for these different molecules, the sucrose versus the sucralose. So now we have a sense of the phone number. You have the SGLT1, receiving sucrose or glucose, and you have the T1R3 receiving sucralose. But what about the caller ID? What is the transmitter linked to the system? And you can use a similar approach, blocking different transmitter systems to figure out what transmitter is important. And basically, spoiler alert, what they found was that glutamate signaling— glutamate is an amino acid and also an excitatory neurotransmitter— was the one that was very important in sucrose, in glucose signaling, whereas there was a more purigenic ATP-based signal for the sucralose. Again, different caller IDs. With glutamate being most important for the real sugar. So simply, 50,000-foot view, sucrose and glucose and sucralose and sweeteners can place a phone call to the vagus nerve, to the nervous system, and therefore to the brain. But the vagus nerve, and by extension the brain, know exactly who's calling based on different receptors linked to different cell populations and different transmitters that are being placed, spewed out onto the vagus nerve. Okay, so they both place a phone call, but they are different phone numbers and different caller IDs, and the brain knows the difference. And that can can feed forward and impact behavior. But the story doesn't end here, not quite yet. The researchers had one more really cool trick up their sleeves. I would do the up my sleeve thing, but I'm not wearing sleeves. So they used optogenetics to trick the system, basically activate neuropod cells and then get signals confused. So specifically what they did is they expressed a channelrhodopsin, another light-sensing molecule, a light-sensing channel, in the neuropod cells. That they can activate with 473 nanometer blue light. So if you shine blue light on these neuropod cells, they turn on. And normally with mice, these conditioned mice, they'll drink more sucrose water because the sucrose water has calories and the mice nervous system has learned that's nutritive than sucralose water. So they can distinguish between the sucrose and the sucralose water because the neuropod cells are transmitting to the nervous system and the nervous system is smart, it knows.. But if you use the blue light to activate the channelrhodopsin on the neuropod cells, you can turn them on at will. And if you turn them on while the mice are drinking the sucralose water without the calories, you trick the mice, you trick their nervous systems into thinking it is sucrose water. And so they end up drinking more. And you can see that here where you have the control light signal, the green light, which will not turn on the neuropod cells. And in mice that have the channelrhodopsin, that's the CCKCRE CHR2. If you shine blue light on them, you will get them to drink more sucralose water because their nervous systems are fooled into thinking it's sucrose water. How freaking cool is that? You can change behavior with light in the gastrointestinal system, tricking the nervous system. So I hope you found that intellectually fascinating, but I want to give you some big takeaways and maybe practical 50,000-foot view thoughts. The first is that your tongue might not know the difference between sucrose and sucralose, or real sugar and artificial sweeteners, but your body Absolutely does. And this can impact behavior patterns. So no, sucralose-sweetened peaches and cream milkshakes and sucralose chocolate cookies do not constitute having your cake and eating it too. Not really. The exact consequences on human behavior aren't clear. And again, I'm not saying that sucralose is worse than actual sugar. That's a much broader conversation. I'm just saying your nervous system does know the difference and that this has impacts on behavior. Which is something worth keeping in mind. The other thing is that by understanding how our bodies sense different inputs and learning how to manipulate these inputs, we are on the cusp of using neuroscience and gut sense science to alter feeding behaviors, potentially in humans, in fascinating new ways. And personally, I am pumped. I am pumped like a halorhodopsin stimulated by green light to see what's coming. And if you got that pun, kudos. But above all, I'd really encourage you to just engage with the science, stay curious, and if you enjoyed this video, or even if you didn't because this is pretty technical, listen to that episode with Diego Borquez and Andrew Huberman because it was very practical, very stimulating, probably more so than me, but I enjoy doing this, and if you're sticking along with me till now, I appreciate you. Bye.