What this is
- This review explores the role of bitter taste receptors () in regulating glucose metabolism through dietary herbs and spices.
- Bitter compounds in plants activate , which are found not only in the mouth but also throughout the gastrointestinal tract.
- Activation of these receptors can influence hormone secretion related to glucose regulation, appetite, and metabolic health.
- The review emphasizes the potential of incorporating bitter foods into diets to improve metabolic function.
Essence
- Bitter compounds in herbs and spices activate , influencing glucose metabolism and hormone secretion, offering a dietary approach to enhance metabolic health.
Key takeaways
- Bitter taste receptors () are present in various tissues beyond the mouth, including the gastrointestinal tract, where they modulate metabolic functions.
- Activation of by bitter phytochemicals can stimulate the release of hormones like and , which are crucial for glucose regulation and appetite control.
- Incorporating bitter herbs and spices into diets could serve as a practical strategy to improve metabolic health and dietary quality.
Caveats
- The review identifies a significant knowledge gap regarding the molecular interactions of bitter compounds with across different tissues.
- Current understanding of how dietary bitter compounds can be effectively utilized for health-promoting purposes remains limited.
Definitions
- TAS2Rs: A family of bitter taste receptors involved in detecting bitter compounds and influencing various physiological responses.
- GLP-1: Glucagon-like peptide-1, a hormone that enhances insulin secretion and regulates glucose metabolism.
- CCK: Cholecystokinin, a hormone that stimulates digestion and promotes satiety.
Simplified
INTRODUCTION
Humans recognize bitter substances through a diverse group of about 25 functional bitter taste receptors (TAS2Rs).They appeared for the first time in cartilaginous and bony fishes around 430-460 million years ago and rapidly expanded in vertebrates during the subsequent transition from aquatic to terrestrial life.This expansion coincided with the emergence of bitter plants and insects that became major dietary sources for the early vertebrates.Animal prey generally lack bitter-tasting substances, with a primary exception of bile; thus, the development of a broad and sensitive bitter detection system conferred a strong survival advantage by enabling navigation and feeding in an increasingly complex terrestrial chemical environment—for example, by detection or avoidance of bitter plant alkaloids,glucosinolates,or phenolic glycosides. 031 031 031 031 031 031 031 031 ,
Calling TAS2Rs “bitter receptors,” however, was a significant disservice to their true biological chemosensory role and vast extraoral functionality, similar to other taste-receptor families.The expansion and diversification of bitter taste receptors in the gut, airways, and immune cells led to their evolutionary repurposing for additional metabolic and immune functions.Today, there is growing support for the notion that bitter substances routinely engage chemosensory receptors all over the human body. In the gut, these receptors are found on enteroendocrine cells, epithelial cells, and some immune cell populations, where they can sense dietary and microbial-derived bitter compounds.Activation of gut TAS2Rs triggers intracellular signaling cascades that can stimulate the secretion of hormones that regulate glucose metabolism, appetite, and gut motility.These receptors also modulate local defense mechanisms, including antimicrobial peptide release and barrier function, linking chemosensation to gut immune responses.Importantly, the sensitivity and responsiveness of TAS2Rs can vary between individuals, reflecting both genetic variation in receptor expression and adaptation to habitual diet.A well-characterized example is the perception differences of 6--propylthiouracil and phenylthiocarbamide that arise from common polymorphic variants in TAS2R38.However, extraoral gastrointestinal TAS2Rs function independently of oral bitterness perception, indicating that individuals with differing oral sensitivity can still exhibit robust gut TAS2R activation. 031 031 031 031 031 031 031 n
