Background On Taste
Taste acts as an end behaviour checkpoint to either accept or reject food, enabling individuals to distinguish nutrient rich foods from noxious substances. There is a great variability amongst taste sensitivity in individuals, which can strongly influence food preferences, nutritional status and health. Taste is one of our five senses and is important in identifying both nutrients and potentially harmful substances and humans are able to discriminate five tastes; sweet, umami, sour, salty, bitter. Salts are recognised by salty ion channel receptors; acids by sour ion channel receptors; carbohydrates, sweeteners and protein receptors are detected by the type 1 family of taste receptors (T1Rs) and the bitter taste, which detects a variety of compounds including potential toxins, is mediated by the type 2 family of taste receptors (T2Rs).
T1Rs and T2Rs are G protein coupled receptors (GPCRs). The genes for each of these T2Rs are potentially polymorphic, resulting in a variety of phenotypes.
Bitter taste is based on an individual’s ability to taste the bitter compound phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). TAS2R38 is known as the bitter taste gene and it affects an individual’s response to taste bitter foods, with polymorphisms in the bitter taste receptor gene (TAS2R38) altering the ability to sense the intensity of bitterness of phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). The perception of bitter taste is thought to protect us from ingestion of toxic substances. A genetic variation in the sensitivity towards PTC and PROP may affect food preferences and susceptibility to certain diseases.
TAS2R38 145 C>G (Pro49Ala), 785 C>T (Ala262Val) & 886 G>A (Val296Iso)
TAS2R38, Haplotypes And Bitterness Sensitivity
TAS2R38 is a member of the TAS2 bitter taste receptor gene family, which, in humans, consists of 25 functional genes and 11 pseudogenes. Three of these SNPs i.e. 145 C>G (Pro49Ala), 785 C>T (Ala262Val) and 886 G>A (Val296Iso), result in three non -synonymous amino acid substitutions i.e. alanine for proline (Proline49Alanine), valine for alanine (Alanine262Valine) and isoleucine for valine (Valine296Isolecuine). These SNPs represent the most common variant alleles of TAS2R38 and are primarily responsible for the phenotype seen i.e. the individual’s ability to perceive bitter taste. These amino acid substitutions give rise to common haplotypes which are strongly associated with bitter sensitivity i.e. PAV (Proline, Alanine, Valine), considered to be the taster variation, associated with bitter sensitivity and AVI (Alanine, Valine, Isoleucine), considered to be the non-taster variation, associated with bitter insensitivity. A substantial proportion of differences in PTC/ PROP sensitivity is explained by these haplotypes, with various combinations of variants being strongly associated with bitter perception. Two rare haplotypes (AAV and AAI) and two extremely rare haplotypes (PAI and PVI) with frequencies of <5% and <1% respectively have also been identified.
Individuals who are homozygous for PAV (PAV/PAV) are classified as super tasters as they have a high perceived PROP intensity and are more sensitive towards bitter taste and those who are heterozygous for PAV (PAV/AVI) are classified just as tasters as they have a moderate perceived PROP intensity and therefore a moderate sensitivity towards the bitter taste. Non-tasters have a low perceived PROP intensity and are therefore not sensitive towards bitter tastes.
Many authors have hypothesized and discussed that genetic variation at TAS2R38 and genetic variations in the sensitivity towards PTC and PROP may impact on food intake, food acceptance and long-term health and susceptibility towards certain disease and that the ability to taste bitterness may influence human eating behaviour via development of individual food preferences.
PROP super tasters have been reported to have a higher sensitivity than non-tasters to various oral stimuli, including bitter tasting compounds and foods such as dark chocolate, caffeine solutions, soy products and green tea, sweet substances, chemical irritants (chilli, ethanol), and the texture of fats. Other reports show that individuals who perceive PROP as extremely bitter show a lower acceptance of Brassica vegetables and avoid strong tasting versions of foods that don’t contain thiourea groups including spicy foods and alcohol.
Taster status has been found to affect intake of certain vegetables, fats and sugars, alcohol and tobacco. It has also been linked to BMI, certain eating behaviours and risk of colon cancer, as well as glucose homeostasis and gut motility.
Intake Of Vegetables
PROP tasters have been found to have lower intake of certain vegetables, such as cruciferous vegetables, which contain bitter compounds such as isothiocyanates.
