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Taste is important in the selection of food and is orchestrated by a group of distinct receptors, the taste G protein-coupled receptors (GPCRs). Taste 1 receptors (Tas1rs in mice and TAS1Rs in humans; also known as T1Rs) detect sweet and umami tastes, and taste 2 receptors (Tas2rs in mice and TAS2Rs in humans; also known as T2Rs) detect bitterness. These receptors are also expressed in extraoral sites, including the gastrointestinal mucosa. Tas2rs/TAS2Rs have gained interest as potential targets to prevent or treat metabolic disorders. These bitter taste receptors are expressed in functionally distinct types of gastrointestinal mucosal cells, including enteroendocrine cells, which, upon stimulation, increase intracellular Ca 2+ and release signalling molecules that regulate gut chemosensory processes critical for digestion and absorption of nutrients, for neutralization and expulsion of harmful substances, and for metabolic regulation. Expression of Tas2rs/TAS2Rs in gut mucosa is upregulated by high-fat diets, and intraluminal bitter 'tastants' affect gastrointestinal functions and ingestive behaviour through local and gut-brain axis signalling. Tas2rs/TAS2Rs are also found in Paneth and goblet cells, which release antimicrobial peptides and glycoproteins, and in tuft cells, which trigger type 2 immune response against parasites, thus providing a direct line of defence against pathogens. This Review will focus on gut Tas2r/TAS2R distribution, signalling and regulation in enteroendocrine cells, supporting their role as chemosensors of luminal content that serve distinct functions as regulators of body homeostasis and immune response., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)

Taste receptors, first described for their gustatory functions within the oral cavity and oropharynx, are now known to be expressed in many organ systems. Even intraoral taste receptors regulate non-sensory pathways, and recent literature has connected bitter taste receptors to various states of health and disease. These extragustatory pathways involve previously unexplored, clinically relevant roles for taste signaling in areas including susceptibility to infection, antibiotic efficacy, and cancer outcomes. Among other physicians, otolaryngologists who manage head and neck diseases should be aware of this growing body of evidence and its relevance to their fields. In this review, we describe the role of extragustatory taste receptors in head and neck health and disease, highlighting recent advances, clinical implications, and directions for future investigation. Additionally, this review will discuss known TAS2R polymorphisms and the associated implications for clinical prognosis., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs) expressed orally and extraorally, elicit signaling in response to a large set of tastants. Among 25 functional TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of chemically diverse ligands. Here we present the cryo-electron microscopy (cryo-EM) structure of the human TAS2R14 in complex with its signaling partner gustducin, and bound to flufenamic acid (FFA), a clinically approved nonsteroidal anti-inflammatory drug. The structure reveals an unusual binding mode, where two copies of FFA are bound at distinct pockets: one at the canonical receptor site within the trans-membrane bundle, and the other in the intracellular facet, bridging the receptor with gustducin. Together with a pocket-specific BRET-based ligand binding assay, these results illuminate bitter taste signaling and provide tools for a site-targeted compound design., Competing Interests: Competing interests The authors declare no competing interests, (© 2024. The Author(s).)

Theacrine, a purine alkaloid derived from Camellia assamica var. kucha, has a distinct bitter taste. Our previous study found the lower recognition threshold of theacrine at 25 °C than 45 °C. This study aims to investigate the bitterness characterizations of theacrine at aforementioned temperatures and its taste perception mechanism. Sensory analysis exhibited higher bitterness intensity for theacrine at 25 °C than 45 °C. Subsequently, flow cytometry was performed to verify the above characterization at the cellular level. It revealed that theacrine could activated the bitter receptor hTAS2R14 and the calcium signal at 25 °C was higher than 45 °C. Ultimately, the interaction mechanism was studied by molecular dynamics simulations, indicating that the conformation of theacrine-hTAS2R14 had a higher binding capacity and better stability at 25 °C. Overall, temperature affected the binding of theacrine to the bitter receptor hTAS2R14, resulting in the stronger bitterness intensity of theacrine at 25 °C than 45 °C., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Aims: To investigate associations between Single Nucleotide Polymorphisms (SNPs) in the TAS1R and TAS2R taste receptors and diet quality, intake of alcohol, added sugar, and fat, using linear regression and machine learning techniques in a highly admixed population., Methods: In the ISA-Capital health survey, 901 individuals were interviewed and had socioeconomic, demographic, health characteristics, along with dietary information obtained through two 24-h recalls. Data on 12 components related to food groups, nutrients, and calories was combined into a diet quality score (BHEI-R). BHEI-R, SoFAAs (calories from added sugar, saturated fat, and alcohol) and Alcohol use were tested for associations with 255 TAS2R SNPs and 73 TAS1R SNPs for 637 individuals with regression analysis and Random Forest. Significant SNPs were combined into Genetic taste scores (GTSs)., Results: Among 23 SNPs significantly associated either by stepwise linear/logistic regression or random forest with any possible biological functionality, the missense variants rs149217752 in TAS2R40, for SoFAAs, and rs2233997 in TAS2R4, were associated with both BHEI-R (under 4% increase in Mean Squared Error) and SoFAAs. GTSs increased the variance explanation of quantitative phenotypes and there was a moderately high AUC for alcohol use., Conclusions: The study provides insights into the genetic basis of human taste perception through the identification of missense variants in the TAS2R gene family. These findings may contribute to future strategies in precision nutrition aimed at improving food quality by reducing added sugar, saturated fat, and alcohol intake., Competing Interests: Declaration of competing interest None., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Masking the bitter taste of foods is one of the key strategies to improve their taste and palatability, particularly in the context of clean labeling, where natural compounds are preferred. Despite the demand, the availability of natural bitter-masking compounds remains limited. Here, we identified the bitter-masking compound 4'-demethyl-3,9-dihydroeucomin ( DMDHE ) isolated from the resin of Daemonorops draco by means of an activity-guided in vivo (sensory bitterness rating of quinine) and in vitro (cell-based bitter response assays) approach. First, a mean bitter-masking effect of -29.6 ± 6.30% on the bitterness perceived from quinine [10 ppm] was demonstrated for an organic solvent extract of the resin of D. draco (= DD [500 ppm]) in a sensory trial. The results were verified in a cell-based bitter assay in which the bitter taste receptor (TAS2R)-dependent proton secretion serves as an outcome measure of the cellular bitter response in parietal HGT-1 cells. By means of preparative RP-18 high-performance liquid chromatography (HPLC) analysis combined with activity-guided sensory evaluations, the most potent bitter-masking fractions were identified. Subsequent quantitative liquid chromatography/high-resolution mass spectrometry/charged aerosol detection/ultraviolet (LC-HRMS/CAD/UV), NMR analysis, followed by gram-scale synthesis, led to the characterization of DMDHE as bitter-masking homoisoflavanone. DMDHE decreased the sensory bitterness of quinine by 14.8 ± 5.00%. Functional involvement of TAS2R14 was demonstrated by means of a CRISPR-Cas9 approach, which revealed a reduction of the DMDHE -evoked bitter-masking effect by 40.4 ± 9.32% in HGT-1 TAS2R14ko versus HGT-1 wt cells.

