White granules on lips

Unlike your tongue, sensors in your intestine can measure the calorie content in sweeteners

Cohavit Gil

A taste may fool your mouth, but not your gut, which can apparently tell the difference between sugar and an artificial sweetener.

According to a new paper published this year in Nature Neuroscience in collaboration with the Bohórquez Lab at Duke University, not only does the gut sense a difference in nutritive value, but it quickly informs the brain of it. The brain then makes nutritional decisions based on, well, gut sense.

Food for thought

“As you can see I am truly a gastronaut, I have the mug,” Melanie Maya Kaelberer, one of the researchers and authors, said with a laugh. Dr. Kaelberer holds up a custom ceramic mug with a big “G” for “gastronaut” on the front.

Gastronaut! A great term, but what does it mean?

A group of neuro-gastroenterologists coined the title to describe what they do. Gastronauts ask questions about how the gut and the brain are connected.

Kaelberer found her calling when she was still in grade school.

“I found it fascinating that your brain has all this control over what you feel, what you do,” she said.

Speaking about her current work, she said, “Early sensory circuits are actually shaping the world that we navigate and as a result, they shape how we perceive, how we feel, and how we think.”

If asked to think about sensing, you might think about how it feels to touch a fuzzy object or smell a delicious meal. But there is so much going on behind the scenes in your body and brain before you even begin to take in that breath- taking sunset or taste that ice cream sundae.

Tracing sensor circuits

Melanie Maya Kaelberer
Melanie Maya Kaelberer. Pic courtesy M. Maya Kaelberer

These “early sensory circuits” are groups of cells throughout the body that send information through electrical pathways (up and down neurons, or nerve cells) and chemical ones (between neurons). These circuits work subconsciously and quietly to create our experience of sense (sight, smell, touch, hearing, and taste, and gut sense).

In daily life, we don’t really notice the effects of the gut, but it is constantly, quietly, deciphering and transmitting information about the food we encounter.

“The gut sense is, in my opinion, the first sense. The very first thing we had to do when we were little single-celled organisms is sense food, sense how we can find food, how we can determine whether food is good to eat or not,” Kaelberer says, “This is the basis of our life.”

It’s no coincidence that we have sayings like “gut feeling,” long associated with intuition. Now, scientists are finding out that the connection transcends semantics; our gut discerns which foods will provide caloric sustenance and our brain uses that information to make dietary choices.

The research at the Bohórquez Lab solved a major mystery within the field: it is known that mice can tell the difference between nutritive sugars and non-nutritive sweeteners even without the sense of taste. When prompted with a choice between sugar and sweetener, the animals choose sugar more often than artificial sweetener, even when they cannot taste the difference.

These scientists sought to find out: how exactly are the animals determining the difference between sugar and sweetener?

They discovered that the neuropod cells in the gut register the difference.

The rise of the neuropod

Neuropod cells in the small intestine labeled in green
Neuropod cells in the small intestine labeled in green. Image courtesy the Bohórquez Lab

Neuropod cells, previously discovered by the Bohórquez Lab, are cells in the gut that form synapses with other nerve cells to transmit real-time information to the brain.

A synapse is the thin gap between two neurons. When the first neuron releases a chemical message in the gap, it turns on a “switch” in the next neuron, thus sending the message on to the next neuron, and the next. Any thought in your brain, any movement in your body, any behavior you need to survive, involves synaptic transmission.

Just like bodily movement, eating calories is important to many organisms’ survival. These gut-dwelling neuropod cells monitor sugar presence and tell the brain what’s going on in the gut, an important mechanism for survival. The Bohórquez Lab researchers discovered how neuropod cells in the gut tell the brain the difference between a caloric sugar and a non-caloric sweetener. This may seem simple, but without new technology and techniques, the discovery would not have been possible.

The road not taken

Kaelberer discusses the challenges and experiments that led up to the discovery, pointing out that while one of the lab’s core principles is, “the question drives the techniques that we use,” that is easier said than done.

“You have a technique in your lab, and it works, so it’s easy to use it again.” But this time the lab decided to take a risk and try entirely new techniques that have never been tried before.

“There were a bunch of avenues that didn’t make it into this paper,” she said, describing one of them.

“There’s a new technology for sensor proteins. They’re pretty cool, we used them in our 2018 Science paper that established neuropod cells. What we used was called a glutamate sensor.” Glutamate is a chemical released into the synapse by the first neuron to increase electrical activity in the next one. Other neurotransmitters, such as gamma aminobutyric acid, can actually inhibit the second neuron’s ability to fire, but glutamate is excitatory.

Kaelberer continues, “What [the sensor protein] does is, if glutamate is present, it fluoresces green. So [the question] we were trying to get at was, what are the different neurotransmitters being released [from neuropod cells] for nutritive sugar over artificial sweetener?”

Once the researchers learned that neuropod cells actively inform the brain about the presence of a sugar or sweetener, they sought to know if the messages differed, depending on whether a sugar or sweetener was detected.

They found that the gut did send different messages depending on caloric content. When neuropod cells detected sugar, they released glutamate; when they detected a sweetener, they released ATP (adenosine triphosphate, the “energy-carrying molecule” in the cell).

Kaelberer shared the lab’s decision to abandon their sensor protein method, “We thought that it would be better to go with pharmacological blocking.” Pharmacological blocking involves using a chemical to slow or halt normal cell activity.

When the team blocked the glutamate pathway, the vagus, a nerve connecting the gut cells to the brain, showed less activity in the presence of sugar (sucrose). But blocking the glutamate pathway did not stop the response to the artificial sweetener (sucralose). This suggests glutamate only informs the brain about sugar, not sweetener.

