Gut feelings

Every November, millions of Americans tuck into a tasty Thanksgiving dinner, most often a traditional roast turkey with all the trimmings. Come December, they feast all over again. Few of the holiday diners realize, however, that their bodies will continue tasting that meal long after they’ve swallowed it.

Scientists are finding that the same taste receptors lining the tongue and palate also occur in the stomach, intestines and other internal organs. They’re finding new receptors that also sense nutrients in our foods. And the more they investigate, the more they learn that these receptors play a crucial role in coordinating our digestion, regulating what we eat and how much — even orchestrating our immune system to defend against pathogens and parasites.

“Rather than being a hollow tube that you don’t want to discuss, the gut is a really fascinating workspace,” says Richard Young, a nutritional physiologist at the University of Adelaide, Australia. Understanding what goes on in that workspace may give clinicians new levers to pull in treating diseases from diabetes to obesity to irritable bowel disease.

Five tastes, and counting

We’re familiar with the portfolio of five basic tastes — sweet, sour, salty, bitter and umami (the savory flavor of chicken broth, mushrooms, cured meats and MSG) — that help us determine whether that turkey dinner is worth eating. There’s growing evidence for other basic tastes, too, possibly including calcium, fat and even water. (Most of the rest of flavor, which lets us distinguish peas from carrots, or potatoes from rice, is really a matter of smell, not taste.)

From a biochemical point of view, these tastes signal the presence of nutrients: The sweetness of the potatoes indicates carbohydrates; the turkey’s umami means protein; the salty gravy is rich in electrolytes. Others are markers of risk: The bitterness of brussels sprouts marks the presence of potential toxins, and sourness can indicate spoilage if leftovers sit too long in the fridge.

Until relatively recently, biologists thought these taste receptors’ job was done once the food had been swallowed. Then, in the early 2000s, physiologist Soraya Shirazi-Beechey of the University of Liverpool and her colleagues turned up a surprise. They were trying to understand how the intestines regulate absorption of glucose, and what they found suggested there must be a glucose sensor in the gut wall. That sensor turned out to be identical to the sweet receptor found in the mouth.

Receptors from stomach to skin

Since Shirazi-Beechey’s pioneering work, researchers have found receptors for sugars, fats, the amino acids that make up proteins, and bitter compounds in the gut — as well as all over the body. “We’re finding them in the stomach, in the intestines, in the pancreas, in the lungs, in the central nervous system, in the testes, in the skin,” says Robert Margolskee, director of the Monell Chemical Senses Center in Philadelphia, who led much of the early work.

Of course, even though these receptors may be the same as the ones in the mouth, they are wired differently: When a glucose molecule triggers a sweet receptor in the intestinal wall, the brain doesn’t perceive it as a sweet taste. So most researchers avoid the term “taste receptors” for places outside of the mouth, preferring the more general term “nutrient receptors” for whatever their role may be in other organs.

As to what all those roles may be: “It’s a huge, fascinating question,” Margolskee says.

In the gut, not surprisingly, the receptors are there to tell the digestive system what it’s dealing with, so that it can release the appropriate enzymes: starch-digesting amylases for the potatoes, protein-digesting proteases for the turkey, and so forth. But those enzymes are only the opening notes in a more complex digestive symphony that’s orchestrated in part by nutrient receptors, one that researchers are just starting to understand.

New clues to diabetes

Once starchy foods are digested, for example, the gut must closely regulate how the resulting sugars — primarily glucose — are allowed to build up in the bloodstream. Too little glucose and the body can’t function; too much can lead to heart disease, kidney and nerve damage, and more. To maintain the proper balance, the gut deploys a coterie of glucose-transporting molecules and regulatory hormones, triggered by nutrient receptors in the intestinal wall.

There is growing evidence that this system breaks down in people with type II diabetes, the version of the disorder that typically develops in adulthood when people gain too much weight. After a carbohydrate-rich meal, sweet receptors in the gut sense the presence of the sugar. In rodents, and probably in people as well, this quickly leads to an increase in a glucose transporter molecule called SGLT-1 to exploit the nutrients. Then, once blood-sugar levels rise, sweet receptor levels drop to ramp the system down again. “It’s a safety mechanism for not overshooting,” says Young.

This safety mechanism seems to be broken in people with type II diabetes, Young’s experiments show. Sweet receptor levels remain high, leaving the guts primed to continue pouring glucose into the blood.

The exact identity of the receptors that trigger this response remains controversial, however. Shirazi-Beechey’s work shows that the sweet receptor is one, but other researchers have shown that SGLT-1 also senses glucose as well as transporting it, and may be even more important. Young is now conducting clinical trials to see whether drugs that block the sweet taste receptor in the gut can damp down the rise in SGLT-1 and therefore blunt the spike in blood sugar.