Genetic variation in the bitter taste receptor gene taste receptor type 2, member 38 (TAS2R38) is associated with an individual's bitter taste sensitivity, food preference and consumption, which may also influence overall diet quality. This study aims to determine whether the TAS2R38 bitter taste receptor genetic variation is associated with overall diet quality using the Korean Healthy Eating Index (KHEI). A total of 41,839 individuals from the Korean Genome and Epidemiology Study were analyzed for their TAS2R38 diplotypes (rs713598, rs1726866, and rs10246939), general characteristics, and KHEI scores by obesity status. Results revealed that in the non-obese group, individuals with the AVI/AVI diplotype had a significantly higher score of 'ratio of white meat to red meat' than individuals with the PAV/* diplotype (3.89 ± 3.23 vs. 3.79 ± 3.18, adjusted p = 0.029). However, obese individuals with the PAV/* diplotype showed a significantly higher level of the mean score of 'moderation' (19.32 ± 5.82 vs. 18.92 ± 5.80, adjusted p = 0.026) and total KHEI score (61.07 ± 12.19 vs. 60.52 ± 12.29, adjusted p = 0.008) than those with the AVI/AVI diplotype. Finally, an interactive effect between bitterness genetic variation and obesity level was observed in those scores of 'ratio of white meat to red meat' (adjusted p = 0.007), 'moderation' (adjusted p = 0.013), and total KEHI (adjusted p = 0.007). In conclusion, TAS2R38 genetic variation is associated with overall diet quality in Koreans, which is more evident in the obese group., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeong-hwa Choi reports financial support was provided by National Research Foundation of Korea. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Yeast extracts (YEs) are used in foods because of their flavour properties and ability to reduce bitterness. The adenosine 5'-monophosphate (AMP) found in YEs is known to decrease the bitterness of some compounds. This study aimed to investigate the ability of YEs to inhibit bitter taste receptors (TAS2Rs) using in vitro cell-based assays. A screen of TAS2Rs activated by AMP and YEs revealed that AMP and the AMP-rich YE activated more TAS2Rs. The inhibitory effect of the AMP-rich YE on seven TAS2Rs activated by bitter agonists was studied. YE reduced TAS2R activation, increased the EC 50 value and decreased the maximum amplitude, demonstrating competitive and non-competitive inhibitions. Amongst the nineteen TAS2Rs tested, seven showed 40 % or greater inhibition after treatment of AMP-rich YE. Our data provide a better understanding of the TAS2R inhibition mechanism of AMP-rich YEs and promote their use as a strategy to reduce bitterness in foods and medicines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BRIAND reports financial support was provided by Biospringer by Lesaffre. THOMAS and MENIN are employees of Biospringer by Lessafre which manufactures and supplies YEs. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Bitterness, as one of the most important physiological sensations in animals, is primarily recognized through the mediation of bitter taste receptors. In recent years, it has been found that these receptors are not only expressed in taste bud cells on the tongue but also in the respiratory, cardiovascular, digestive, reproductive, and nervous systems. They are involved in regulating various fundamental physiological processes and are now considered important targets for the treatment of various diseases. This paper reviewed the structure, classification, distribution, and signaling pathways of bitter taste receptors, their relationship with different diseases, and the role of bitter taste receptors agonists, aiming to provide a basis for scientific research on bitter taste receptors.

A microfluidic tongue-on-a-chip platform has been evaluated relative to the known sensory properties of various sweeteners. Analogous metrics of typical sensory features reported by human panels such as sweet taste thresholds, onset, and lingering, as well as bitter off-flavor and blocking interactions were deduced from the taste receptor activation curves and then compared. To this end, a flow cell containing a receptor cell array bearing the sweet and six bitter taste receptors was transiently exposed to pure and mixed sweetener samples. The sample concentration gradient across time was separately characterized by the injection of fluorescein dye. Subsequently, cellular calcium responses to different doses of advantame, aspartame, saccharine, and sucrose were overlaid with the concentration gradient. Parameters describing the response kinetics compared to the gradient were quantified. Advantame at 15 μM recorded a significantly faster sweetness onset of 5 ± 2 s and a longer lingering time of 39 s relative to sucrose at 100 mM with an onset of 13 ± 2 s and a lingering time of 6 s. Saccharine was shown to activate the bitter receptors TAS2R8, TAS2R31, and TAS2R43, confirming its known off-flavor, whereas addition of cyclamate reduced or blocked this saccharine bitter response. The potential of using this tongue-on-a-chip to bridge the gap with in vitro assays and taste panels is discussed.

Beyond the key bitter compound kaempferol 3- O -(2‴- O -sinapoyl-β-d-sophoroside) previously described in the literature ( 1 ), eight further bitter and astringent-tasting kaempferol glucosides ( 2 - 9 ) have been identified in rapeseed protein isolates ( Brassica napus L.). The bitterness and astringency of these taste-active substances have been described with taste threshold concentrations ranging from 3.3 to 531.7 and 0.3 to 66.4 μmol/L, respectively, as determined by human sensory experiments. In this study, the impact of 1 and kaempferol 3- O -β-d-glucopyranoside ( 8 ) on TAS2R-linked proton secretion by HGT-1 cells was analyzed by quantification of the intracellular proton index. mRNA levels of bitter receptors TAS2R3, 4, 5, 13, 30, 31, 39, 40, 43, 45, 46, 50 and TAS2R8 were increased after treatment with compounds 1 and 8 . Using quantitative UHPLC-MS/MS MRM measurements, the concentrations of 1 - 9 were determined in rapeseed/canola seeds and their corresponding protein isolates. Depending on the sample material, compounds 1 , 3 , and 5 - 9 exceeded dose over threshold (DoT) factors above one for both bitterness and astringency in selected protein isolates. In addition, an increase in the key bitter compound 1 during industrial protein production (apart from enrichment) was observed, allowing the identification of the potential precursor of 1 to be kaempferol 3- O -(2‴- O -sinapoyl-β-d-sophoroside)-7- O -β-d-glucopyranoside ( 3 ). These results may contribute to the production of less bitter and astringent rapeseed protein isolates through the optimization of breeding and postharvest downstream processing.

Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents 1,2 . TAS2R14 is also widely expressed in extragustatory tissues, suggesting its extra roles in diverse physiological processes and potential therapeutic applications 3 . Here we present cryogenic electron microscopy structures of TAS2R14 in complex with aristolochic acid, flufenamic acid and compound 28.1, coupling with different G-protein subtypes. Uniquely, a cholesterol molecule is observed occupying what is typically an orthosteric site in class A G-protein-coupled receptors. The three potent agonists bind, individually, to the intracellular pockets, suggesting a distinct activation mechanism for this receptor. Comprehensive structural analysis, combined with mutagenesis and molecular dynamic simulation studies, elucidate the broad-spectrum ligand recognition and activation of the receptor by means of intricate multiple ligand-binding sites. Our study also uncovers the specific coupling modes of TAS2R14 with gustducin and G i1 proteins. These findings should be instrumental in advancing knowledge of bitter taste perception and its broader implications in sensory biology and drug discovery., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Dietary intake and alcohol consumption might be influenced by genetic variations in taste receptor genes. The objectives of this study were to examine the relationship between polymorphisms in the bitter taste receptor genes TAS2R13 (rs1015443) and TAS2R38 (rs1726866, rs10246939, and rs713598) as well as alcohol consumption and body fat percentage in college students. Four hundred and two students with a mean age of 20.2 years participated in this study. An NIH Diet History Questionnaire (DHQ II) was used to collect data on their dietary intake, while an AUDIT survey was used to determine their level of alcohol consumption. Bitter taste receptor gene polymorphisms were assessed by TaqMan allelic discrimination assays. Despite significant associations between TAS2R13 (rs1015443) and certain aspects of alcohol consumption, including the frequency of alcohol intake, no significant associations were found between TAS2R13 (rs1015443) and alcohol consumption after accounting for confounding variables in the regression model. Neither association was found regarding percent of body fat. In contrast, ethnicity and gender significantly influenced percent of body fat ( p < 0.001), while no significant association was observed between TAS2R13 (rs1015443) and percent of body fat. Likewise, TAS2R38 (rs1726866, rs10246939, and rs713598) demonstrated no significant association with alcohol consumption and percent of body fat. These results were controlled for confounding factors, such as ethnicity and gender. Body fat percentage and alcohol consumption may be influenced by ethnicity, gender, and age rather than SNPs of TAS2R13 and TAS2R38 genes. Assessing taste genes' interactions with diet and body composition might be useful in identifying human disease risk.