With terrestrial adaptation, plants also became the dominant dietary sources of carbohydrates, supplying starches, sugars, and fermentable fibers that supported expanding human metabolic demands. Consequently, hominids were faced with the dual challenge of extracting energy from plant-derived carbohydrates while simultaneously ingesting the bitter phytochemicals that frequently co-occur in the same tissues.This evolutionary pressure likely favored the coupling of bitter chemosensing with metabolic control systems that regulate intestinal glucose handling and postprandial hormone release.This makes TAS2Rs especially relevant for engineering foods that deliver metabolic signals without adding digestible energy, distinguishing them conceptually from TAS1R-driven pathways. The focus on TAS2Rs in this review does not imply that bitter tastants uniquely regulate gut hormone secretion; rather they represent a distinct and underutilized chemosensory entry point for modulating shared metabolic pathways. 031 031
Spices and herbs are uniquely positioned to leverage this system, offering not just flavor but also potential modulatory effects through their concentrated bitter-tasting constituents.The structural diversity of bitter compounds in herbs and spices allows for engagement of multiple TAS2Rs,providing a broad signaling repertoire that can be tailored to individual sensitivities and dietary patterns. By incorporating bitter spices and herbs into the diet, it may be possible to harness these evolutionary chemosensory pathways to support metabolic health and modulate postprandial energy handling. However, a significant knowledge gap remains in understanding how these compounds interact with TAS2Rs at the molecular level across different tissues and how they can be effectively used for health-promoting purposes. In this narrative review, we address this gap by focusing on the effects of bitter-tasting substances on carbohydrate metabolism and, specifically, their influence on glucose uptake and appearance in the blood, using both human clinical data and cell culture models. 031 031
METHODS
This narrative review was developed through a summary of our work on the subject combined with an extensive search of scientific literature using databases including PubMed, Google Scholar, Web of Science, and Scopus accessed via institutional subscriptions at North Carolina State University, covering publications up to December 2025. Only peer-reviewed studies published in English were considered. The review concentrated on research published in the past 10 years. Keywords used in the search strategy included the following: “bitter taste receptors” OR “TAS2Rs” OR “bitter compounds” OR “phytochemicals” AND “glucose regulation” OR “GLP-1” OR “CCK” OR “postprandial glucose” OR “glucose absorption” OR “glucose metabolism” AND “spices” OR “herbs” OR “bitters” OR “culinary bitterness” OR “dietary interventions” OR “metabolic health.”
SPICES AND HERBS IN TRADITIONAL BITTER PREPARATIONS
The use of spices and herbs predates modern humans, as evident from dental calculus of Neanderthals from El Sidrón cave in northern Spain dated to 50 600-47 300 BCE that contained bitter-tasting dihydroazulene and chamazulene found in yarrow (L.) and chamomile (L.).The same individuals were also heterozygous tasters, because divergent alleles of TAS2R38 were maintained.This, together with a substantial expansion of α-amylasecopy variants in the genomes of early hominids, points to a prominent dietary transition toward increased consumption of plants and storage carbohydrates (tubers, roots, nuts, and grains) outside of rainforest areas.Because many wild plant foods naturally harbor bitter phytochemicals, the increase of carbohydrate loads in human diets also increased the consumption of plants containing bitter phytochemicals. On the other hand, additional exposure of foods to fermentation or heating (Maillard reactions) also generates bitter-tasting substances such as hydrophobic peptides, quinones, furanones, and pyrazines.Partial debittering of plant foods was achieved in the form of cookingor nixtamalization with hot limestones,but it was not until the development of modern crop cultivars and industrial debittering that human diets experienced significant reduction of bitter tastes.Consistent with this knowledge, modern higher-quality diets are intrinsically more bitter, and promoting greater acceptance of bitter flavors could contribute to improved dietary patterns in the general population. Achillea millefolium Matricaria chamomilla AMY1 031 031 031 031 031 031 031 031 031 ,
