Decreased taste sensitivity to sucrose in dopamine D3 receptor mutant mice.

Dopamine plays a key role in food rewards and sweet-taste stimulation. We examined the basis for behavioral responses to sweet taste in dopamine D3 receptor-deficient (D3-/-) mice by determining whether the absence of D3 receptors affects the sensitivity to dilute sucrose solutions. In experiment 1, we measured the intensity generalization threshold of conditioned taste aversion (CTA) to a 0.2 M sucrose solution. Results showed that the generalization thresholds were 0.025-0.05 M in D3-/- mice and 0.0025-0.005 M in wild-type (WT) mice. In experiment 2, we found that D3-/- and WT mice had similar capabilities to form and extinguish CTAs. Since the intensity generalization threshold is mainly due to a combination of sweet-taste sensitivity and the robust nature of CTA formation, the results showed that taste sensitivity to sucrose in D3-/- mice was lower than that in WT mice. In experiment 3, to test whether the peripheral sensory signaling may also be affected by the disruption of the dopamine D3 receptors, the mRNA expression levels of sweet-taste-related proteins in taste buds of D3-/- mice were determined. The T1R1 and BDNF mRNA expression levels in D3-/- mice were higher than the controls, whereas T1R2, T1R3, α-gustducin, and TRPM5 mRNA were similar. These findings suggest that disruption of dopamine D3 receptor-mediated signaling decreases the sweet-taste sensitivity and alters the mRNA expression levels of some taste-related molecules.

Taste receptor gene expression is associated with decreased eGFR in patients with diabetes.

Dysgeusia is not only associated with zinc deficiency but also with certain drugs or diseases, including diabetes and renal failure. It often lowers the patient's quality of life and hinders access to proper nutrition. The underlying mechanism is unclear and there is a lack of awareness among patients. Here, we focused on lingual taste receptor gene expression in diabetes and elucidated the relationship between taste receptor gene expression and renal function. Forty-seven patients with diabetes and 10 healthy subjects (control group) were enrolled. Lingual foliate papillae were scraped and the derived cDNA was quantified by real-time polymerase chain reaction. Dysgeusia was assessed using SALSAVE?. All statistical analyses were performed using JMP? software 13. The expression of T1R1 and T1R2 was significantly upregulated in type 2 diabetes patients as compared with that in healthy subjects (P<0.01) but did not change in type 1 diabetes patients. T1R3 expression positively correlated and Scnn1 expression negatively correlated with estimated glomerular filtration rate, suggesting that altered taste receptor gene expression could reflect impaired renal function. Thus, alterations in T1R3 and Scnn1 expression in diabetes correlated with renal function. Taste receptor gene expression dysregulation could indicate dysgeusia associated with impaired renal function in patients with diabetes. J. Med. Invest. 69 : 120-126, February, 2022.

Development of a screening system for agents that modulate taste receptor expression with the CRISPR-Cas9 system in medaka.

Taste recognition mediated by taste receptors is critical for the survival of animals in nature and is an important determinant of nutritional status and quality of life in humans. However, many factors including aging, diabetes, zinc deficiency, infection with influenza or cold viruses, and chemotherapy can trigger dysgeusia, for which a standard treatment has not been established. We here established an engineered strain of medaka (Oryzias latipes) that expresses green fluorescent protein (GFP) from the endogenous taste 1 receptor 3 (T1R3) gene locus with the use of the CRISPR-Cas9 system. This T1R3-GFP knock-in (KI) strain allows direct visualization of expression from this locus by monitoring of GFP fluorescence. The pattern of GFP expression in the T1R3-GFP KI fish thus mimicked that of endogenous T1R3 gene expression. Furthermore, exposure of T1R3-GFP KI medaka to water containing monosodium glutamate or the anticancer agent 5-fluorouracil resulted in an increase or decrease, respectively, in GFP fluorescence intensity, effects that also recapitulated those on T1R3 mRNA abundance. Finally, screening for agents that affect GFP fluorescence intensity in T1R3-GFP KI medaka identified tryptophan as an amino acid that increases T1R3 gene expression. The establishment of this screening system for taste receptor expression in medaka provides a new tool for the development of potential therapeutic agents for dysgeusia.

A Genome-Wide Association Study Predicts the Onset of Dysgeusia Due to Anti-cancer Drug Treatment.