Bitter taste involves the detection of diverse chemical compounds by a family of G protein-coupled receptors, known as taste receptor type 2 (TAS2R). It is often linked to toxins and harmful compounds and in particular bitter taste receptors participate in the regulation of glucose homeostasis, modulation of immune and inflammatory responses, and may have implications for various diseases. Human TAS2Rs are characterized by their polymorphism and differ in localization and function. Different receptors can activate various signaling pathways depending on the tissue and the ligand. However, in vitro screening of possible TAS2R ligands is costly and time-consuming. For this reason, in silico methods to predict bitterant-TAS2R interactions could be powerful tools to help in the selection of ligands and targets for experimental studies and improve our knowledge of bitter receptor roles. Machine learning (ML) is a branch of artificial intelligence that applies algorithms to large datasets to learn from patterns and make predictions. In recent years, there has been a record of numerous taste classifiers in literature, especially on bitter/non-bitter or bitter/sweet classification. However, only a few of them exploit ML to predict which TAS2R receptors could be targeted by bitter molecules. Indeed, the shortage and incompleteness of data on receptor-ligand associations in literature make this task non-trivial. In this work, we provide an overview of the state of the art dealing with this specific investigation, focusing on three ML-based models, namely BitterX (2016), BitterSweet (2019) and BitterMatch (2022). This review aims to establish the foundation for future research endeavours focused on addressing the limitations and drawbacks of existing models., (© 2024 Wiley Periodicals LLC.)

Bitterness is one of the five basic tastes generally considered undesirable. The widespread presence of bitter compounds can negatively affect the palatability of foods. The classification and sensory evaluation of bitter compounds have been the focus in recent research. However, the rigorous identification of bitter tastes and further studies to effectively mask or remove them have not been thoroughly evaluated. The present paper focuses on identification of bitter compounds in foods, structural-based activation of bitter receptors, and strategies to reduce bitter compounds in foods. It also discusses the roles of metabolomics and virtual screening analysis in bitter taste. The identification of bitter compounds has seen greater success through metabolomics with multivariate statistical analysis compared to conventional chromatography, HPLC, LC-MS, and NMR techniques. However, to avoid false positives, sensory recognition should be combined. Bitter perception involves the structural activation of bitter taste receptors (TAS2Rs). Only 25 human TAS2Rs have been identified as responsible for recognizing numerous bitter compounds, showcasing their high structural diversity to bitter agonists. Thus, reducing bitterness can be achieved through several methods. Traditionally, the removal or degradation of bitter substances has been used for debittering, while the masking of bitterness presents a new effective approach to improving food flavor. Future research in food bitterness should focus on identifying unknown bitter compounds in food, elucidating the mechanisms of activation of different receptors, and developing debittering techniques based on the entire food matrix., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bitterness from phenylthiocarbamide and 6-n-propylthiouracil (PROP) varies with polymorphisms in the TAS2R38 gene. Three SNPs form two common (AVI, PAV) and four rare haplotypes (AAI, AAV, PVI, and PAI). AVI homozygotes exhibit higher detection thresholds and lower suprathreshold bitterness for PROP compared to PAV homozygotes and heterozygotes, and these differences may influence alcohol and vegetable intake. Within a diplotype, substantial variation in suprathreshold bitterness persists, and some AVI homozygotes report moderate bitterness at high concentrations. A second receptor encoded by a gene containing a functional polymorphism may explain this. Early work has suggested that PROP might activate TAS2R4 in vitro, but later work did not replicate this. Here, we identify three TAS2R4 SNPs that result in three diplotypes-SLN/SLN, FVS/SLN, and FVS/FVS-which make up 25.1%, 44.9%, and 23.9% of our sample. These TAS2R4 haplotypes show minimal linkage disequilibrium with TAS2R38, so we examined the suprathreshold bitterness as a function of both. The participants ( n = 243) rated five PROP concentrations in duplicate, interleaved with other stimuli. As expected, the TAS2R38 haplotypes explained ~29% ( p < 0.0001) of the variation in the bitterness ratings, with substantial variation within the haplotypes (AVI/AVI, PAV/AVI, and PAV/PAV). Notably, the TAS2R4 diplotypes (independent of the TAS2R38 haplotypes) explained ~7-8% of the variation in the bitterness ratings ( p = 0.0001). Given this, we revisited if PROP could activate heterologously expressed TAS2R4 in HEK293T cells, and calcium imaging indicated 3 mM PROP is a weak TAS2R4 agonist. In sum, our data are consistent with the second receptor hypothesis and may explain the recovery of the PROP tasting phenotype in some AVI homozygotes; further, this finding may potentially help explain the conflicting results on the TAS2R38 diplotype and food intake.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors 1 . Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants 2-6 , although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with G gust (also known as gustducin) and G i1 . Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of G gust and G i1 . Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Variation in common taste receptor type 2 member 38 (TAS2R38) haplotypes is associated with bitter-taste sensitivity, but associations with dietary intake and risk factors for chronic disease are inconsistent., Objectives: To determine whether common TAS2R38 haplotypes are associated with dietary intake and risk factors for chronic disease using cross-sectional data from the Canadian Longitudinal Study on Aging (n = 26,090). Outcomes were assessed among the full sample and stratified by sex., Methods: Taster status was determined from TAS2R38 haplotypes, and the respondents were classified as supertasters, tasters, and nontasters. Primary outcome variables were the consumption frequencies of vegetables, sweet-tasting foods, alcoholic beverages, and visceral adiposity index (VAI). Secondary outcome variables were the individual VAI components. Multivariable regression models adjusted for sociodemographic and lifestyle factors were used to assess associations between the taster status and outcome variables., Results: Among the sample, 5655, 12,821, and 7614 respondents were classified as supertasters, tasters, and nontasters, respectively. Vegetable consumption was significantly higher among nontasters than among supertasters (1.23 ± 0.26 and 1.20 ± 0.22, respectively, P = 0.02). Among males, the consumption of sweet-tasting foods (0.40 ± 8.80 and 0.38 ± 7.55, P = 0.02) and green salad (0.35 ± 0.31 and 0.33 ± 0.27, P = 0.02) was also higher for nontasters than supertasters. Nontasters were more likely to be regular alcohol consumers compared with supertasters among the full sample (odds ratio [95% confidence interval]: 1.12 [1.03, 1.22]; P = 0.01) and among females (OR: 1.13; 95% CI: 1.01, 1.27; P = 0.04). No significant associations were observed between TAS2R38 haplotypes and VAI, although high-density lipoprotein cholesterol was significantly lower among supertasters than nontasters (1.45 ± 0.59 and 1.47 ± 0.63, respectively; P = 0.04)., Conclusions: Among middle- to older-aged adults, minor associations are observed between TAS2R38 haplotypes, dietary intake, and high-density lipoprotein cholesterol. Genetic predisposition to bitter-taste sensitivity is linked to diet; however, further research is needed to understand the relevance for chronic disease risk., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Human type 2 taste receptor (TAS2R) genes encode bitter-taste receptors that are activated by various bitter ligands. It has been said that TAS2R38 may detect bitter substances and then suppress their intake by controlling gustatory or digestive responses. The major haplotypes of TAS2R38 involve three non-synonymous, closely-linked single-nucleotide polymorphisms (SNPs), leading to three amino acid substitutions (A49P, V262A and I296V) and resulting in a PAV or AVI allele. The allele frequency of AVI/PAV was 0.42/0.58 in this study. The genotype frequency distributions of TAS2R38 were 18.32%, 46.95% and 33.95% for AVI/AVI, AVI/PAV and PAV/PAV, respectively, and were in Hardy-Weinberg equilibrium. Five haplotype combinations of minor alleles were identified: AVI/AAV, AVI/AVV, AAI/PAV, AVI/PVV, AVI/AAI, with corresponding frequencies of 0.49%, 0.10%, 0.10%, 0.05%, 0.05%, respectively, in 2,047 Japanese Tohoku Medical Megabank Organization (ToMMo) subjects (2KJPN). The 16 subjects with these minor alleles were excluded from the questionnaire analysis, which found no significant differences among the major TAS2R38 genotypes (AVI/AVI, AVI/PAV and PAV/PAV) in the intake frequency of cruciferous vegetables or in the frequency of drinking alcohol. This result differs from previous data using American and European subjects. This is the first study to analyze the relationship between TAS2R38 genotype and the eating and drinking habits of Japanese subjects. It was also shown that there were no relationships at all between the genetic polymorphism of TAS2R46 and the phenotypes such as clinical BMI, eating and drinking habits among the 3 genotypes of TAS2R46 (∗/∗, ∗/W, W/W) at position W250∗ (∗stop codon).

