Bitterness receptors are found not only on the tongue but also in all parts of the body and they protect us from invading bacteria
- Proteins used to sense bitter taste are found not only on the tongue, but also in various organs all over the body, which do not come into contact with food at all.
- New research has found that these proteins, known as taste receptors, trigger an extremely rapid defense response that can kill bacteria.
- Stimulating these receptors with bitter compounds can enhance normal immune responses and reduce our dependence on antibiotics.
Imagine the worst cold you've ever had in your life. Your nose is completely blocked. You are lost in the air. The pressure in your sinuses sends waves of pain around your head. You can't smell, so eating is like chewing cardboard. You feel sick and feel completely miserable. Now imagine that these symptoms always return, even if there is relief from time to time for a few days. You are never free. Never.
Unfortunately, this is the reality in the lives of patients with chronic gout, or chronic sinusitis, which is called, by its technical name, Rhinosinusitis: A disease of the nose and other areas of the upper respiratory tract that affects about 35 million Americans. Treatment in many cases often involves prolonged periods of taking antibiotics and steroids. If these drugs do not help, the sufferers must undergo a delicate surgery on the skull to clean the nasal cavities of infections. These surgeries seem to be becoming more common because modern society's overuse of antibiotics is reducing their effectiveness. Today, one in five antibiotic prescriptions in the US is given to an adult suffering from merinosinusitis and the disease has become a factor in the vicious circle that contributes to the increase in the prevalence of dangerous bacteria resistant to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA).
And here we enter the story. We want to break the cycle. We and many other researchers are trying to understand the defense mechanisms of the immune system that the cells found on the inner walls of the airways, called epithelial cells, activate against respiratory infections. An average person inhales more than 10,000 liters of air a day, most of it through the nose, and the air contains countless bacteria, fungi and viruses. Our nose is the front line of respiratory defense. With every breath, waste particles, viruses, bacteria and fungal spores are trapped there. Yet amazingly, most people walk around breathing freely without any hindrance from respiratory infection.
It turns out that one of the reasons for this is on the tip of our tongue, literally, and we didn't even think of it. Recently it became clear that the proteins found on the tongue, and were known as the bitter taste receptors, have another function: protection from bacteria. Our research showed that these receptors, also found in the nose, trigger three bacterial-fighting responses. First, they send signals that cause the cells to mechanically expel the invaders by moving cilia, tiny hair-like protrusions on the surface of the cells. Second, the receptor proteins signal certain cells to release nitrogen monoxide (NO) molecules that kill bacteria. And third, the receptors signal other cells to send out proteins called Defensins that act against bacteria.
But some researchers made an even more amazing discovery: these receptors are found not only on the tongue and nose but also in all other respiratory tracts, as well as in the heart, lungs, intestines and other organs. We and other scientists now believe that these receptors are part of the innate human immune system. This system is different from the more familiar components of the immune system, such as antibodies and cells that move around our body and fight invaders, but it may be faster than them. The familiar immune system sometimes requires many hours or even whole days to produce antibodies against a particular bacterium or virus. But the reactions of the taste receptors occurs within a few minutes. Even though its reaction is more general and it is not aimed at a specific bacteria, it acts as an early warning system for anything.
A taste of danger
Indeed, if you think of the taste receptors as sentinels that react to substances entering the body, then the role they play in the immune system seems logical. When they reside on the cells that form the taste buds in the tongue, the receptors stimulate the cells to send signals to the brain about the nutritional value of the food entering the mouth or to warn of possible toxicity. The tongue distinguishes five basic types of taste: bitter, sweet, salty, sour andUmami. The sense of taste therefore acts as the gatekeeper of the digestive system. The information it provides about the food we eat allows us to decide whether to swallow it or not. The bitter taste receptors are able to distinguish the presence of toxic plant chemicals, including a group of substances called alkaloids, which include strychnine וnicotine. The tastes we now define as "bitter" are often perceived by the brain as unpleasant because the receptors evolved during evolution to alert the presence of chemicals suspected of being harmful.
Alertness to harm is key to survival, and may be why there are so many different taste receptors. Each of the other tastes: sweet, salty, sour and umami, has only one type of receptor, on the other hand there are at least 25 types of receptors that detect bitter compounds. These receptors, known as the "type 2 taste receptor family," or Rs2T, likely evolved to detect and protect us from ingesting a wide variety of toxins.
Early clues to the activity of such receptors elsewhere in the body emerged in 2009, when researchers at the University of Iowa discovered Rs2T on epithelial cells lining the lungs. A sticky layer of mucus spread over these cells traps microbes and irritants that are inhaled. Then, the tiny cilia on top of the cells move at a rate of 8 to 15 times a second, simultaneously, pushing the irritants toward the throat where we swallow or spit them out. The Iowa team found that cilia in human lungs move at a faster rate when bitter compounds stimulate Rs2T receptors. Hence, Rs2Ts help in clearing the airways of inhaled and potentially dangerous substances, those that have a bitter taste in the mouth.