Dysgeusia is a major side effect of anti-cancer drug treatment. Since dysgeusia significantly lowers the patient's QOL, predicting and avoiding its onset in advance is desirable. Accordingly, aims of the present study were to use a genome-wide association study (GWAS) to identify genes associated with the development of dysgeusia in patients taking anti-cancer drugs and to predict the development of dysgeusia using associated single nucleotide polymorphisms (SNPs). GWAS was conducted on 76 patients admitted to the Department of Hematology, Tokushima University Hospital. Using Sanger sequencing for 23 separately collected validation samples, the top two SNPs associated with the development of dysgeusia were determined. GWAS identified rs73049478 and rs41396146 SNPs on the retinoic acid receptor beta (RARB) gene associated with dysgeusia development due to the administration of anti-cancer drugs. Evaluation of the two SNPs using 23 validation samples indicated that the accuracy rate of rs73049478 was relatively high (87.0%). Thus, the findings of the present study suggest that the rs73049478 SNP of RARB can be used to predict the onset of dysgeusia caused by the administration of anti-cancer drugs.

Association between Sour Taste SNP KCNJ2-rs236514, Diet Quality and Mild Cognitive Impairment in an Elderly Cohort.

Differences in sour-taste thresholds have been identified in cognition-related diseases. Diet is a modulator of cognitive health, and taste perception influences dietary preferences and habits. Heritable genetics and polymorphisms in the KCNJ2 gene involved in the transduction of sour taste have been linked to variations in sour taste and non-gustatory functions. However, relationships between sour taste genetics, mild cognitive impairment, and diet quality are yet to be elucidated. This study investigated the associations between the presence of the KCNJ2-rs236514 variant (A) allele, diet quality indices, and mild cognitive impairment evaluated by the Mini-Mental State Examination (MMSE), in a secondary cross-sectional analysis of data from the Retirement Health & Lifestyle Study. Data from 524 elderly Australians (≥65y) were analyzed, using standard least squares regression and nominal logistic regression modeling, with demographic adjustments applied. Results showed that the presence of the KCNJ2-A allele is associated with increased proportions of participants scoring in the range indicative of mild or more severe cognitive impairment (MMSE score of ≤26) in the total cohort, and males. These associations remained statistically significant after adjusting for age, sex, and diet quality indices. The absence of association between the KCNJ2-A allele and cognitive impairment in women may be related to their higher diet quality scores in all indices. The potential link between sour taste genotype and cognitive impairment scores may be due to both oral and extra-oral functions of sour taste receptors. Further studies are required on the role and relationship of neurotransmitters, sour taste genotypes and sour taste receptors in the brain, and dietary implications, to identify potential risk groups or avenues for therapeutic or prophylactic interventions.

Dual binding mode of "bitter sugars" to their human bitter taste receptor target.

The 25 human bitter taste receptors (hTAS2Rs) are responsible for detecting bitter molecules present in food, and they also play several physiological and pathological roles in extraoral compartments. Therefore, understanding their ligand specificity is important both for food research and for pharmacological applications. Here we provide a molecular insight into the exquisite molecular recognition of bitter ß-glycopyranosides by one of the members of this receptor subclass, hTAS2R16. Most of its agonists have in common the presence of a ß-glycopyranose unit along with an extremely structurally diverse aglycon moiety. This poses the question of how hTAS2R16 can recognize such a large number of "bitter sugars". By means of hybrid molecular mechanics/coarse grained molecular dynamics simulations, here we show that the three hTAS2R16 agonists salicin, arbutin and phenyl-ß-D-glucopyranoside interact with the receptor through a previously unrecognized dual binding mode. Such mechanism may offer a seamless way to fit different aglycons inside the binding cavity, while maintaining the sugar bound, similar to the strategy used by several carbohydrate-binding lectins. Our prediction is validated a posteriori by comparison with mutagenesis data and also rationalizes a wealth of structure-activity relationship data. Therefore, our findings not only provide a deeper molecular characterization of the binding determinants for the three ligands studied here, but also give insights applicable to other hTAS2R16 agonists. Together with our results for other hTAS2Rs, this study paves the way to improve our overall understanding of the structural determinants of ligand specificity in bitter taste receptors.

Effects of chemotherapy on gene expression of lingual taste receptors in patients with head and neck cancer.