Tasters have been hypothesized to have lower acceptance and intake of bitter tasting fruits and vegetables (grapefruit juice, cruciferous vegetables), on the basis of earlier studies which found a relationship showing positive association between PROP taste sensitivity and perceived bitterness in certain compounds such as caffeine, quinine and naringin (the bitter compound in grapefruit). Many bitter tasting foods are anticarcinogenic (e.g. flavonoids, glucosinolates and phenols) and so these findings may have important health implications.
In a study of the bitter taste perception of food, PAV homozygotes rated vegetables containing glucosinolate (a natural bitter tasting compound present in cruciferous vegetables) as 60% more bitter than AVI homozygotes did, whereas PAV/AVI heterozygotes gave most glucosinolate-generating vegetables intermediate scores of bitterness. An analysis of food selection in an Italian population showed that AVI/AVI non-taster homozygotes consumed more cruciferous vegetables than individuals carrying a single copy of the PAV taster haplotype.
In a study done on children, tasters have been shown to give lower liking scores to raw broccoli compared to non-tasters, but no differences were observed for liking cooked broccoli; perhaps because certain bitter compounds such as isoflavones and isothiocyanates are degraded during cooking. Another study found 3-6 year old PROP tasters to have a lower acceptance of raw spinach. Other studies have found similar findings with regard to PROP tasters and lower preference for bitter food. Another study found an 80% increased intake of raw broccoli from PROP tasters when it was served with a dip compared to when it was served on its own, possibly because the dip masked the bitterness of the broccoli. Authors recommended that children who are sensitive to bitter tastes may require additional strategies to accept and consume bitter tasting fruits and veggies (e.g. addition of dips and sauces, offering milder juice blends and providing greater access to foods in the environment). Another study found an increased intake in total vegetable intake in PROP tasters vs. non-tasters.
While many studies indicate a reduced intake of bitter vegetables such as cruciferous vegetables in PROP sensitive individuals, not all studies have reported relationships between PROP taster status or TAS2R38 and acceptance or intake of bitter tasting foods. Inconsistencies could be due to method of recording dietary intake via self-report or perhaps differences in socio-economic status and ethnicity may play a role. Differences in the different food environments of individuals and access to certain foods, but more studies are needed on this.
Effect On Sweet Taste
It appears that super tasters might have a reduced intake of high sugar foods however there are contradictory results in studies with respect to PROP status and sweet taste in adults.
Results on PROP taster sensitivity and intake of high sugar foods are mixed. In children, several studies have found increased intake of sweet foods amongst PROP tasters, however some reports show individuals who perceive PROP as extremely bitter (PROP taster) to avoid strong tasting versions of foods that don’t contain thiourea groups, including sweets and reporting PROP super tasters to have a reduced intake of high fat and high sugar foods.
Variations in the TAS2R38 gene may explain individual differences in sweet preferences among children. In a study by Joseph et al, no relationship was found with sweet genotypes, however sucrose detection thresholds were related to variations in the bitter taste receptor gene TAS2R38 amongst children. This gene partially explains why children differ in their ability to perceive the bitter compound propylthiouracil as well as their individual differences in sweet preferences. Several studies in adults have also linked the perception of bitter ligands on this receptor to sucrose or sweet tastes in adults. Joseph et al. carried out a study to understand how variations in children’s sucrose detection thresholds relate to their age, gender, taste genotype, body composition and dietary intake of added sugars. Sucrose detection thresholds were tested individually in 7-14-year-old children, five genetic variants of taste genes were assayed i.e. sweet genes TAS1R3 and GNAT3 and the three variants on the bitter receptor gene TAS2R38. Body weight and height were taken in all children.
The study found that children with a bitter- sensitive allele of TAS2R38 reported consuming more added sugar than those with the less sensitive allele. These results are consistent with previous reports from Menella et al. (2005) that children with a bitter sensitive allele preferred cereal and beverages with higher sugar content than those without.
Age, gender, and indices of obesity were related to child to child differences in sucrose thresholds with girls being more sensitive than boys, older children more sensitive that younger children and fatter or more centrally obese children more sensitive relative to others. Overall the results indicated that inborn differences in bitter taste sensitivity may affect childhood dietary sugar intake with long term health consequences. The developing bitter and sweet taste systems may have a more complex interplay than previously thought.
It is thought that the relationship between PROP status and sweet liking might differ between children and adults, with a higher sweet taste preference in children declining over time and PROP tasters possibly having a higher taste preference for sweet foods, because the sweetness is more pronounced. Keller recommended that with regard to intake of sweet foods in children, more studies are needed.