Inherent bitterness of spices and herbs found its way into many formulations dating back to classical antiquity.Bitter-tasting mithridate and theriaca (also called tiryaq and treacle) remedies in the form of honey electuary typically contained gentian, St. John’s wort, parsley, anise, ginger, and cinnamon in a complex mixture of up to 70 ingredients, as recorded by Celsus and Galen, and targeted the gastrointestinal tract as an antidote to ingested poisons.The importance of consuming bitter herbs was also recognized in many traditional texts (eg, as a choice of[Hebrew, meaning “with bitter herbs they shall eat it”]). This tradition continued in the form of bitter aperitifs or digestifs targeting gastrointestinal health, such as Chartreuse and Bénèdictine (France); amaro, Fernet, and Campari (Italy); Kräuterlikör, Jägermeister, and Underberg (Germany); Appenzeller Alpenbitter (Switzerland); Becherovka (Czechoslovakia); and Angostura and Peychaud’s (Americas), among others. Although their bitter profiles vary, they are typically dominated by gentian, wormwood, angelica, hyssop, anise, caraway, yarrow, bitter orange, and cinchona.Modern research supports the traditional use of these preparations, showing that bitter mixtures can stimulate digestive secretions, modulate gut motility, and affect satiety, as we discuss later in this review. 031 031 031 031 , maror
DIVERSITY OF BITTER PHYTOCHEMICALS IN SPICES AND HERBS
Spices are defined by the US Food and Drug Administration as any “aromatic vegetable substances … whose significant function in food is seasoning”. The term “herbs” is traditionally restricted only to dry aerial parts (leaves and flowers). In modern times, consumption of spices varies from 0.5 g din Europe to 1.8 g din Africa and 2.6-4.4 g din Asia and Latin America for an average adult.Although spices and herbs are traditionally used for their modulation of taste, flavor, color, texture, or food preservation, their bitter compounds contribute not only to the sensory complexity of culinary ingredients but also to their functional roles as chemical defenses in plants.It is plausible, therefore, that many bitter phytochemicals evolved to interact with conserved chemosensory pathways in the mammalian gastrointestinal system, suggesting a co-evolutionary chemical dialogue between plants and animal physiology, particularly in the upper gastrointestinal tract, much like the well-established bitter-signaling crosstalk between the microbiome and the colon. 031 031 031 031 –1 –1 –1
Bitterness is a common sensory property of many spices and herbs.presents a brief and incomplete summary of the distribution of bitter compounds across botanicals, their phytochemical classifications, and known activations of human bitter-taste receptors.The data set highlights a broad distribution of bitter phytochemicals across different plant tissues and chemical classes. Alkaloids are the most common bitter compounds, appearing in barks (quinine), fruits (berberine, piperine), seeds (xylopine, theobromine), and leaves (skimmianine), and activating a wide range of the TAS2Rs. Sesquiterpene lactones, notably in flowers (eg, chamomile), leaves (eg, wormwood), and roots (eg, dandelion, chicory), show strong activation of TAS2R46, suggesting this receptor plays a central role in detecting plant-derived lactones. Some receptors, such as TAS2R14 and TAS2R46, are frequently activated by multiple compound classes, indicating broad ligand specificity. In contrast, receptors like TAS2R2 and TAS2R16 are selectively activated by specific compounds (eg, curcumin and sinigrin, respectively), suggesting narrow functional roles. Certain phytochemicals, like amarogentin and humulone, are effective at very low concentrations, reflecting high receptor sensitivity (Table 1). Table 1 031 031 ,