Around the same time, scientists at the University of Colorado's Anschutz Medical Campus studied the bitter taste receptors found on a special type of cells in the noses of rats called cells Solitary chemosensory (literally: isolated chemosensory cells), which probably react to irritants. They found that the activity of these cells increases when they recognize bacterial molecules called: Acyl-homoserine lactones (AHLs). Dangerous type bacteria Gram-negative Molecules of AHLs are released when they form a biological membrane. Biological membranes consist of communities of bacteria, such as Pseudomonas aeruginosa, which stick to each other. Being organized in a membrane increases their resistance to antibiotics 1,000 times more than less organized bacteria, making them much more difficult to destroy. The researchers from Colorado showed that AHL molecules, which stimulate the formation of the biological membrane, also stimulate activity in chemosensory cells. AHL molecules were thus the first substances, unique to bacteria, found to stimulate cells bearing bitter taste receptors, thus supporting the idea that the receptors respond to outside invaders.
These findings intrigued us, so in 2011 we started looking for taste receptors in epithelial cells in human noses. We conducted the research in collaboration with taste experts, At the Monel Center for Chemical Senses
in Philadelphia, a leading institution in taste and smell research. Our research started as a small side project just to see if we could find bitter taste receptors in cells in the nose, like the Iowa researchers found in health. But when we discovered hints that certain taste receptors could influence how susceptible people are to rhinosinusitis, the project soon became a major focus of our lab.
Super tasty
In our research, we mainly focused on one particular bitter taste receptor: T2R38, the most studied receptor in the T2R family. The protein that builds the T2R38 receptor in humans appears in several versions as a result of polymorphism: slight differences in the genes that encode them. Indeed, we found most of the common versions of the receptor in the cilia cells that line the nose and cheeks.
Finding this abundance of receptors led us to study the effect of the different forms of T2R38 on the behavior of cells in the nose and throat. When two of these forms are on the tongue they have a radically different effect on taste. One form of the two versions is very sensitive as a taste detector in the mouth, and the other, does not react at all. About 30% of Caucasians inherit two copies of the insensitive version of the T2R38 gene (one from each parent) and these people are considered "untasteful" for certain bitter compounds. In contrast, about 20% of white people have two copies of the T2R38 gene in the active version, and they are the ones who feel these compounds to an extreme degree, and are considered "supertasters". Those who inherit one copy of each of these genetic variants are somewhere between the two extremes.
When we examined tissues removed in surgeries of the temples and nose, we compared the behavior of nasal cells with each of the two forms. (We knew which versions were in the cells by sequencing their genes.) To activate the receptors, we exposed the cells to a substance called Phenylthiocarbamide (PTC), often used in taste tests in T2R38 research. We were excited to discover that cells taken from hypertaster patients, as opposed to cells taken from full-tasters, were the ones that produced large amounts of nitric oxide.
The findings gave an additional boost to our idea about the connection between the immune system and the sense of taste. Nitrogen monoxide molecules perform two important actions against bacteria in the respiratory tract. They can stimulate the cells in the respiratory tract to increase the rate of cilia movement, and they can also kill bacteria directly. Since nitrogen monoxide is a gas, its molecules can quickly flutter from the cells lining the airways and reach the mucous membrane and the bacteria. When the substance penetrates the bacterial cells, it causes damage to their membranes, enzymes and DNA. Normally, our guts produce large amounts of nitrogen monoxide that flows through the respiratory tract and keeps them free of infections.
This dual mode of action against bacteria led us to hypothesize that different variants of T2R38 could alter the susceptibility of individuals to upper respiratory tract infections. Indeed, in the laboratory we found that when T2R38 receptors are activated in the noses of supertasters, the nitrogen monoxide secreted in them causes the cilia to move at an increased rate and directly destroys more bacteria compared to cells in the noses of non-tasters. Later in the study, we also discovered that AHLs, the bacterial compounds found to stimulate the chemosensory cells in the noses of mice, also directly stimulate T2R38 receptors in humans. But while mammary cells of supertasters sense AHLs molecules of bacterial origin via T2R38 receptors and produce nitric oxide, mammary cells of non-tasters do not. These properties make the cells in the noses of supertasters much better AHL-producing bacteria killers than the cells in the noses of non-tasters. These observations led us to the conclusion that epithelial cells in the respiratory tract use T2R38 receptors, which are used in the tongue as bitter taste receptors, to detect bacterial activity and stimulate defense mechanisms.
Since we discovered the presence of T2R38 receptors in the cilia of human nasal epithelial cells, our knowledge of the role of these taste receptors in the nose has expanded even further. We found that, as in mice, these receptors are also found in solitary chemosensory cells in human noses. Solitary chemosensory cells are indeed solitary, i.e. isolated: they are scattered all over the nasal cavities but they occupy only one percent of all the cells there. On their surface there are not only bitter taste receptors of the T2R type but also sweet taste receptors of the T1R type. We found that when the T2Rs in these cells are stimulated, the cells signal the cells around them to release anti-bacterial proteins called defensins into the lining of the respiratory tract. These proteins can kill many disease-causing bacteria, including Pseudomonas aeruginosa and MRSA.