If so, his findings could reshape our thinking about type II diabetes. Until now, clinicians have thought that blood sugar goes up in people with diabetes because insulin becomes less effective at removing glucose from the blood. But if Young is right, the problem — and thus ways to address it — may be broader than that. “Rather than treat diabetes as a disorder of glucose disposal, we can treat it as a disorder of glucose handling from the time it crosses the gut wall,” says Young.

A bitter truth about sweeteners?

Young’s results raise an uncomfortable point. We have always assumed that artificial sweeteners merely activate the sweet receptors in the mouth, providing a pleasant taste without the calories. But at least a few recent human studies suggest that their effect may be much less neutral. If sweet-taste receptors in the gut play an important role in regulating digestion and blood sugar levels, then artificial sweeteners may disrupt these key processes by triggering those receptors like actual sugars do.

In an as-yet-unpublished experiment, Young gave 27 healthy volunteers capsules to swallow three times a day. In half the cases, the daily dose of capsules contained artificial sweetener equivalent to a liter and a half of diet soda, while for the other half they contained a placebo. After two weeks, Young found, the volunteers who had consumed the artificial sweetener showed a bigger spike in blood sugar in response to a dose of glucose than those who got the placebo. Young’s team is now repeating the study with type II diabetics, where he expects the sweeteners will cause even more disruption.

To most researchers’ surprise, even bitter receptors may get into the glucose game. These receptors occur on the surface of at least some of the intestinal cells that secrete glucose-regulating hormones. And a few studies have found that certain bitter-receptor gene variants are associated with increased risk of diabetes, though it is not clear why. A recent study even found that one particular bitter compound, derived from hops, improved glucose control in diabetic mice.

(Alas, that doesn’t mean that diabetics can medicate themselves with ale. “Beer is definitely not an antidiabetic treatment,” says molecular biologist Maik Behrensof the Technical University of Munich, one of the leaders of that study. “There’s alcohol, there’s loads of calories....”)

How we know what’s enough

Nutrient receptors in the digestive tract do more than just manage the digestive process, though. They also play a key role in decisions about what to eat, and how much. One of the most striking features of eating behavior, both in humans and in other animals, is how tightly the body controls calorie intake to maintain weight at a fixed point. (The modern epidemic of expanding waistlines is a notable exception here, which we’ll return to in a moment.)

In a classic experiment from the 1970s, rhesus macaque monkeys that received nutrient-rich liquid supplements reduced the size of their next meal to exactly compensate for the calories in the supplement. Since each supplement, whatever its caloric content, was delivered in an identical volume of water through a stomach tube, the animals could not have been monitoring the taste of the supplements or the amount they swallowed. Instead, the digestive tract must have directly sensed the caloric content. “The system works for fat calories, it works for amino acid calories, and it works for carbohydrate calories. It’s basically a caloric detection mechanism that’s irrespective of the nature of the calories,” says Harvey Grill, who directs the obesity unit at the University of Pennsylvania’s Institute of Diabetes, Obesity and Metabolism.

In the decades since that experiment, researchers have learned that both nutrients and physical sensations such as stomach fullness act together to trigger a spate of interacting hormones with names like CCK, PYY and GLP-1 that regulate satiation, the feeling that we’ve eaten enough and it’s time to push back from the table. The details of this hormonal dance, including the particular nutrient receptors involved, are still being worked out.

More calories, please

Satiation is not the only mechanism determining our eating behavior. As omnivores with a wide range of possible foods, humans often face choices. Should I have a bigger helping of turkey and stuffing, or make room for green beans instead? And what about that second piece of pie? Choices like this involve a second drive, which scientists call appetition (an urge to eat more of what we like).

In appetition, nutrient receptors provide the critical data that help us select what to eat. Not surprisingly, animals — including humans — have evolved to prefer foods that deliver a big slug of calories. That’s why you’re likely to take a second helping of potatoes or turkey, but not celery sticks. Perhaps more surprisingly, we learn this anew for every novel food we add to our diets: Does this unfamiliar flavor signal something calorically worthwhile, or not?

To prove that calories, and not just a pleasant taste, make the difference, in another classic experiment Anthony Sclafani of Brooklyn College and his colleagues gave mice a choice between two bottles filled with calorie-free, flavored water. When the animals drank the cherry-flavored water, they also received a sugar solution through a stomach tube. When they drank from the grape-flavored bottle, the stomach tube gave them plain water. Even though the mice never tasted the sweet sugar solution in the mouth, their guts somehow knew which was the good stuff, and the mice quickly learned to prefer the cherry-flavored water.

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Sclafani and his colleagues have since shown that the same learning applies whether the stomach tube delivers sugar, fat or protein. Nutrient sensors in the gut, it appears, are shaping appetition by detecting the caloric content of the meal. But which ones? Mice genetically modified to lack sweet or umami receptors still sense the calories, says Sclafani, which suggests that other receptors are responsible for the effect.