Background: The bitter taste receptor gene TAS2R38 is a member of the human TAS2R gene family. Polymorphisms in TAS2R38 affect the ability to taste the bitterness of phenylthiourea (PTC) compounds, thus affecting an individual's food preference and health status., Methods: We investigated polymorphisms in the TAS2R38 gene and the sensitivity to PTC bitterness among healthy Chinese college students in Hubei province. The association of TAS2R38 polymorphisms and PTC sensitivity with body mass index (BMI), food preference, and health status was also analyzed. A total of 320 healthy college students were enrolled (male: 133, female: 187; aged 18-23 years). The threshold value method was used to measure the perception of PTC bitterness, and a questionnaire was used to analyze dietary preferences and health status. Polymerase chain reaction (PCR) was used to analyze polymorphisms at three common TAS2R38 loci (rs713598, rs1726866, and rs10246939)., Results: In our study population, 65.00% of individuals had medium sensitivity to the bitterness of PTC; in contrast, 20.94% were highly sensitive to PTC bitterness, and 14.06% were not sensitive. For the TAS2R38 gene, the PAV/PAV and PAV/AAI diplotypes were the most common (42.19% and 40.63%, respectively), followed by the homozygous AVI/AVI (8.75%) and PAV/AVI (5.00%) diplotypes., Conclusion: There was a significant correlation between the sensitivity to PTC bitterness and sex, but there was no correlation between the common diplotypes of TAS2R38 and gender. Polymorphisms in the TAS2R38 gene were associated with the preference for tea, but not with one's native place, BMI, health status, or other dietary preferences. There was no significant correlation between the perception of PTC bitterness and one's native place, BMI, dietary preference, or health status. We hope to find out the relationship between PTC sensitivity and TAS2R38 gene polymorphisms and dietary preference and health status of Chinese population through this study, providing relevant guidance and suggestions for dietary guidance and prevention of some chronic diseases in Chinese population., (© 2022. The Author(s).)

Taste sensing is a sophisticated chemosensory process, and bitter taste perception is mediated by type 2 taste receptors (TAS2Rs), or class T G protein-coupled receptors. Understanding the detailed molecular mechanisms behind taste sensation is hindered by a lack of experimental receptor structures. Here, we report the cryo-electron microscopy structures of human TAS2R46 complexed with chimeric mini-G protein gustducin, in both strychnine-bound and apo forms. Several features of TAS2R46 are disclosed, including distinct receptor structures that compare with known GPCRs, a new "toggle switch," activation-related motifs, and precoupling with mini-G protein gustducin. Furthermore, the dynamic extracellular and more-static intracellular parts of TAS2R46 suggest possible diverse ligand-recognition and activation processes. This study provides a basis for further exploration of other bitter taste receptors and their therapeutic applications.

Background: The inter-individual differences in taste perception find a possible rationale in genetic variations. We verified whether the presence of four different single nucleotide polymorphisms (SNPs) in genes encoding for bitter (TAS2R38; 145G > C; 785T > C) and sweet (TAS1R3; −1572C > T; −1266C > T) taste receptors influenced the recognition of the basic tastes. Furthermore, we tested if the allelic distribution of such SNPs varied according to BMI and whether the associations between SNPs and taste recognition were influenced by the presence of overweight/obesity. Methods: DNA of 85 overweight/obese patients and 57 normal weight volunteers was used to investigate the SNPs. For the taste test, filter paper strips were applied. Each of the basic tastes (sweet, sour, salty, bitter) plus pure rapeseed oil, and water were tested. Results: Individuals carrying the AV/AV diplotype of the TAS2R38 gene (A49P G/G and V262 T/T) were less sensitive to sweet taste recognition. These alterations remained significant after adjustment for gender and BMI. Moreover, a significant decrease in overall taste recognition associated with BMI and age was found. There was no significant difference in allelic distribution for the investigated polymorphisms between normal and overweight/obese patients. Conclusions: Our findings suggest that overall taste recognition depends on age and BMI. In the total population, the inter-individual ability to identify the sweet taste at different concentrations was related to the presence of at least one genetic variant for the bitter receptor gene but not to the BMI.

Human bitter taste receptor TAS2R14 (T2R14) can widely perceive bitterness, which has always been an issue for people to overcome. This study was aimed at identifying bioactive peptides obtained from Oncorhynchus mykiss nebulin hydrolysates as bitter taste receptor blockers by physicochemical property prediction, molecular docking, and in vitro determination of bitterness intensity using electronic tongue. Exploration of the interaction mechanism of these peptides with T2R14 by molecular docking models indicated that peptides ADM and ADW had high affinities for T2R14 to block the binding of bitter substances into the receptor. Addition of ADM and ADW to quinine caused reduction in bitterness intensity, with IC 50 values of 420.32 ± 6.26 μM and 403.29 ± 4.10 μM, respectively. Hydrogen bond interaction and hydrophobic interaction were responsible for manifesting the high affinities of these peptides for the receptor. Residues Thr86, Asp168, and Phe247 may be the key amino acids within the binding site., (Copyright © 2021. Published by Elsevier Ltd.)

Several studies have used taste sensitivity to 6-n-propylthiouracil (PROP) to evaluate interindividual taste variability and its impact on food preferences, nutrition, and health. We used a supervised learning (SL) approach for the automatic identification of the PROP taster categories (super taster (ST); medium taster (MT); and non-taster (NT)) of 84 subjects (aged 18-40 years). Biological features determined from subjects were included for the training system. Results showed that SL enables the automatic identification of objective PROP taster status, with high precision (97%). The biological features were classified in order of importance in facilitating learning and as prediction factors. The ratings of perceived taste intensity for PROP paper disks (50 mM) and PROP solution (3.2 mM), along with fungiform papilla density, were the most important features, and high estimated values pushed toward ST prediction, while low values leaned toward NT prediction. Furthermore, TAS2R38 genotypes were significant features (AVI/AVI, PAV/PAV, and PAV/AVI to classify NTs, STs, and MTs, respectively). These results, in showing that the SL approach enables an automatic, immediate, scalable, and high-precision classification of PROP taster status, suggest that it may represent an objective and reliable tool in taste physiology studies, with applications ranging from basic science and medicine to food sciences.

Bitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCRs). The experimental structure of these receptors has yet to be determined, and key-residues controlling their function remain mostly unknown. We designed an integrative approach to improve comparative modeling of TAS2Rs. Using current knowledge on class A GPCRs and existing experimental data in the literature as constraints, we pinpointed conserved motifs to entirely re-align the amino-acid sequences of TAS2Rs. We constructed accurate homology models of human TAS2Rs. As a test case, we examined the accuracy of the TAS2R16 model with site-directed mutagenesis and in vitro functional assays. This combination of in silico and in vitro results clarifies sequence-function relationships and proposes functional molecular switches that encode agonist sensing and downstream signaling mechanisms within mammalian TAS2Rs sequences., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Recent data have shown anti-inflammatory effects for trans -resveratrol (RSV) and rosmarinic acid (RA) in various immune-competent cell models through reduction of lipopolysaccharide (LPS)-induced interleukin 6 (IL-6) release. Because both compounds have been reported to taste bitter, we hypothesized an involvement of human bitter taste sensing receptors (TAS2Rs) on IL-6 release in LPS-treated human gingival fibroblasts (HGF-1). First, the bitter taste intensity of RSV and RA was compared in a sensory trial with 10 untrained panelists, of whom 90% rated a 50 ppm of RSV in water solution more bitter than 50 ppm of RA. A mean 19 ± 6% reduction of the RSV-induced bitter taste intensity was achieved by co-administration of 50 ppm of the bitter-masking, TAS2R43 antagonist homoeriodictyol (HED). Mechanistic experiments in a stably CRISPR-Cas9-edited TAS2R43ko gastric cell model revealed involvement of TAS2R43 in the HED-evoked effect on RSV-induced proton secretion, whereas the cellular response to RSV did not depend upon TAS2R43 . Next, the IL-6 modulatory effect of 100 μM RSV was studied in LPS-treated immune-competent HGF-1 cells. After 6 h of treatment, RSV reduced the LPS-induced IL-6 gene expression and protein release by -46.2 ± 12.7 and -73.9 ± 2.99%, respectively. This RSV-evoked effect was abolished by co-administration of HED. Because real-time quantitative polymerase chain reaction analyses revealed a regulation of TAS2R50 in RSV with or without HED-treated HGF-1 cells, an siRNA knockdown approach of TAS2R50 was applied to verify TAS2R50 involvement in the RSV-induced reduction of the LPS-evoked IL-6 release in HGT-1 cells.