Neuropod cell (green) and two of its receptors, SGLT1 and T1R3. Neuropod synapses with a nerve cell (blue)
Neuropod cell (green) and two of its receptors, SGLT1 and T1R3. Neuropod synapses with a nerve cell (blue). Image courtesy of the Bohórquez Lab

A counterintuitive find

Kaelberer shares one of the biggest surprises: it was not the sweet-taste receptor (purple label, T1R3) that detected the nutritive sugar, but another, a sodium-glucose transporter (orange label, SGLT1).

A receptor is a protein in a cell’s surface that detects molecules (sugar in this case) in the vicinity. Some receptors cause the cell to change its activity based on environmental cues. In this case, depending on the levels of sucrose or sucralose in the gut, the neuropod cell releases neurotransmitters into the synapse with a vagus nerve cell (blue), causing an electrical signal to be sent to the brain.

Kaelberer explains her surprise: “The classic held belief is that sweet-taste receptors detect sweetness. There are sweet-taste receptors in the gut, and we were like, ‘clearly this is going to be the pathway [to detect sugar].’” But it turns out that the sweet-taste receptors in the gut only detect artificial sweetener, not nutritive sugar.

“This was one of those moments [when you say] ‘Wow that’s pretty cool!’ Because the moment you’re using two different receptors you have the opportunity to release two different neurotransmitters,” Kaelberer said. “That was one of the big surprises.”

One finding usually leads to another. But as the scientists worked, they found that getting new experiments to work wasn’t always easy.

The lab group wanted to know whether neuropod cells could influence an animal’s choice between sugar and sweetener. Spoiler alert: they do.

Optogenetics in the gut of a freely moving mouse. The ferrule holds the fiber in place so that the light can be precisely aimed at the target area, in this case the neuropod cells found in the duodenum, which is part of the intestines
Optogenetics in the gut of a freely moving mouse. The ferrule holds the fiber in place so that the light can be precisely aimed at the target area, in this case the neuropod cells found in the duodenum, which is part of the intestines. Image courtesy the Bohórquez Lab

Optogenetics to the rescue

To tackle this question, the scientists did something novel: they used light to control neuropod cells’ activity in the gut of a freely-moving mouse. It’s called optogenetics. It involves inserting a gene that’s made light-sensitive into specific cells. Shining a light on those cells causes the cells to either activate (send a signal to the next neuron), or silence them (no signal to the next neuron).

“The biggest stump story in here is the optogenetics,” Kaelberer says with a smile, “we had to get optogenetics to work in the gut. However, optogenetics are developed to work in the brain.” She admits the task wasn’t easy.

“If we take that same [light-containing] fiber…and stick it into the gut, it perforates the gut wall, it breaks through and it’s very bad for the animal,” Kaelberer said. “We were stuck. We were fortunate because Polina Anikeeva [MIT researcher and publication author] came down to Duke to give a talk and she passed around this flexible fiber… It was exactly what we hoped…” Using it allowed the gut to move freely and didn’t puncture the wall.

Old rigid fiber versus new flexible fiber for optogenetics in the gut
Old rigid fiber versus new flexible fiber for optogenetics in the gut. Image courtesy the Bohórquez Lab

“That ended up being a big jump,” she says.

Kaelberer shares a quote from Roman philosopher Seneca: “’Luck is when opportunity meets preparedness.’ We were prepared, we were primed for this, and we were just looking for the opportunity and there it was.”

The scientists used optogenetics in the gut to influence a mouse’s decisions to drink sugar versus sweetener. Kaelberer explains what was going on.

“The gut is signaling this difference between artificial sweetener and real sugar. Is it the neuropod cells? Let’s block them. We silenced them using this inhibitory optogenetic channel, halo-rhodopsin. So [the neuropod cells] are no longer able to signal. That was enough to then have [the mice] drink evenly between the artificial sweetener and the real sugar. At this point now all [the mice] have is the taste on their tongue. As far as the tongue is concerned, the two [tastes are of] the same sweetness.”

When the scientists shut off the neuropod cells, the animals lost their preference for nutritive sugar. When they turned the neuropod cells back on, the animal completely recovered their preference for sugar. The experiment thus demonstrated that neuropod cells are necessary for sugar preference.

The tongue in the gut

Green light at a frequency of 532 nm is used to silence receptors of neuropod cells in the gut in a genetically modified halo-rhodopsin mouse
Green light at a frequency of 532 nm is used to silence receptors of neuropod cells in the gut in a genetically modified halo-rhodopsin mouse. Image courtesy the Bohórquez Lab

But the scientists took it a step further and tricked the mice into thinking sweetener water was just as good as sugar water.

Kaelberer laughs, “I don’t like to think of myself as tricking mice. That’s a little mischievous. But yeah, that’s exactly what we did.”

They again used optogenetics to activate the neuropod cells when the mouse drinks artificial sweetener. These mice consumed more artificial sweetener than the mice with no optogenetic manipulation.

This experiment confirms that the neuropod cells act like the tongue of the gut: they sense sugar and get the brain to use the information they send to drive behavior, such as consuming more sugar.

Kaelberer has two takeaways: “The gut is driving this gratifying effect of eating food,” and “the gut is actually contributing to some of these feelings of what we should consume and when we should consume it.” So it isn’t the body listening to the brain; it’s the other way around.

Cohavit Gil is a neuroscience nerd and creative writer with a B.S. in psychology from the University of Massachusetts, Amherst.

Click here for the original article

Leave a Reply

Your email address will not be published.