This nutrient-seeking drive is strong enough to override ordinary oral taste preferences. When Sclafani offered mice a choice between a saccharine-sweetened solution and an unsweetened one that at the same time delivered sugar through the stomach tube, the mice quickly switched their preference from the sweet taste of the saccharine, which they favored to begin with, and ended up drinking four times as much of the unsweetened drink with the caloric kick. “That’s telling us that yes, taste can drive intake, but over a 24-hour period it’s really the stimulation of the gut receptors that’s having a sustained effect,” says John Glendinning, a sensory physiologist at Barnard College in New York, who collaborates with Sclafani. This appetitive urge to eat more of high-calorie foods is strong enough to override satiety mechanisms, he says, and may help explain why so many people gain weight on modern, calorie-rich diets.

Bypassing the problem

For obvious reasons — stomach tube, anyone? — most of the work on appetition and satiety has been done on rodents. But most experts believe the same processes operate in humans, too. The strongest evidence for this may come from what is, hands-down, the most reliable way of producing weight loss in obese people: gastric bypass surgery, in which doctors remove or bypass most of the stomach and the upper part of the small intestine, or duodenum. “The effects of bypass surgery are so profound that you can’t ignore them,” says Fiona Gribble, a clinical biochemist at the University of Cambridge. Most patients quickly lose the majority of their excess weight, and they keep it off. Moreover, blood sugar levels return to healthy levels in the vast majority of diabetic patients, even before they lose much weight.

What could be the cause of this? The duodenum contains a large population of nutrient-sensing cells, which are removed or bypassed during surgery. Sclafani thinks the loss may block appetition, so that people no longer feel any motivation to eat. Gribble, on the other hand, thinks bypass surgery’s success is more a matter of enhancing satiety. As evidence, she points to a newer form of the surgery known as sleeve gastrectomy, which does not remove or bypass the duodenum but merely narrows the stomach. “When you get rid of the stomach as a holding zone, everything whistles straight through,” she says. As a result, the meal makes it farther down the gut before being fully digested and absorbed. The lower portions of the intestines have more cells that secrete satiety hormones, and she thinks that processing food at this spot leads to higher levels of those hormones and therefore to satiety setting in more quickly.

Either way, nutrient sensors are almost certain to be involved, scientists think. And that opens the way for companies to develop drugs to blunt appetition or enhance satiety — essentially matching the effect of bypass operations without the need for this major surgery. “That would be huge,” says Glendinning. “Pharmaceutical companies would obviously pounce on that as a target for regulating intake.”

The gut as guardian

Occasionally, our digestive systems have to deal with problems that go beyond mere digestion. That potato salad could have sat out too long and begun to develop a nasty growth of pathogenic bacteria. In many parts of the world, even the water in your glass could be contaminated with protozoan parasites. When we encounter such pathogens, the gut is our first line of defense — and here, too, taste receptors seem to help sound the alert.

Many toxins, bacterial and otherwise, bind to bitter taste receptors. When this happens in the stomach, it holds back its contents, emptying them into the intestines more slowly. Lower down in the intestines, bitter receptors trigger mucus production, producing diarrhea that helps flush out toxins more quickly. Both responses reduce the time the threat spends in the small intestine, where it could be absorbed into the body.

Receptors in the gut also help alert the immune system to invading parasites, recent studies have shown. Ordinarily, the immune system maintains a balance between two sorts of immune response: a so-called type I inflammatory response that’s effective against viruses and bacteria, and a type II response that works against larger parasites. When researchers knocked out the ability of mouse gut cells to respond when their taste receptors were tickled, the altered animals were less able to mount a type II response. Instead, their inflammatory type I system kicked into overdrive. The relative lack of parasites in modern developed nations — and, hence, less stimulation to these receptors in the gut — may thus help explain some of the modern prevalence of inflammatory bowel diseases in people, says Hong Wang, a molecular biologist at Monell who led the study.

But it’s hard to tell which receptors are responsible for the shift, because sweet, umami and bitter receptors (and some other receptors as well) all use the same activation machinery once the signal enters cells. And Wang’s experiment knocked out this internal machinery — for all of them. Bitter receptors are the likeliest candidate, since they recognize the widest range of substances, not just nutrients. Another candidate is the receptor for succinate, a metabolite produced by bacteria and protozoans. It’s not exactly a taste receptor, but it operates through the same machinery, says Wang’s Monell colleague Peihua Jiang.

Clearly, researchers still have lots to learn about taste receptors, and other receptors, in the gut. Some researchers are now looking there for olfactory — smell — receptors, too, says Sandra Steensels, a biomedical researcher at Weill Cornell Medical College in New York. So far, only one thing seems certain: Whether you wolf down your holiday dinner or savor every mouthful, you’ll be tasting a lot more than you think.