Effect On Fat
Non-tasters tend to be less sensitive to the texture of fats which may result in higher overall intakes of fats and super tasters tend to have a reduced intake of high fat foods. In a review by Tepper et al., most, but not all studies, reported PROP non-tasters to have a lower ability to distinguish fat content and creaminess in certain fatty foods. PROP non-tasters have shown higher preferences for dietary fats (full fat milk, high fat salad dressings, sweet-fat dairy mixtures) and have also been found to consume more servings of discretionary fats and high energy foods than tasters. PROP tasters have given higher taste intensity ratings for the essential fatty acid linoleic acid, compared with non-tasters. It is possible that non -tasters are better able to tolerate higher fat foods compared to tasters because they are less sensitive to unpleasant chemo sensory effects, imparted by free fatty acids.
Several studies have also reported associations between PROP status and liking/intake of fat containing foods in children, with non-tasters showing a preference to/ increased intake for fat, however some studies found no association. Keller discussed that for sweet and fatty foods, the relationship between perception and taste is likely an inverse U-shaped curve, where the optimal preferred concentration depends on age, developmental and genetic factors.
Effect On BMI/Weight And Eating Behaviours
There is conflicting evidence around inverse correlations between PROP tasters and calorie consumption/BMI/weight status. Some findings support this and others don’t, suggesting a multifactorial role in the pathway linking PROP tasting and food perception and preference with feeding behaviour and body weight. There is evidence that the ability to taste, especially bitter taste, may affect food preferences, which in turn may impact dietary behaviour and therefore risk of metabolic conditions such as obesity and diabetes. Some findings contradict this. Whilst the haplotypes that comprise bitter taste and TAS2R38 functionality may in part influence an individual’s eating behaviour and weight influence, certain other factors such as gender, aging and smoking status may diminish the taste of food, modify fat deposition and alter antimicrobial sensing profile.
A study by Keller et al. found a significant association between three TAS2R38 variants and body fat percentage in females. An interaction between sex hormone and taste signalling affecting appetite and intake may account for this gender specificity and a high taste acuity may reduce dietary overconsumption and reduce risk of obesity. In this study by Keller et al., they tested whether the TAS2R38 variants may be related to eating behaviour, anthropometric parameters, metabolic traits and consumer goods intake in the German Sorbs, a self-contained population from Eastern Germany.
Data suggested that genetic variations in TAS2R38 is related to individual body composition measures and may influence consumer goods intake in the Sorbs, particularly via individual sensitivity to bitter taste. They concluded that genetic variations of TAS2R38 in Sorbs may be related to anthropometric measures and glucose homeostasis and that the ability to taste bitterness may influence intake of amount of alcohol and tobacco. The main findings are that a significant relationship of TAS2R38 genetic variation with percentage of body fat in women was found and further, an association with phenotypes related to glucose homeostasis in men. They also observed that PAV haplotype carriers show significantly lower tobacco intake per day compared to homozygous AVI haplotype carriers. PAV allele carriers showed consistently lower 30-minute plasma glucose levels compared to homozygous AVI and, in a subsequent study, TAS2R38 AVI/AVI haplotype was similarly associated with high plasma glucose levels. PAV haplotype carriers had a slightly lower BMI and body fat percentage than homozygous AVI carriers, although this was non-significant. It is thought that PAV allele carriers may potentially show more selective eating behaviour strategies and ability to taste bitterness might potentially influence glucose homeostasis via a more cognitive based route i.e. eating behaviour. The AVI/AVI non-taster group showed lower dietary restraint, albeit non-significant, with PAV allele carriers therefore showing increased restraint and decreased disinhibition values. These are similar to findings from Tepper et al.
Genetic Variations Of TAS2R38 And Innate Defence System
Ortega et al evaluated the haplotypes of bitter taste receptor TAS2R38 in an identification sample of 210 Caucasian women in different weight conditions, which included anorexia nervosa (52 participants) and obesity (72 participants) compared to 82 healthy matched controls. In an extended sample of 1319 participants, an increased frequency of obesity was found in subjects carrying the AVI/AVI haplotype. This was more robust in women over 40 years of age.
The association of surfactant protein D (SPD) and manna binding lectin (MBL) was also tested in an independent sample, of 534 people, picturing the general population. SPD and MBL are proteins that are involved in the innate immune defence system. Increased SPD and MBL concentrations were found in non smoking AVI carriers.
It is possible that in the context of obesity associated impairment of circulating MBL and SPD, subjects with AVI haplotype may be more susceptible to host pathogen interactions and increased low grade inflammation, however more in-depth research is needed to determine if the link between TAS2R38 and the release of immunological agents have clinical implications.