Differences in taste perception have been related to eating behavior, nutritional status, and diseases. Recently, taste receptors have been identified in several extra-oral tissues, such as the gastrointestinal tract, where they seem to influence processes like digestion, sense of satiety as well as energy balance and intraluminal changes occurring in obesity. Our study aims to analyze differences in taste perception among 42 obese patients (OB) and 41 normal-weight subjects (LEAN). Polymorphisms in the gene codifying for the bitter taste receptor TAS2R38 and its expression on the surface of the gastric mucosa were tested and compared among OB and LEAN. Taste intensity of PROP (6-n-propylthiouracil), quinine, sucrose, citric acid and NaCl were measured on a labeled magnitude scale. DNA from peripheral whole blood was extracted and three polymorphisms in the TAS2R38 gene (rs713598, rs1726866, rs10246939) analyzed. Gastric biopsies were collected during bariatric surgery in OB and during endoscopy in LEAN. RNA was extracted and TAS2R38 gene expression assessed by RT-Real-Time qPCR. Anamnestic and anthropometric data were recorded in all participants during baseline visits. Logistic regression analysis showed that OB perceives sweet (sucrose) and bitter (PROP or 6-n-propylthiouracil) taste more intensely than LEAN (p-value = 0.02 and p-value = 0.005, respectively). While polymorphisms in TAS2R38 gene did not differ among OB and LEAN, we observed a significant increase of TAS2R38 mRNA levels in the stomach of OB compared to LEAN (p = 0.01). Our results provide new evidence of a link between obesity and altered taste perception as well as TAS2R38 expression in the stomach., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Mammalian taste buds comprise types I, II, and III taste cells, with each type having specific characteristics: glia-like supporting cells (type I), taste receptor cells (type II), and presynaptic cells (type III). In this study, to characterize the peripheral taste-sensing systems in chickens, we analyzed the distributions of the mammalian types I, II, and III taste cell markers in chicken taste buds: glutamate-aspartate transporter (GLAST) for type I; taste receptor type 1 members 1 and 3 (T1R1 and T1R3), taste receptor type 2 member 7 (T2R7), and α-gustducin for type II; and synaptosomal protein 25 (SNAP25) and neural cell adhesion molecule (NCAM) for type III. We found that most GLAST + taste cells expressed α-gustducin and SNAP25 and that high percentages of T1R3 + or α-gustducin + taste cells expressed SNAP25 and NCAM. These results demonstrated a unique subset of chicken taste cells expressing multiple taste cell type marker proteins. Taken together, these results provide new insights into the taste-sensing mechanisms in vertebrate taste buds., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Intestinal release of incretin hormones after food intake promotes glucose-dependent insulin secretion and regulates glucose homeostasis. The impaired incretin effects observed in the pathophysiologic abnormality of type 2 diabetes have triggered the pharmacological development of incretin-based therapy through the activation of glucagon-like peptide-1 (GLP-1) receptor, including GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP4) inhibitors. In the light of the mechanisms involved in the stimulation of GLP-1 secretion, it is a fundamental question to explore whether glucose and lipid homeostasis can be manipulated by the digestive system in response to nutrient ingestion and taste perception along the gastrointestinal tract. While glucose is a potent stimulant of GLP-1 secretion, emerging evidence highlights the importance of bitter tastants in the enteroendocrine secretion of gut hormones through activation of bitter taste receptors. This review summarizes bitter chemosensation in the intestines for GLP-1 secretion and metabolic regulation based on recent advances in biological research of bitter taste receptors and preclinical and clinical investigation of bitter medicinal plants, including bitter melon, hops strobile, and berberine-containing herbs (e.g. coptis rhizome and barberry root). Multiple mechanisms of action of relevant bitter phytochemicals are discussed with the consideration of pharmacokinetic studies. Current evidence suggests that specific agonists targeting bitter taste receptors, such as human TAS2R1 and TAS2R38, may provide both metabolic benefits and anti-inflammatory effects with the modulation of the enteroendocrine hormone secretion and bile acid turnover in metabolic syndrome individuals or diabetic patients with dyslipidemia-related comorbidities., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Nutrient sensing plays important roles in promoting satiety and maintaining good homeostatic control. Taste receptors (TAS) are located through the gastrointestinal tract, and recent studies have shown they have a relationship with metabolic disorders. The aim of this study was to analyze the jejunal expression of TAS1R2, TAS1R3, TAS2R14 and TAS2R38 in women with morbid obesity, first classified according to metabolic syndrome presence (MetS; n = 24) or absence (non-MetS; n = 45) and then classified according to hepatic histology as normal liver ( n = 28) or nonalcoholic fatty liver disease ( n = 41). Regarding MetS, we found decreased expression of TAS2R14 in MetS patients. However, when we subclassified patients according to liver histology, we did not find differences between groups. We found negative correlations between glucose levels, triglycerides and MetS with TAS1R3 expression. Moreover, TAS2R14 jejunal expression correlated negatively with the presence of MetS and ghrelin levels and positively with the jejunal Toll-like receptor (TLR)4, peroxisome proliferator-activated receptor (PPAR)-γ, and interleukin (IL)-10 levels. Furthermore, TAS2R38 expression correlated negatively with TLR9 jejunal expression and IL-6 levels and positively with TLR4 levels. Our findings suggest that metabolic dysfunctions such as MetS trigger downregulation of the intestinal TASs. Therefore, taste receptors modulation could be a possible therapeutic target for metabolic disorders.

Importance: Bitter taste receptors (T2Rs) have been implicated in sinonasal innate immunity, and genetic variation conferred by allelic variants in T2R genes is associated with variation in upper respiratory tract pathogen susceptibility, symptoms, and outcomes. Bitter taste receptor phenotype appears to be associated with the clinical course and symptom duration of SARS-CoV-2 infection., Objective: To evaluate the association between T2R phenotype and patient clinical course after infection with SARS-CoV-2., Design, Setting, and Participants: A prospective cohort study was performed from July 1 through September 30, 2020, at a tertiary outpatient clinical practice and inpatient hospital in the United States among 1935 participants (patients and health care workers) with occupational exposure to SARS-CoV-2., Exposure: Exposure to SARS-CoV-2., Main Outcomes and Measures: Participants underwent T2R38 phenotype taste testing to determine whether they were supertasters (those who experienced greater intensity of bitter tastes), tasters, or nontasters (those who experienced low intensity of bitter tastes or no bitter tastes) and underwent evaluation for lack of infection with SARS-CoV-2 via polymerase chain reaction (PCR) testing and IgM and IgG testing. A group of participants was randomly selected for genotype analysis to correlate phenotype. Participants were followed up until confirmation of infection with SARS-CoV-2 via PCR testing. Phenotype of T2R38 was retested after infection with SARS-CoV-2. The results were compared with clinical course., Results: A total of 1935 individuals (1101 women [56.9%]; mean [SD] age, 45.5 [13.9] years) participated in the study. Results of phenotype taste testing showed that 508 (26.3%) were supertasters, 917 (47.4%) were tasters, and 510 (26.4%) were nontasters. A total of 266 participants (13.7%) had positive PCR test results for SARS-CoV-2. Of these, 55 (20.7%) required hospitalization. Symptom duration among patients with positive results ranged from 0 to 48 days. Nontasters were significantly more likely than tasters and supertasters to test positive for SARS-CoV-2 (odds ratio, 10.1 [95% CI, 5.8-17.8]; P < .001), to be hospitalized once infected (odds ratio, 3.9 [1.5-10.2]; P = .006), and to be symptomatic for a longer duration (mean [SE] duration, 23.7 [0.5] days vs 13.5 [0.4] days vs 5.0 [0.6] days; P < .001). A total of 47 of 55 patients (85.5%) with COVID-19 who required inpatient admission were nontasters. Conversely, 15 of 266 patients (5.6%) with positive PCR test results were supertasters., Conclusions and Relevance: This cohort study suggests that T2R38 receptor allelic variants were associated with participants' innate immune response toward SARS-CoV-2. The T2R phenotype was associated with patients' clinical course after SARS-CoV-2 infection. Nontasters were more likely to be infected with SARS-CoV-2 than the other 2 groups, suggesting enhanced innate immune protection against SARS-CoV-2.