| Plant tissue | Spice or herb | Bitter principle | Phytochemical group | TAS2R activation (effective concentration, µM) 1 |
|---|---|---|---|---|
| Bark | Cinchona | Quinine | Alkaloids | TAS2R1, 4, 7, 10, 14, 39, 40, 41, 43, 44, 46 (10-1000) |
| Cinnamon | Coumarin | Coumarins | TAS2R10,14 (300) | |
| Quassia | Quassin | Triterpene lactones | TAS2R4, 10, 14, 30, 46, 47 (300) | |
| Flowers | Chamomile | Nobilin | Sesquiterpene lactones | TAS2R46 (0.1) |
| Clove | Gallic acid | Gallotannins | TAS2R4, 14 (0.2-220) | |
| Hops | Humulone | α Acids | TAS2R1, 14, 40, 47 (0.01-30) | |
| Saffron | Picrocrocin | Monoterpene glycosides | Unknown (22) | |
| Fruits | Barberry | Berberine | Alkaloids | TAS2R38, 46 (10) |
| Bitter orange (also called chenpi) | Naringin | Flavanone glycosides | Unknown (10-220) | |
| Pepper, black | Piperine | Alkaloids | TAS2R14 (10) | |
| Leaves | Basil, oregano | Rosmarinic acid | Caffeic acid esters | Unknown (103) |
| Parsley | Apigenin | Flavone glycosides | TAS2R14, 39, 43 (1-30) | |
| Rosemary, sage | Carnosic acid | Diterpenes | Unknown | |
| Rue (ruta) | Skimmianine | Alkaloids | TAS2R14 | |
| Wormwood | Absinthin | Sesquiterpene lactones | TAS2R10, 14, 46, 47 (0.1-100) | |
| Roots | Angelica | Furanocoumarins | Furanocoumarins | TAS2R10, 14, 49 |
| Rhizomes | Chicory | Lactucopicrin | Sesquiterpene lactones | TAS2R43, 46 |
| Dandelion | Taraxacin | Sesquiterpene lactones | TAS2R46 (0.1-100) | |
| Gentian | Amarogentin | Secoiridoid glycosides | TAS2R1, 4, 39, 43, 46, 47, 50 (3-300) | |
| Turmeric | Curcumin | Curcuminoid | TAS2R2 | |
| Seeds | Cacao | Theobromine | Alkaloids | TAS2R14 (1000) |
| Celery | Butylphthalide | Phthalide lactones | Unknown | |
| Fenugreek | Diosgenin | Saponins | Unknown | |
| Grains of Selim (also called diarr) | Xylopine | Alkaloids | Unknown | |
| Hyssop | Marrubiin | Diterpene lactone | TAS2R46 (0.3) | |
| Mustard | Sinigrin | Glucosinolates | TAS2R16, 38 (100) | |
| Nigella (also called qizha) | Thymoquinone | Quinones | Unknown |
BITTER RECEPTORS FROM A FUNCTIONAL PERSPECTIVE
Classical TAS2Rs in the oral cavity enable a general aversion to the unpleasant bitter taste as an early signal to avoid ingestion of poisonous plants, insects, scavenged animal carcasses, and other spoiled foods.In primates, the number of functional TAS2R genes varies from 18 to 26, whereas humans maintain 25 active TAS2R genes and 8 nonfunctional pseudogenes, all clustered on 3 chromosomes.This clustering is evolutionarily preserved in mammals: mouse mTAS2R genes exist in 3 similar clusters, although some subgroups of the TAS2R genes show a clear tendency for both expansion and contraction.This process may have increased or decreased functional redundancy of bitter-taste perception, as well as allowed for additional new functionality of the broad-specificity human TAS2R10, TAS2R14, TAS2R43, and TAS2R46 genes that also exist as the expanded mTAS2R gene subgroups in mice (). Expansion of TAS2R gene clusters had a clear evolutionary advantage on land: their number peaked at 74 loci in coelacanths, 50-136 loci in anuran frogs, and 36-50 loci in lizards.Yet there was no advantage of TAS2R functionality in the marine environment: birds (penguins) and mammals (cetaceans) that returned to the ocean experienced a near-complete loss of TAS2Rs. 031 031 031 031 Figure 1 031 031 031 , ,
