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.

Gastric parietal cells secrete chloride ions and protons to form hydrochloric acid. Besides endogenous stimulants, e.g., acetylcholine, bitter-tasting food constituents, e.g., caffeine, induce proton secretion via interaction with bitter taste receptors (TAS2Rs), leading to increased cytosolic Ca2+ and cAMP concentrations. We hypothesized TAS2R activation by bitter tastants to result in proton secretion via cellular Na+ influx mediated by transient receptor potential channels (TRP) M4 and M5 in immortalized human parietal HGT-1 cells. Using the food-derived TAS2R agonists caffeine and l-arginine, we demonstrate both bitter compounds to induce a TRPM4/M5-mediated Na+ influx, with EC50 values of 0.65 and 10.38 mM, respectively, that stimulates cellular proton secretion. Functional involvement of TAS2Rs in the caffeine-evoked effect was demonstrated by means of the TAS2R antagonist homoeriodictyol, and stably CRISPR-Cas9-edited TAS2R43ko cells. Building on previous results, these data further support the suitability of HGT-1 cells as a surrogate cell model for taste cells. In addition, TRPM4/M5 mediated a Na+ influx after stimulating HGT-1 cells with the acetylcholine analogue carbachol, indicating an interaction of the digestion-associated cholinergic pathway with a taste-signaling pathway in parietal cells.

Tuft cells are a type of rare epithelial cells that have been recently found to utilize taste signal transduction pathways to detect and respond to various noxious stimuli and pathogens, including allergens, bacteria, protists and parasitic helminths. It is, however, not fully understood how many different types of pathogens they can sense or what exact molecular mechanisms they employ to initiate targeted responses. In this study, we found that an anaerobic pathobiont microbe, Ruminococcus gnavus (R. gnavus), can induce tuft cell proliferation in the proximal colon whereas the microbe\'s lysate can stimulate these proximal colonic tuft cells to release interleukin-25 (IL-25). Nullification of the Gng13 and Trpm5 genes that encode the G protein subunit Gγ13 and transient receptor potential ion channel Trpm5, respectively, or application of the Tas2r inhibitor allyl isothiocyanate (AITC), G protein Gβγ subunit inhibitor Gallein or the phospholipase Cβ2 (PLCβ2) inhibitor U73122 reduces R. gnavus-elicited tuft cell proliferation or IL-25 release or both. Furthermore, Gng13 conditional knockout or Trpm5 knockout diminishes the expression of gasdermins C2, C3 and C4, and concomitantly increases the activated forms of caspases 3, 8 and 9 as well as the number of TUNEL-positive apoptotic cells in the proximal colon. Together, our data suggest that taste signal transduction pathways are not only involved in the detection of R. gnavus infection, but also contribute to helping maintain gasdermin expression and prevent apoptotic cell death in the proximal colon, and these findings provide another strategy to combat R. gnavus infection and sheds light on new roles of taste signaling proteins along with gasdermins in protecting the integrity of the proximal colonic epithelium.

The influence of roasting on tea bitterness remains unclear. With Wuyi Rock tea (WRT) as an example, this study investigated the impact of roasting on WRT\'s bitterness, utilizing an integrated approach involving sensory evaluation, bitter compound profiling, and cell-based calcium imaging. Sensory analysis revealed that roasting effectively reduced the perceived bitterness of WRT. This reduction was supported by decreases in various bitter compounds, including 19 flavanols, 11 flavonols, 12 phenolic acids, 2 purine alkaloids, and 9 bitter amino acids, which diminished by 16%, 26%, 19%, 2%, and 70%, respectively. Furthermore, we established two heterogeneous bitter receptor expression systems: TAS2R39/Gα15-HEK293T and TAS2R14/Gα15-HEK293T cell lines. These systems quantitatively confirmed the reduction in bitterness, demonstrating 51% and 62% decreases in intracellular calcium mobilization within the transfected cells, respectively. These findings provide compelling evidence for the bitterness-ameliorating effect of roasting, expanding our knowledge of the role of roasting in shaping the flavor of tea.

Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has remained a public health threat since late 2019. Among the strategies rapidly developed to prevent and treat COVID-19, the antiviral medication Paxlovid (nirmatrelvir/ritonavir combination) has shown remarkable efficacy in reducing viral load and relieving clinical symptoms. Unexpectedly, a persistent bitter/bad taste, referred to as \"Paxlovid mouth\", has been frequently noted. Consistent with this, dysgeusia (altered taste) is listed as a main adverse effect of Paxlovid based on clinical trial data. Nirmatrelvir inhibits Mpro, a SARS-CoV-2 main protease, whereas ritonavir prolongs the activity of nirmatrelvir by slowing its metabolism. Prior usage of ritonavir in other conditions has not been linked to a persistent bad taste, despite the fact that ritonavir tastes bitter. Therefore, we hypothesized that nirmatrelvir may account for Paxlovid mouth by activating one or more of the 25 human TAS2R bitter taste receptors. Here, we show that TAS2R1 is the primary bitter receptor activated by nirmatrelvir, at concentrations as low as 15 μM, which overlaps with plasma concentrations of nirmatrelvir in a subset of patients. We also show that saccharin, a non-nutritive sweetener that may block the activity of TAS2R1, has little or no effect on nirmatrelvir-stimulated TAS2R1 activity. Such findings may help identify novel strategies to alleviate Paxlovid mouth and increase treatment compliance.