Children have difficulty swallowing capsules. Yet, when presented with liquid formulations, children often reject oral medications due to their intense bitterness. Presently, effective strategies to identify methods, reagents, and tools to block bitterness remain elusive. For a specific bitter-tasting drug, identification of the responsible bitter receptors and discovery of antagonists for those receptors can provide a method to block perceived bitterness. We have identified a compound (6-methylflavone) that can block responses to an intensely bitter-tasting anti-human immunodeficiency virus (HIV) drug, tenofovir alafenamide (TAF), using a primary human taste bud epithelial cell culture as a screening platform. Specifically, TAS2R39 and TAS2R1 are the main type 2 taste receptors responding to TAF observed via heterologously expressing specific TAS2R receptors into HEK293 cells. In this assay, 6-methylflavone blocked the responses of TAS2R39 to TAF. In human sensory testing, 8 of 16 subjects showed reduction in perceived bitterness of TAF after pretreating (or "prerinsing") with 6-methylflavone and mixing 6-methylflavone with TAF. Bitterness was completely and reliably blocked in two of these subjects. These data demonstrate that a combined approach of human taste cell culture-based screening, receptor-specific assays, and human psychophysical testing can successfully discover molecules for blocking perceived bitterness of pharmaceuticals, such as the HIV therapeutic TAF. Our hope is to use bitter taste blockers to increase medical compliance with these vital medicines. SIGNIFICANCE STATEMENT: Identification of a small molecule that inhibits bitter taste from tenofovir alafenamide may increase the compliance in treating children with human immunodeficiency virus infections., (Copyright © 2021 The Author(s).)

Background: Given the observed olfactory and gustatory dysfunctions in patients with COVID-19 and recent findings on taste receptors possible important activities in the immune system, we elected to estimate the correlation between COVID-19 mortality and polymorphism of a particular type of bitter taste receptor gene called TAS2R38, in a worldwide epidemiological point of view., Methods: Pooled rate of each of the rs713598, rs1726866, rs10246939, and PAV/AVI polymorphisms of the TAS2R38 gene was obtained in different countries using a systematic review methodology and its relationship with the mortality of COVID-19. Data were analyzed by the comprehensive meta-analysis software and SPSS., Results: There was only a significant reverse Pearson correlation in death counts and PAV/AVI ratio, p = 0.047, r = -0.503. Also, a significant reverse correlation of PAV/AVI ratio and death rate was seen, r = -0.572 p = 0.021. rs10246939 ratio had a significant positive correlation with death rate, r = 0.851 p = 0.031. Further analysis was not significant. Our results showed that the higher presence of PAV allele than AVI, and a higher rate of G allele than A in rs10246939 polymorphism in a country, could be associated with lower COVID-19 mortality. While assessing all three polymorphisms showed a huge diversity worldwide., Conclusion: Due to extraoral activities of bitter taste receptor genes, especially in mucosal immunity, this gene seems to be a good candidate for future studies on COVID-19 pathophysiology. Also, the high worldwide diversity of TAS2R38 genes polymorphism and its possible assassination with mortality raises concerns about the efficiency of vaccine projects in different ethnicities., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Bitterness is an inherent organoleptic characteristic affecting the flavor of Zanthoxylum bungeanum Maxim. In this study, the vital bitter components of Z. bungeanum were concentrated through solvent extraction, sensory analysis, silica gel chromatography, and thin-layer chromatographic techniques and subsequently identified by UPLC-Q-TOF-MS. Two components with the highest bitterness intensities (BIs), such as 7-methoxycoumarin and 8-prenylkaempferol were selected. The bitter taste perceived thresholds of 7-methoxycoumarin and 8-prenylkaempferol were 0.062 mmol/L and 0.022 mmol/L, respectively. Moreover, the correlation between the contents of the two bitter components and the BIs of Z. bungeanum were proved. The results of siRNA and flow cytometry showed that 7-methoxycoumarin and 8-prenylkaempferol could activate the bitter receptor hTAS2R14. The results concluded that 7-methoxycoumarin and 8-prenylkaempferol contribute to the bitter taste of Z. bungeanum., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The careful evaluation of food is important for survival throughout the animal kingdom, and specialized chemoreceptors have evolved to recognize nutrients, minerals, acids, and many toxins. Vertebrate bitter taste, mediated by the taste receptor type 2 (T2R) family, warns against potentially toxic compounds. During evolution T2R receptors appear first in bony fish, but the functional properties of bony fish T2R receptors are mostly unknown. We performed a phylogenetic analysis showing the "living fossil" coelacanth (Latimeria chalumnae) and zebrafish (Danio rerio) to possess T2R repertoires typical for early-diverged species in the lobe-finned and the ray-finned clade, respectively. Receptors from these two species were selected for heterologous expression assays using a diverse panel of bitter substances. Remarkably, the ligand profile of the most basal coelacanth receptor, T2R01, is identical to that of its ortholog in zebrafish, consistent with functional conservation across >400 Myr of separate evolution. The second coelacanth receptor deorphaned, T2R02, is activated by steroid hormones and bile acids, evolutionary old molecules that are potentially endogenously synthesized agonists for extraoral T2Rs. For zebrafish, we report the presence of both specialized and promiscuous T2R receptors. Moreover, we identified an antagonist for one of the zebrafish receptors suggesting that bitter antagonism contributed to shape this receptor family throughout evolution., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Taste is a fundamental mechanism whereby compounds are detected orally, yet it is highly variable among individuals. The variability in taste that is attributable to genetics is not well-characterized despite its potential role in food selection, and therefore, eating habits that contribute to risk of overweight and obesity. In order to implicate measures of taste function and preference as potentially deterministic factors in adverse eating behaviors that lead to obesity, it must be shown that a relationship exists between genetic variation in taste receptor genes and psychophysical measures of taste in the absence high body mass index. The primary objective of this pilot study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in taste receptor genes and 3 different psychophysical measures of taste in healthy young adults. Sweet, salt, umami, fat, sour, and bitter taste receptor gene SNPs were genotyped in 49 participants (ages 24.6 ± 0.6 years) who completed testing to determine oral detection threshold (DT), suprathreshold sensitivity (ST) and taste preference (PR). A simultaneous association test was conducted between each SNP and the 3 taste outcomes (DT, ST, and PR). Twelve SNPs were associated with at least one of the 3 taste outcomes. Associations were observed between SNPs in taste receptor genes and psychophysical measures of sweet, fat, umami, and salt taste. These results suggest that differences in interindividual psychophysical measures of tastes, namely DT, ST, and PR, may be partially attributed to genetic variation in taste receptor genes. Future studies are warranted to investigate if these findings have consequences for habitual dietary intake of foods that elicit these tastes., (Copyright © 2020. Published by Elsevier Inc.)