OBJECTIVES/HYPOTHESIS: We aimed to test the hypothesis that chemotherapy changes the gene expression of taste receptors in the tongue to induce dysgeusia in patients with head and neck cancer. STUDY DESIGN: Prospective observation study. METHODS: We enrolled 21 patients who received chemoradiotherapy and five patients who underwent radiotherapy for head and neck cancer. The messenger RNA (mRNA) levels of the taste receptor subunits T1R1, T1R2, T1R3, and T2R5 were measured in lingual mucosa scrapings obtained with a small spatula. The perception thresholds of umami, sweet, and bitter tastes were assessed by the whole mouth gustatory test. RESULTS: In four patients with severe stomatitis induced by chemoradiotherapy, the mRNA levels of T1R1, T1R2, T1R3, and T2R5 in the lingual mucosa were significantly decreased. However, in 17 patients with mild/moderate stomatitis, the mRNA levels of T1R3 were significantly and transiently decreased, whereas those of T1R1 and T1R2 remained unchanged and those of T2R5 mRNA were significantly and transiently increased after chemotherapy. There was a significant negative correlation between the perception thresholds of umami or sweet tastes and lingual mRNA levels of T1R3 in patients with mild/moderate stomatitis after chemotherapy. Although the perception threshold of bitter taste remained unchanged, lingual mRNA levels of T2R5 were significantly increased in patients who complained of phantogeusia after chemotherapy. CONCLUSION: Chemotherapy specifically changed the gene expression of T1R3 and T2R5 in head and neck cancer patients with mild/moderate stomatitis, resulting in both dysgeusia of umami and sweet tastes as well as phantogeusia. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:E103-E109, 2016.

Multiple loss-of-function variants of taste receptors in modern humans.

Despite recent advances in the knowledge of interindividual taste differences, the underlying genetic backgrounds have remained to be fully elucidated. Much of the taste variation among different mammalian species can be explained by pseudogenization of taste receptors. Here I investigated whether the most recent disruptions of taste receptor genes segregate with their intact forms in modern humans by analyzing 14 ethnically diverse populations. The results revealed an unprecedented prevalence of 25 segregating loss-of-function (LoF) taste receptor variants, identifying one of the most pronounced cases of functional population diversity in the human genome. LoF variant frequency in taste receptors (2.10%) was considerably higher than the overall LoF frequency in human genome (0.16%). In particular, molecular evolutionary rates of candidate sour (14.7%) and bitter (1.8%) receptors were far higher in humans than those of sweet (0.02%), salty (0.05%), and umami (0.17%) receptors compared with other carnivorous mammals, although not all of the taste receptors were identified. Many LoF variants are population-specific, some of which arose even after population differentiation, not before divergence of the modern and archaic human. I conclude that modern humans might have been losing some sour and bitter receptor genes because of high-frequency LoF variants.

Taste genetics and gastrointestinal symptoms experienced in chronic kidney disease.

BACKGROUND/OBJECTIVES: It is unknown what causes uraemic symptoms in renal disease. Chronic kidney disease (CKD) patients are known to have increased levels of urea, sodium, potassium and phosphate in their saliva compared with those without renal disease. The present cross-sectional study investigated associations between known genetic traits of taste and self-reported upper gastrointestinal (GI) symptoms experienced in CKD patients with the changes in saliva composition found in renal failure. SUBJECTS/METHODS: Fifty-six CKD patients (35 males, 21 females, age 67±14 years), with stages 4 and 5 renal failure, selected from a tertiary hospital renal outpatient clinic participated in this study. Subjects answered a questionnaire to assess upper GI symptoms and tested for the genetic taste recognition thresholds of thiourea, phenylthiocarbamide and sodium benzoate. Saliva samples were collected to determine biochemical composition. Possible associations between genetic taste variations, saliva composition and upper GI symptoms were investigated. RESULTS: Of the 56 patients enroled, 29 (52%) reported major upper GI uraemic symptoms, whereas 27 (48%) had no symptoms or only minor complaints of dry mouth. There was a strong association between the symptomatic burden a patient experienced and the genetic ability to taste thiourea (P<0.0003). Uraemic symptoms of taste changes (P<0.004) and nausea (P<0.002) were found to be related to a patient's genetic ability to taste thiourea. CONCLUSIONS: This study provides evidence that the genetic ability to taste thiourea as bitter, in combination with the increase in active compounds found in CKD patient's saliva, impacts on the uraemic upper GI symptoms experienced.

A case study on the association of variation of bitter-taste receptor gene TAS2R38 with the height, weight and energy intake in Japanese female college students.