Prednisolone is a frequently prescribed steroid with a bitter, unpalatable taste that can result in treatment refusal. Oral suspensions or powder dosage forms are often prescribed, particularly to pediatric patients, as they improve swallowability and ease of dose adjustment. Consequently, the bitterness of prednisolone is more apparent in these dosage forms. Few studies have investigated prednisolone\'s bitterness. Thus, in this study, 50 adults evaluated the bitterness of prednisolone using the generalized Labeled Magnitude Scale (gLMS), in comparison with quinine, a standard bitter substance. Overall, prednisolone-saturated solution demonstrated the same extent (mean gLMS score: 46.8) of bitterness as 1 mM quinine solution (mean gLMS score: 40.1). Additionally, large individual differences were observed in the perception of the bitterness of prednisolone and quinine. Perceived flavors of some drugs are reportedly associated with bitter-taste receptor (TAS2Rs) polymorphisms. Therefore, we investigated the relationship between subjects\' genetic polymorphisms of TAS2R19, 38, and 46, and their sensitivity to bitterness. Although a relationship between TAS2R19 polymorphisms and the perception of quinine bitterness was observed, no significant relationship was found between the perceived bitterness of prednisolone and the investigated genes. Ultimately, the results show that despite individual differences among subjects, the cause of prednisolone\'s strong bitterness is yet to be elucidated.

The bitter taste is generally considered an undesirable sensory attribute. However, bitter-tasting compounds can significantly affect the overall flavor of many foods and beverages and endow them with various beneficial effects on human health. To better understand the relationship between chemical structure and bitterness, this paper has summarized the bitter compounds in foodstuffs and classified them based on the basic skeletons. Only those bitter compounds that are confirmed by human sensory evaluation have been included in this paper. To develop food products that satisfy consumer preferences, correctly ranking the key bitter compounds in foodstuffs according to their contributions to the overall bitterness intensity is the precondition. Generally, three methods were applied to screen out the key bitter compounds in foods and beverages and evaluate their sensory contributions, including dose-over-threshold factors, taste dilution analysis, and spectrum descriptive analysis method. This paper has discussed in detail the mechanisms and applications of these three methods. Typical procedures for separating and identifying the main bitter compounds in foodstuffs have also been summarized. Additionally, the activation of human bitter taste receptors (TAS2Rs) and the mechanisms of bitter taste transduction are outlined. Ultimately, a conclusion has been drawn to highlight the current problems and propose potential directions for further research.

In the wild, mice have developed survival strategies to detect volatile cues that warn them of potential danger. Specific olfactory neurons found in the Grueneberg ganglion olfactory subsystem can detect alarm pheromones emitted by stressed conspecifics, as well as kairomones involuntarily released by their predators. These volatile chemical cues allow intra- and interspecies communication of danger, respectively. Alarm pheromones, kairomones and bitter taste ligands share a common chemical motif containing sulfur or nitrogen. Interestingly, three specific bitter taste receptors (TAS2Rs) have been found in the Grueneberg ganglion neurons that are implicated in danger signalling pathways. We have recently developed a TAS2R-expressing heterologous system that mimics the Grueneberg ganglion neuron responses after kairomone stimulation. Here, we demonstrated by in vitro, ex vivo and in vivo experiments that the biological secretions from the raccoon (Procyon lotor) and the skunk (Mephitis mephitis) were acting as potent sources of kairomones. They activated the Grueneberg ganglion neurons and induced fear-related behaviours in mice. Identification of new sources of semiochemicals is a first step towards an understanding of the interspecies danger communication that takes place in the Grueneberg ganglion.

BACKGROUND: Since it is known that bitter taste receptors (TAS2Rs) are expressed and functionally active in various extra-oral cells, their genetic variability and functional response initiated by their activation have become of broader interest, including in the context of cancer.
METHODS: A systematic research was performed in PubMed and Google Scholar to identify relevant publications concerning the role of TAS2Rs in cancer.
RESULTS: While the findings on variations of TAS2R genotypes and phenotypes and their association to the risk of developing cancer are still inconclusive, gene expression analyses revealed that TAS2Rs are expressed and some of them are predominately downregulated in cancerous compared to non-cancerous cell lines and tissue samples. Additionally, receptor-specific, agonist-mediated activation induced various anti-cancer effects, such as decreased cell proliferation, migration, and invasion, as well as increased apoptosis. Furthermore, the overexpression of TAS2Rs resulted in a decreased tumour incidence in an in vivo study and TAS2R activation could even enhance the therapeutic effect of chemotherapeutics in vitro. Finally, higher expression levels of TAS2Rs in primary cancerous cells and tissues were associated with an improved prognosis in humans.
CONCLUSIONS: Since current evidence demonstrates a functional role of TAS2Rs in carcinogenesis, further studies should exploit their potential as (co-)targets of chemotherapeutics.

Food compounds with a bitter taste have a role in human health, both for their capability to influence food choice and preferences and for their possible systemic effect due to the modulation of extra-oral bitter taste receptors (TAS2Rs). Investigating the interaction of bitter food compounds with TAS2Rs is a key step to unravel their complex effects on health and to pave the way to rationally design new additives for food formulation or drugs. Here, we propose a collection of food bitter compounds, for which in vitro activity data against TAS2Rs are available. The patterns of TAS2R subtype-specific agonists were analyzed using scaffold decomposition and chemical space analysis, providing a detailed characterization of the associations between food bitter tastants and TAS2Rs.