Background: Severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) has been identified as the pathogen causing the outbreak of coronavirus disease-2019 (COVID-19) commencing in Wuhan, China, in December 2019. Multiple reports have shown subjective loss of taste and smell as an early and hallmark symptom for COVID-19., Methods: A retrospective study was performed in our clinical practice during July 2020 on patients positive for SARS-CoV-2 via polymerase chain reaction. All patients were categorized into 3 groups (supertasters, tasters, and nontasters) via taste sensitivity to phenylthiocarbamide, thiourea, and sodium benzoate with taste strip testing. The results of the taste strip tests were correlated with clinical course., Results: A total of 100 patients (mean, 51 [range, 24-82] years of age; 44 [44%] women) were assessed. We found that 21 of 100 (21%) were nontasters, 79 of 100 (79%) were tasters, and 0 of 100 (0%) were supertasters (p < 0.001). Twenty-one of 21 (100%) (p < 0.001) of the patients requiring inpatient admission were classified as nontasters. All 79 (100%) (p < 0.001) of the patients who displayed mild to moderate symptoms not requiring admission were classified as tasters., Conclusion: Our results show objective data that taste disturbance, specifically global loss of taste, appears to correlate with the clinical course specific to each individual, because 100% of the patients requiring inpatient admission were classified as nontasters., (© 2020 ARS-AAOA, LLC.)

Polyphenols are phytochemical compounds found mostly in plants with several biological properties. Many of the benefits attributed to fruits and vegetables have been linked to their content in these molecules. As a result, the last decade has witnessed an increase in polyphenol-derived compounds claiming diverse therapeutic properties. Although the mechanism of action of such compounds is yet to be fully disclosed, one of the components that recently has been proposed to participate significantly in the health properties of polyphenols is the type 2 taste receptors (T2Rs). These receptors are responsible for the detection of bitter taste and represent the first line of defence against potentially harmful components in food. The recent discovery of extra-oral T2Rs in several metabolically active tissues has generated intense interest in the potential health impact. Given that most phenolic molecules taste bitter, exploring the T2Rs as a putative pharmacological target for the development of plant-based drug therapies is a promising field of research. Some T2Rs are involved in the control of cilia beat frequency and smooth muscle relaxation in the air tract together with leukocyte homeostasis, important events disrupted in the high prevalence of respiratory diseases. Furthermore, T2Rs are involved in nutrient-gut interactions to modulate gut hormones that influence gastrointestinal motility, appetite and glycemia. Thus, this commentary focuses on the latest novelty advances in relation to the peripheral expression of T2Rs, and polyphenols and T2Rs relationship from a therapeutic point of view., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The choroid plexus (CP) epithelial cells establish an important blood-brain interface, the blood-cerebrospinal fluid barrier (BCSFB), which constitutes a complementary gateway to the blood-brain-barrier for the entrance of several molecules into the central nervous system (CNS). However, the mechanisms that operate at the BCSFB to regulate the molecular traffic are still poorly understood. The taste signalling machinery, present in many extra-oral tissues, is involved in the chemical sensing of the composition of body fluids. We have identified this pathway in rat CP and hypothesised that it could also be present in the human BCSFB. In this study, we characterised the bitter taste receptors (TAS2Rs) expression profiling in human CP by combining data retrieved from available databases of the human CP transcriptome with its expression analysis in a human CP cell line and immunohistochemistry of human CP sections from men and women. TAS2R4, 5, 14 and 39 expression was confirmed in human CP tissue by immunohistochemistry and in HIBCPP cells by RT-PCR, immunofluorescence and Western blot. Moreover, the presence of downstream effector proteins GNAT3, PLCβ2 and TRPM5 was also detected in HIBCPP cells. Then, we demonstrated that HIBCPP cells respond to chloramphenicol via TAS2R39 and to quercetin via TAS2R14. Our findings support an active role of TAS2Rs at the human BCSFB, as surveyors of the bloodstream and CSF compositions. These findings open new avenues for studies on the uptake of relevant compounds for targeted therapies of the CNS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Genetic variability in the ability to taste thiourea compounds has been studied for 80+ years. Over the last 3 decades, many studies have reported perceived intensity of concentrated propylthiouracil (PROP) associates with greater intensity from a broad range of stimuli, including nonbitter tastants, irritants, and retronasally delivered odorants. Thus, PROP phenotype has become a common measure of individual differences in orosensation. Much, but not all, of the phenotypic variation in PROP bitterness is explained by TAS2R38 polymorphisms. While differences in PROP bitterness are clearly due to genetic variation, mechanistically it is challenging to envision how this receptor (narrowly tuned to the N-C=S moiety) relates to overall orosensory response. Here, we report data for 200+ individuals who had been genotyped for TAS2R38 and phenotyped for PROP in a laboratory setting. Participants also reported the intensity of quinine, capsaicin, and sucrose on a general Labeled Magnitude Scale. Our data recapitulate earlier reports associating PROP bitterness with the intensity of the predominant qualities of sucrose, quinine, and capsaicin; however, we also find correlations between the intensities of sucrose, quinine, and capsaicin were much stronger with each other than with PROP. As expected, TAS2R38 diplotype did not associate with the intensity of sucrose, quinine, or capsaicin. The strength of PROP-capsaicin and PROP-sucrose relationships increased after grouping participants by TAS2R38 diplotype, with the greatest increases in association observed within homozygotes. Collectively, this suggests the suprathreshold intensity of PROP is a confounded phenotype that captures both genetic variation specific to N-C=S compounds and overall orosensation., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: Numerous studies have pointed to profound nongustatory roles of tastants and the corresponding taste receptors expressed in the alimentary canal in the modulation of digestive and metabolic functions. Already in early reports, the intriguing possibility to use tastants as drug-like effectors for the treatment of metabolic diseases was raised. With this review, focusing on the most recent literature, we intend to question how close we meanwhile came to the initial promise - the use of tastants as medicines., Recent Findings: Although the enormous complexity and experimental variability of studies investigating the effects of tastants on physiological functions still has not revealed a common fundament from which subsequent therapeutic measures could be designed, more and more evidence is mounting on an involvement of taste receptors and taste signaling molecules in the maintenance and fine regulation of gastrointestinal functions and immunity., Summary: Although the initial goal - using tastants to treat metabolic disorders - has, by far, not been reached, numerous promising findings suggest that dietary interventions could be devised to support conventional therapies in the future.

Airway smooth muscle (ASM) hyperresponsiveness and airway remodeling are pathological drivers of disease progression and mortality in asthma. Importantly, approximately 50% of affected individuals are unable to reliably manage disease symptoms using the current standard of care. Recently, T2Rs have been identified as a novel class of G protein-coupled receptors expressed in the airway that on activation can induce ASM relaxation and reduction in airway tone. Further, agonists of T2Rs may also remedy airway remodeling, which has been difficult to manage with currently available medications. In this review, we will discuss the recent developments in T2R biology and their role in cellular physiology (particularly ASM) and expand on the therapeutic potential of T2R agonists in treatment of asthma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

(1) Background: Recent studies have investigated the expression of taste-related genes in the organs of various animals, including humans; however, data for additional taxa are needed to facilitate comparative analyses within and among species. (2) Methods: We investigated the expression of taste-related genes in the intestines of rhesus macaques, the non-human primates most commonly used in experimental models. (3) Results: Based on RNAseq and qRT-PCR, genes encoding bitter taste receptors and the G-protein gustducin were expressed in the gut of rhesus macaques. RNAscope analysis showed that one of the bitter receptors, TAS2R38, was expressed in some cells in the small intestine, and immunohistochemical analysis revealed the presence of T2R38-positive cells in the villi of the intestines. (4) Conclusions: These results suggest that bitter receptors are expressed in the gut of rhesus macaques, supporting the use of macaques as a model for studies of human taste, including gut analyses.

Diphenhydramine, a sedating antihistamine, is an agonist of human bitter taste receptor 14 (hTAS2R14). Diphenhydramine hydrochloride (DPH) was used as a model bitter medicine to evaluate whether the umami dipeptides (Glu-Glu and Asp-Asp) and their constituent amino acids (Glu, Asp) could suppress its bitterness intensity, as measured by human gustatory sensation testing and using the artificial taste sensor. Various concentrated (0.001-5.0 mM) Glu-Glu, Asp-Asp, Glu and Asp significantly suppressed the taste sensor output of 0.5 mM DPH solution in a dose-dependent manner. The effect of umami dipeptides and their constituent amino acids was tending to be ranked as follows, Asp-Asp > Glu-Glu >> Gly-Gly, and Asp > Glu >> Gly (control) respectively. Whereas human bitterness intensity of 0.5 mM DPH solution with various concentrated (0.5, 1.0, 1.5 mM) Glu-Glu, Asp-Asp, Glu and Asp all significantly reduced bitterness intensity of 0.5 mM DPH solution even though no statistical difference was observed among four substances. The taste sensor outputs and the human gustatory sensation test results showed a significant correlation. A surface plasmon resonance study using hTAS2R14 protein and these substances suggested that the affinity of Glu-Glu, Asp-Asp, Glu and Asp for hTAS2R14 protein was greater than that of Gly-Gly or Gly. The results of docking-simulation studies involving DPH, Glu-Glu and Asp-Asp with hTAS2R14, suggested that DPH is able to bind to a space near the binding position of Glu-Glu and Asp-Asp. In conclusion, the umami dipeptides Glu-Glu and Asp-Asp, and their constituent amino acids, can all efficiently suppress the bitterness of DPH.