Although genetic susceptibility may in part determine an individual’s eating behaviour and its influence on weight, this relationship may be blunted with aging and/or by smoking status, which also diminishes the taste of food, reduces the ability to fight infection and alters that antimicrobial sensing protein profile. Ortega et al. hypothesised that since TAS2R38 bitter taste receptor controls the antimicrobial capacity of the chemosensory cells of the respiratory epithelium, subjects with decreased sensitivity and resultant impaired bacterial detection and clearance in the upper airways, are more prone to organisms reaching the lungs, promoting increased secretion of collectins located at pulmonary mucosal surfaces. This may have direct impact on the development of obesity-associated impairment of MBL and SPD. Weight gain, age and smoking are triggering factors that may result in low grade inflammation and could be amplified in AVI haplotype carriers. Over the long term this may worsen inflammation, leading to obesity and obesity related metabolic disturbances. Mechanisms responsible for these associations need to be investigated further.
Turner et al. also discussed how SCFAs may offer some protection against metabolic conditions and that there is a high likelihood that T2R and other taste receptors form a part of these pathways. T2Rs regulate many GI functions including GI motility, appetite regulation, nutrient uptake, and fluid secretion as well as having a major effect on gut microbiota. In the lungs, T2R have been found to protect against bacterial invasion. Overall it is thought that a role for T2Rs in the complex relationship between gut microbiota and obesity may exist but further research is needed to establish this. Authors concluded overall that T2Rs are involved in a range of mechanisms that can lead to obesity and proposed that extra bitter oral receptors interact with gut bacteria to influence food intake and gut motility, both of which influence risk for obesity development. Details of interaction remain to be elucidated. The overall evidence suggested T2Rs play a role in maintaining balance among diet, weight and healthy microbiome and if the role can be defined, T2Rs can be manipulated to prevent or treat obesity.
Alcohol And Smoking
Tobacco smoke contains a complex mixture of chemical substances of varying structure and functionality, some of which activate different taste receptors. Bitter taste has evolved to identify potentially toxic compounds to protect individuals against harmful foods and so an aversion to this taste may prevent smoking and dependence on nicotine. Non-taster individuals are thought to be more likely to smoke because of their inability to taste bitter compounds in tobacco smoke, however results on this are conflicting. Risso et al. examined the association between TAS2R38 PAV, AVI and rarer haplotypes and cigarette smoking in a large number of individuals from three independent cohorts of both European American (EA) and African American (AA) individuals. Data were collected on tobacco use and all participants were genotyped for TAS2R38 polymorphisms. Results showed a significant association between common TAS2R38 haplotypes and smokers in EAs where carriers of the taster PAV haplotype and PTC tasters were significantly less likely to be current smokers. Carriers of the non-taster AVI haplotype and PTC non-tasters were significantly more likely to be regular smokers. On the contrary, in two large samples of African Americans, including a total of over 7000 participants, no association was found between the major TAS2R38 haplotypes and smoking status.
The study concluded that TAS2R38 haplotypes are associated with smoking status in European- Americans but not African-American populations and PTC taster status may play a role in protecting individuals from cigarette smoking in certain populations. Mangold et al. (2008) observed a higher smoking quantity among non-tasters vs. tasters.
The study by Keller et al. on German Sorbs, discussed earlier, found that individuals carrying homozygous or heterozygous PAV haplotype (related to a high tasting phenotype) smoke significantly less cigarettes per day than homozygous AVI carriers, in line with the thought that these individuals avoid bitterness and tobacco. Results are consistent with those of Duffy and colleagues (2014), who demonstrated that homozygous PAV carriers show lower alcohol intake compared to individuals homozygous for AVI.
Colon Cancer Risk
Bitter taste receptors are also expressed in other parts of the GIT and evidence has shown a higher incidence of colonic neoplasms in PROP tasters, however results from Carrai contradict this .
In the study by Basson et al (2005), 251 men who underwent screening lower endoscopy, were tested for the associations between bitterness of PROP (a measure of taste genetics) and the number of colonic polyps (a measure of colon cancer risk). A subset of 86 patients reported weekly vegetable intake, excluding salads or potatoes. A significant correlation was seen between PROP bitterness (rated by the patients) and polyp number (independent from the age associated increased in number of polyps). Men over 66 years of age saw the strongest PROP-polyp relationship and older men with polyps were more likely to be overweight or obese. Amongst the subset reporting vegetable intake, there was a lower vegetable consumption amongst men who tasted PROP as more bitter. These preliminary findings suggested that colon cancer risk may be affected by taste genetics, possibly through intake of vegetables.