One of the critical factors that determines individual differences in dietary behavior and nutritional status is the sensory-affecting quality of food, in particular its taste. Variation of one bitter taste receptor gene, TAS2R38, which is associated with the differential sensitivity to phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), has been demonstrated to affect the dietary intake pattern. A case study was performed to examine the association of the TAS2R38 genotypes/haplotypes with the body size (height, weight and BMI) and with the food and nutrient intake. Eighty-four college students, all females, with an age range of 18-21 y were recruited from the University of Shizuoka. The genotypes of two common single nucleotide polymorphisms in TAS2R38 (A49P and I296V) were determined by PCR-restriction fragment length polymorphism (RFLP) method. The height, weight and body mass index (BMI), and (in a subgroup of 47 subjects) food and nutrition intake estimated from 3 d of food recording, were compared between homozygotes for the PTC/PROP-nontaster haplotype (AI haplotype) and carriers with the PTC/PROP-taster haplotype (PV haplotype). The results show that the homozygotes with AI haplotype were taller and heavier than the carriers of PV haplotype, while BMI values were similar between them. The former group also had higher energy and carbohydrate intakes than the latter group. Neither vegetable nor dairy product intake was different between the homozygotes with AI haplotype and the carriers of PV haplotype. In conclusion, the PTC/PROP-nontaster TAS2R38 genotype/haplotype was associated with height and weight but not with BMI, which may in turn have influenced the energy and carbohydrate intakes.

A conditioned aversion study of sucrose and SC45647 taste in TRPM5 knockout mice.

Previously, published studies have reported mixed results regarding the role of the TRPM5 cation channel in signaling sweet taste by taste sensory cells. Some studies have reported a complete loss of sweet taste preference in TRPM5 knockout (KO) mice, whereas others have reported only a partial loss of sweet taste preference. This study reports the results of conditioned aversion studies designed to motivate wild-type (WT) and KO mice to respond to sweet substances. In conditioned taste aversion experiments, WT mice showed nearly complete LiCl-induced response suppression to sucrose and SC45647. In contrast, TRPM5 KO mice showed a much smaller conditioned aversion to either sweet substance, suggesting a compromised, but not absent, ability to detect sweet taste. A subsequent conditioned flavor aversion experiment was conducted to determine if TRPM5 KO mice were impaired in their ability to learn a conditioned aversion. In this experiment, KO and WT mice were conditioned to a mixture of SC45647 and amyl acetate (an odor cue). Although WT mice avoided both components of the stimulus mixture, they avoided SC45647 more than the odor cue. The KO mice also avoided both stimuli, but they avoided the odor component more than SC45647, suggesting that while the KO mice are capable of learning an aversion, to them the odor cue was more salient than the taste cue. Collectively, these findings suggest the TRPM5 KO mice have some residual ability to detect SC45647 and sucrose, and, like bitter, there may be a TRPM5-independent transduction pathway for detecting these substances.

Genetic variation in taste perception: does it have a role in healthy eating?

Taste is often cited as the factor of greatest significance in food choice, and has been described as the body's 'nutritional gatekeeper'. Variation in taste receptor genes can give rise to differential perception of sweet, umami and bitter tastes, whereas less is known about the genetics of sour and salty taste. Over twenty-five bitter taste receptor genes exist, of which TAS2R38 is one of the most studied. This gene is broadly tuned to the perception of the bitter-tasting thiourea compounds, which are found in brassica vegetables and other foods with purported health benefits, such as green tea and soya. Variations in this gene contribute to three thiourea taster groups of people: supertasters, medium tasters and nontasters. Differences in taster status have been linked to body weight, alcoholism, preferences for sugar and fat levels in food and fruit and vegetable preferences. However, genetic predispositions to food preferences may be outweighed by environmental influences, and few studies have examined both. The Tastebuddies study aimed at taking a holistic approach, examining both genetic and environmental factors in children and adults. Taster status, age and gender were the most significant influences in food preferences, whereas genotype was less important. Taster perception was associated with BMI in women; nontasters had a higher mean BMI than medium tasters or supertasters. Nutrient intakes were influenced by both phenotype and genotype for the whole group, and in women, the AVI variation of the TAS2R38 gene was associated with a nutrient intake pattern indicative of healthy eating.

Apolipoprotein E epsilon4 genotype and gender: effects on memory.

OBJECTIVE: Episodic recognition memory for odors and visual was assessed in apolipoprotein E (ApoE) epsilon4-positive and epsilon4-negative men and women diagnosed with Alzheimer disease (AD) and a healthy age- and gender-matched comparison group. METHODS: A total of 38 AD patients and 38 age- and gender-matched healthy older adults completed a recognition memory task involving three categories of stimuli: odors, faces, and symbols. RESULTS: In the healthy comparison group, men who were epsilon4 negative outperformed epsilon4-positive men in recognition memory for odors and committed fewer false-positive errors. However, there were no significant differences between epsilon4-negative and epsilon4-positive women in the comparison group. No significant gender or ApoE status differences were detected in recognition memory for faces or symbols in the comparison group. In patients with AD, epsilon4-negative women outperformed epsilon4-positive women in recognition memory for odors and committed significantly fewer false-positive errors. However, there were no significant differences between epsilon4-positive and epsilon4-negative men. There were no significant gender or ApoE status differences in recognition memory for faces or symbols in AD patients. CONCLUSION: The results demonstrate that recognition memory for olfactory stimuli may be particularly impaired in healthy older men with the epsilon4 allele. In patients with AD, odor memory impairments may be less severe in women who are negative for the epsilon4 allele. The results offer new insight into how recognition memory is affected by gender, the epsilon4 allele, and the modality of the stimulus to be remembered in healthy older adults and patients with AD.