Background: Taste sensitivity is one of the most important biological determinants of food choice. Polymorphisms within the bitter taste receptor genes TAS2R3 (rs765007), TAS2R5 (rs2234012), TAS2R19 (rs10772420), and TAS2R50 (rs1376251) may affect bitter taste sensitivity and thus food choices and thereby metabolic biomarkers in blood. The aim of this study was to investigate associations between selected TAS2Rs&nbsp; single nucleotide polymorphisms (SNPs) and the choice of the most popular bitter food items in&nbsp;&nbsp;&nbsp; a Polish population, BMI and blood biomarkers in elderly women., Methods: The study group included 116 Polish women over 60 years of age. Intake of Brassica vegetables, grapefruit and coffee was assessed using a food frequency questionnaire. Biochemical parameters were measured using the spectrophotometric method. Genotyping was performed using the high resolution melting method., Results: We show an association between SNPs of the TAS2R3 gene and the frequency of Brassica vegetable intake, between SNPs of the TAS2R5 gene and the frequency of grapefruit intake, and between the simultaneous effects of polymorphisms within TAS2R3 and TAS2R5 and the frequency of eating Brassica vegetables in general. We found no association between the genetic polymorphisms of TAS2R19 or TAS2R50 that were examined and the frequency of bitter-tasting food intake. Moreover, the SNPs of the selected TAS2Rs genes may be associated with the lipid profile, serum level of glucose and CRP, depending on the frequency of consumption of particular bitter-tasting items., Conclusions: The genetic polymorphisms analyzed in the study seem not to contribute significantly to variability in bitter-tasting food intake in elderly women, although they may influence metabolic biomarkers dependent on the intake of particular bitter-tasting food items.

Bitter taste receptors (TAS2R) are expressed in many non-sensor tissues including skeletal muscles but their function remains unexplored. The aim of this study is to investigate the role of TAS2R in rat abdominal skeletal muscles contractions using denatonium, a TAS2R agonist. Low concentration of denatonium (0.01 mmol/l) caused a significant decrease of amplitudes of the electrical field stimulation (EFS)-induced contractions in abdominal skeletal muscles preparations in vitro. This inhibitory effect was significantly reduced when the preparations were pre-incubated with gentamicin (0.02 mmol/l) used as a non-specific inhibitor of IP3 formation or with BaCl(2) (0.03 mmol/l) applied to block the inward-rectifier potassium current. All experiments were performed in the presence of pipecuronium in order to block the nerve stimulation of the contractions. The data obtained suggest that denatonium decreases the force of rat abdominal muscles contractions mainly via activation of TAS2R, phosphatidylinositol 4,5-biphosphate and its downstream signal metabolites.

A major challenge in taste research is to overcome the flavour imperfections in food products and to build nutritious strategies to combat against obesity as well as other related metabolic syndromes. The field of molecular taste research and chemical senses has contributed to an enormous development in understanding the taste receptors and mechanisms of taste perception. Accordingly, the development of taste-modifying compounds or taste modulators that alter the perception of basic taste modalities has gained significant prominence in the recent past. The beneficial aspects of these substances are overwhelming while considering their potential taste-modifying properties. The objective of the present review is to provide an impression about the taste-modulating compounds and their distinctive taste-modifying properties with reference to their targets and proposed mechanisms of action. The present review also makes an effort to discuss the basic mechanism involved in oro-gustatory taste perception as well as on the effector molecules involved in signal transduction downstream to the activation of taste receptors.

The blood-cerebrospinal fluid barrier is constituted by choroid plexus epithelial cells (CPEC) that regulate molecular trafficking between the blood and the cerebrospinal fluid. We hypothesize that taste receptors expressed in CPEC monitor the composition of these body fluids in a sex hormone dependent way. Thus, we compared the expression of taste related genes in the choroid plexus of sham and ovariectomized female rats, and then studied the effect of 17β-estradiol and progesterone in their expression and function. We found that the bitter receptors Tas2r109, Tas2r144, and the taste-related genes Plcb2 and Trpm5 were down-regulated by ovarian hormones in vivo and ex vivo with functional implications. Knocking-down Tas2r144 with a specific siRNA in a CPEC line (Z310) effectively reduced the Ca 2+ response to the bitter compound denatonium benzoate, in a similar manner to female sex hormones alone, suggesting that female sex hormones downregulated the responses of CPEC to chemical stimuli by reducing Tas2r144., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Being averse to bitter taste is a common phenomenon for humans and other animals, which requires the pharmaceutical and food industries to source compounds that can block bitterness intensity and increase consumer acceptability. In this work, beef protein alcalase hydrolysates (BPAH) and chymotrypsin hydrolysates (BPCH) were reacted with glucose to initiate Maillard reactions that led to the formation of glycated or advanced glycation end products (AGEs), BPAH-AGEs and BPCH-AGEs, respectively. The degree of glycation was higher for the BPAH-AGEs (47-55%) than the BPCH-AGEs (30-38%). Analysis by an electronic tongue instrument showed that BPAH-AGEs and BPCH-AGEs had bitterness scores that were significantly ( p < 0.05) less than quinine. The addition of BPAH-AGEs or BPCH-AGEs to quinine led to significant ( p < 0.05) reductions (up to 38%) in bitterness intensity of quinine. The use of 3% hydrolysate to react with glucose yielded glycated peptides with a stronger ability to reduce quinine bitterness than when 1% was used. Calcium release from HEK293T cells stably expressing the T2R4 human bitter taste receptor was significantly ( p < 0.05) attenuated by BPAH-AGEs (up to 96%) and BPCH-AGEs (up to 92%) when compared to the BPAH (62%) and BPCH (3%) or quinine (0%). We concluded that BPAH-AGEs and BPCH-AGEs may be used as bitter taste blockers to formulate better tasting foods.

Objectives/hypothesis: Taste sensitivity varies greatly among individuals influencing eating behavior and health, consequently the disorders of this sense can affect the quality of life. The ability to perceive the bitter of thiourea compounds, such as phenylthiocarbamide (PTC), has been largely reported as a marker of the general taste sensitivity, food preferences, and health. PTC sensitivity is mediated by the TAS2R38 receptor and its genetic common variants. We study the role of the TAS2R38 receptor in taste disorders with the aim of understanding if these can be genetically determined., Study Design: Prospective cohort study., Methods: Differences in the PTC responsiveness between the patients cohort and healthy controls were assessed. All subjects received standardized tests for smell and taste function and were genotyped for the TAS2R38 gene., Results: PAV/PAV homozygous patients gave high PTC ratings, whereas PAV/AVI genotypes reported lower values, which are similar to those determined in AVI/AVI or rare genotypes. In addition, the patients cohort did not meet the Hardy-Weinberg equilibrium at the TAS2R38 locus, showing a very low frequency of subjects carrying the PAV/AVI diplotype. Independently, in healthy controls who were in equilibrium at the locus, PAV/PAV homozygous and heterozygous rated PTC bitterness higher compared to AVI/AVI or rare genotypes., Conclusions: Our findings, by showing that an only taster haplotype (PAV) is not sufficient to evoke high responses of TAS2R38 receptor in patients with taste disorders, suggest that the genetic constitution may represent a risk factor for the development of taste disorders., Level of Evidence: 2c Laryngoscope, 129:E307-E312, 2019., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)