On the contrary the study by Carrai et al found a suggested association between human bitter tasting phenotype and risk of colorectal cancer in two different populations of Caucasian origin, with non-tasters having the risk. Carrai et al carried out a study to evaluate a possible correlation between all of the common genetic variabilities of TAS2R38 and the resulting tasting ability and colorectal cancer risk in a total of 1203 cases of colorectal cancer and 1332 controls from German and Czech populations. In the Czech population, carriers of the AVI/AVI diplotype presented a statistically non-significant tendency to increase CRC risk and in the German population a significant association between AVI/AVI diplotype carriers and increased risk of CRC was seen compared to PAV/PAV carriers. Furthermore, non-tasters (AVI/AVI; AAV/AVI) were associated with an increased risk of CRC in German population compared to tasters (PAV/PAV; PAV/PVV). When analysing the three SNPs separately, they did not find any association with CRC risk, however analysing the distribution of major diplotypes between case and controls, AVI/AVI (non-tasters) was found to be associated with increased CRC risk and the association was stronger when comparing the two groups together, with a stronger association in Germans. No association with colon cancer was found when analysing the three SNPs separately. This association suggests that the distinct phenotypes which reflect the inability to taste bitter compounds, could be a marker for impaired function of receptors in the GIT, with non-taster individuals possibly reacting slower in eliminating xenobiotics in the gut and consequently being at higher risk for CRC. Gender differences were not found to be a modifying factor for either population. The authors recommended a larger, independent study be carried out to further investigate this association between bitter tasting phenotype and CRC.
Change In Taste Sensitivity With Age
Several studies suggest that taste sensitivity diminishes with increasing age.
In a study by Menella et al., to determine how age interacts with diplotype to affect PROP taste perception, they found that the association between TAS2R38 genotype and PROP taste sensitivity phenotype was resilient against effects of race/ethnicity (amongst all ages) and sex (in children and adolescents) but age was a modifier of the association, especially amongst AVI/PAV heterozygotes. Children heterozygote for AVI/PAV haplotype were more sensitive to the bitterness of PROP than adults with the same diplotype and adolescents were intermediate.
These findings are consistent with other earlier studies observing age related changes in the perception of PTC and PROP. Authors concluded that these age-related changes in taste sensitivity are more pronounced in individuals with particular genotypes and the interaction is thought to have a broad impact because many people in the population are heterozygous.
Individuals carrying the haplotype PAV for TAS2R38 are considered to be bitter tasters and those carrying the AVI genotype are considered to be non-tasters for bitter compounds, with carriers of the PAV/PAV diplotype considered to be super tasters, those with the PAV/AVI diplotype considered to be ‘tasters’ (rather than super tasters) and those with the AVI/AVI diplotype non-tasters.
Tasters i.e. individuals with TAS2R38 PAV genotype are more likely to have a reduced intake of Brassica and cruciferous vegetables. These vegetables offer important nutrients and health benefits and people with this high bitter tasting phenotype should look at ways to mask the bitterness of their vegetables e.g. cooking them, serving them with dips, adding other flavours and making milder juices/smoothies to encourage increased intake.
They may also have a high intake of sweet and sugary foods, especially in children, although this is controversial as mixed results have been seen. Monitoring of their sugar intake is recommended and ways to reduce this if intake is found to be high.
Non-tasters i.e. individuals with AVI/AVI genotype are more likely to have higher fat intakes, lower dietary inhibition/ increased disinhibition and higher BMI, although results with this are also mixed. This genotype has also been associated with higher tobacco and alcohol intakes. Being aware of these habits can help to target appropriate intervention earlier on and reduce risk of developing some of these unhealthy behaviours and undesirable consequences.
T2Rs may play a role in maintaining balance among diet, weight and healthy microbiome. There may also be a link between human bitter tasting phenotype and colon cancer risk, however results of this are also mixed and more studies are needed.
It should be noted that age, gender, smoking status, cultural factors and access to certain foods have all been found to influence some of the studies done on these various phenotypic traits and may account for some of the variability and inconsistencies in results. Taste sensitivity may also reduce with age.
Figure 1 – Theoretical pathway linking PTC genoptype (TAS2R38) and PROP phenotype to chronic health.
Keller KL, Adise S. Variation in the ability to taste bitter thiourea compounds: implications for food acceptance, dietary intake and obesity risk in children. Annu Rev Nutr. 2016. 36: 6.1-6.27.
Review: Interactions between Bitter Taste, Diet and Dysbiosis: Consequences for Appetite and Obesity.
Turner et al, 2018.