Lack of support for the inability to taste phenylthiocarbamide as an endophenotypic marker in patients with schizophrenia and their first-degree relatives.

OBJECTIVE: This study sought to replicate recent findings that both patients and relatives are significantly more likely to be phenylthiocarbamide (PTC) nontasters than healthy controls, and that within the patient group, nontasters have more severe positive and/or negative symptoms than tasters. Associations between PTC-tasting status and olfactory identification scores also were examined. METHOD: PTC perception and olfactory identification were assessed in 48 patients with schizophrenia or schizoaffective disorder, 28 first-degree relatives, and 32 healthy volunteers. RESULTS: The three groups did not differ in PTC taste sensitivity. Findings did not change after: a sensitivity analysis that re-categorized participants who "possibly" tasted PTC, excluding Caucasian participants, or restricting the sample of patients to only those with schizophrenia. Among the patients, tasters and nontasters did not differ with regard to positive, negative, or general psychopathology symptoms. In the combined sample and the three groups separately, there were no associations between PTC-tasting status and olfactory identification scores. CONCLUSIONS: This study, conducted specifically as an attempt to replicate previously reported findings, failed to provide support for PTC perception as an endophenotypic marker for schizophrenia. Further research is warranted.

Altered taste function in mice deficient in the 65-kDa isoform of glutamate decarboxylase.

The 65-kDa isoform of glutamate decarboxylase (GAD65) is considered to play an important role for GABA synthesis in the central nervous system. Using mice with targeted ablation of the GAD65 gene (GAD65(-/-) mice) we investigated a possible involvement of GABAergic neurotransmission in several taste functions. Preference/aversion responses to four basic tastes were not different between GAD65(-/-) and wild-type mice during a 48-h two-bottle choice test. GAD65(-/-) mice consumed less sucrose-quinine mixtures than did wild-type mice. The injection of midazolam (5 mg/kg), a benzodiazepine agonist, significantly increased the consumption of 100 mM sucrose in the wild-type mice. The same injection, however, failed to increase intake of the 100 mM sucrose in GAD65(-/-) mice. These results suggest that GAD65-generated GABA is not implicated in basic taste functions such as simple detection and discrimination. Rather, more complex processing of taste information including taste mixtures and palatability may be finely tuned by GAD65-mediated GABA synthesis.

Taste and smell in familial dysautonomia.

Familial dysautonomia (FD) is one of the classic diseases characterised by taste and smell abnormalities. However, these typical features are based on data obtained from two separate crude studies published in 1964. In the present study psychophysical-cognitive and reflex-like facial-behavioral responses to taste and smell, in nine patients with FD and 15 healthy controls, were recorded. Five taste stimulants were presented to both study groups, while a selection of common household odors was used for FD patients only. The patients with FD showed a markedly higher incidence of recognition failures for salty, bitter, sweet, and water stimuli than the controls, but rate of recognition of sour stimuli was almost identical in the two groups. Estimates by the subjects on a hedonic scale of 0 to 10 and facial display in FD indicated a relatively normal sensitivity to sour stimuli and to a lesser extent to bitter stimuli. Water, sweet, and salty stimuli evoked non-discriminatory responses. These findings indicate specific dyageusia rather than general ageusia. Smell was found to be normal. In children with taste and smell impairment, a systematic evaluative approach may help in planning palatable diets for adequate and comfortable nutrition.

Oral Crohn's disease: report of two cases in brothers with metallic dysgeusia and a review of the literature.

Between 4% and 14% of patients with intestinal Crohn's disease (CD) may manifest the typical oral changes of this disorder. These changes include labial and intraoral inflammatory tissue hyperplasia with fissuring ("cobblestoning") and swelling. In addition, angular cheilitis and regional lymphadenopathy may be present. We report two cases of oral CD in brothers, in whom the unusual symptoms of metallic dysguesia and gingival bleeding were prominent features. Despite the well-recognized familiar incidence of CD, a review of the literature shows that in no previous case reports has familial oral CD been noted. Successful symptomatic and objective treatment results were obtained with a mouthwash preparation of triamcinolone acetonide, tetracycline, and lidocaine.