When the receptors for the sweet taste undergo excitation, they deactivate the activity of the receptors for the bitter taste, probably to prevent the cells from secreting too many deadly proteins at the wrong time. In the past, they already discovered that sweet taste receptors are found in other parts of the body, such as the pancreas, where they sense the sugars in the blood and stimulate cells that produce insulin, a hormone that regulates blood glucose levels. However, our research shows that sweet and bitter taste receptors, when found on the same cell, have opposite roles.
These experiments suggest that the taste receptors make up the early warning arm of the immune response system in the respiratory tract. They appear different from other well-studied early warning proteins known as receptors Toll Like Receptors or TLR. These receptors also trigger immune responses when certain bacterial molecules activate them, as do T2R receptors, but there is at least one important difference between them: some of the responses of TLR receptors - such as sending signals to genes so that they start producing antibodies that signal the immune system to destroy certain invaders - are responses Much slower, lasting several hours or even days. In contrast, T2R38 and similar bitterness receptors react within seconds to minutes. These taste receptors may be of great importance at the beginning of the infection in activating a rapid response that puts the immune system on alert. The role of other receptors in the immune system may be crucial in fighting persistent infection. In such a situation, they work to mobilize the system when the first response is not enough.
Vulnerable people
The large number of genetic variants of T2R receptors for the bitter taste makes their role in the immune response even more interesting. Most of the types of bitter taste receptors, 25 in number, have genetic variants that increase or decrease their response to certain bitter substances and therefore different people have different sensitivity to these substances. If indeed the response to bitterness plays a role in the immune response to invading bacteria, then the same genetic variants may also create differences in the way people fight infections. Higher function of taste receptors provides better protection against infections and vice versa.
We began to test this idea in people and discovered clues to the validity of our hypothesis. The millions of patients with chronic rhinosinusitis are a natural population for experimentation and a group that needs help. In questionnaires that dealt with their quality of life, those suffering from rhinosinusitis reached a lower rating even than patients suffering from heart and lung diseases. In addition, those suffering from rhinosinusitis are prone to develop dangerous lung infections and aggravate diseases of the lower respiratory tract, such as asthma. We therefore tested bacterial cultures taken from patients with rhinosinusitis. We found that even supertasters are not completely vaccinated, the frequency of gram-negative bacteria infections in their noses is much lower than that of non-tasters. And it makes sense, Gram-negative bacteria produce AHLs, the compounds that stimulate the receptors in these people's noses. The receptors in turn stimulate nearby cells that release nitric oxide. Other bacteria do not produce AHLs and therefore they will not encounter this immune response.
Subsequent clinical trials supported the hypothesis that T2R38 receptors play a role in the response to sinusitis. Two studies conducted by our research group in Pennsylvania showed that people with two copies of a supertaster version of T2R38 were less likely to develop severe rhinosinusitis than people with two nontaster copies, or people with one copy of each type. Martin Desrozier, an otolaryngologist at the University of Montreal Medical Center in Canada (CHUM), and his colleagues confirmed that the inactive version of the T2R38 gene is more often found in patients than in healthy people. In the same study, severe rhinositis was also found to be associated with certain variants of two other types of receptors from the same family: T2R14 and T2R49.
Also in other organs besides the nose connections between taste receptors and immune response are beginning to be revealed. In 2014, scientists showed that when chemosensory cells in the urinary tract recognize Escherichia coli bacteria, they use T2R receptors to stimulate the bladder to release urine. It seems that this is an attempt by the body to wash out the urinary tract and get the bacteria out to prevent a bladder infection. Another new study showed neutrophils and lymphocytes, two types of white blood cells essential to the body's immune response, also use T2R38 to detect AHL molecules of Pseudomonas bacteria.
Now we want to learn if chemicals that stimulate the T2R receptors can be used as a medicine for patients with rhinosinusitis. Our hypothesis is that these substances may trigger stronger responses of the immune system that will kill the bacteria. A wide range of bitter compounds in the food we eat and drink every day can possibly be used as medicines: substances from the familyThe humulons and the lupulones which are found in the bitterness that gives bitterness to the beer, Isothiocyanates found in green vegetables, such as Brussels sprouts and bitter chemicals, such as Limonene, found in lemon. In the past it was found that the bitter substance absinthe, which is extracted from the wormwood plant and is found in the spicy drink absinthe, stimulates T2R receptors in solitary chemosensory cells. In our laboratory we test several compounds that may act as drugs. New drugs based on bitter compounds may one day be able to fight infections without the need for regular antibiotics.
We believe that a taste test or a genetic test of T2R could, in the end, alert us to susceptibility to infections. The natural variation in these taste receptors could help answer an age-old question: Why do some people often get respiratory infections, while others never get them? Using bitter taste receptors to solve the mystery would be a really sweet solution.