The second notable feature of the TAS2Rs is their spatial distribution. Beyond the classical localization throughout the oral cavity and the increased abundance in its posterior part, where TAS2Rs recognize bitter gustatory stimuli and lingering bitter aftertastes,these receptors can be also found in other tissues exposed to the external environment, such as the respiratory, urinary, and extraoral gastrointestinal systems, where they operate independently of conscious taste. In those locations, they are often associated with the ciliated epithelial cells and contribute to innate immune defenses, production of type 2 immune cytokines IL-4 and IL-13, and prevention of pathogen invasion.Additionally, bitter ligands induce relaxation of smooth muscles in airways,the vascular system,and the gut, where the gastric emptying is also delayed.Many of the blood cells express functional TAS2Rs, including leukocytesand monocytesthat seem to respond to bitter ligands with the chemotactic transmigration. Because blood cells, as well as brain and heart tissues, are not directly exposed to the external environment, there is also a high chance that endogenous TAS2R ligands exist, as has been shown for bile acids (namely, TAS2R1, TAS2R4, TAS2R14, TAS2R39, TAS2R46)and bitter peptides. 031 031 031 031 031 031 031 031 031 031 031 , ,
![Evolutionary relationships between the ortholog human (hTAS2R) and mouse (mTAS2R) bitter-taste receptors, summarized after Hayakawa et aland Lossow et al.Clustering is based on multiple sequence alignment of the individual bitter receptors; their chromosomal localization is color coded. Human TAS2R2, 12 (26), 15, 18, 62, 63, and 64 are not listed, due to nonfunctional pseudogene status. Human TAS2R44 (31), 47 (30), 48 (19, 23), 49 (20), and 50 (51) gene names are synonymous. Human TAS2R5 does not seem to have an ortholog in mice. *Human TAS2Rs with broad specificity. [031] [031]](https://europepmc.org/articles/PMC13201886/bin/nuag031f1.jpg.jpg "Click to view full size")
Evolutionary relationships between the ortholog human (hTAS2R) and mouse (mTAS2R) bitter-taste receptors, summarized after Hayakawa et aland Lossow et al.Clustering is based on multiple sequence alignment of the individual bitter receptors; their chromosomal localization is color coded. Human TAS2R2, 12 (26), 15, 18, 62, 63, and 64 are not listed, due to nonfunctional pseudogene status. Human TAS2R44 (31), 47 (30), 48 (19, 23), 49 (20), and 50 (51) gene names are synonymous. Human TAS2R5 does not seem to have an ortholog in mice. *Human TAS2Rs with broad specificity. [031] [031]
Gastrointestinal Bitter Receptors and Neuroendocrine Regulation
The extraoral distribution of the human TAS2Rs follows several clear trends. Whereas all 25 TAS2Rs are expressed in the oral cavity, the colon tissues do not express a cluster of the related receptors TAS2R7, TAS2R8, and TAS2R9 (mouse ortholog mTAS2R130), as well as 2 receptors with broad specificity: TAS2R16 and TAS2R41 (mouse ubiquitous orthologs mTAS2R143 and mTAS2R126).This abundance of bitter receptors may be driven by higher amounts of microbiota and the microbial bitter ligands at these sites. Finally, 2 TAS2R genes from chromosome 7—TAS2R4 and TAS2R38—are ubiquitously expressed throughout the gut, and this pattern is evolutionally conserved (mouse orthologs mTAS2R108 and mTAS2R138).The ubiquitous gut expression of related TAS2R48 and TAS2R49 is also observed in humans, but not rodents that express mTAS2R143 and mTAS2R126 instead(). 031 031 031 Figure 2
The early connection between TAS2Rs, bitter chemosensing, and metabolic regulation was established when a large number of the TAS2R promoters were reported to contain the binding sites for SREBP-2, indicating that dietary cholesterol levels may modulate intestinal TAS2R expression, although the precise signaling cascade remains to be fully established.TAS2R stimulation of cholecystokinin (CCK) secretion was also enhanced directly by SREBP-2 in cultured cells and in mice.These findings were also extended to glucagon-like peptide-1(GLP-1) in the Amish Family Diabetes Study.The effects on TAS2R gene expression and correlation with GLP-1 increases in response to different classes of bitter plant phytochemicals were confirmed in a preclinical model.The colocalization of TAS2R5 and GLP-1 was also confirmed in human duodenal and ileac tissues.It is likely, therefore, that bitter phytochemicals can engage this established enteroendocrine framework via TAS2R signaling as operating within the canonical ileal brake. 031 031 031 031 031 031
![Expression profile of the bitter taste receptors (TAS2Rs) in the different regions of the human gastrointestinal tract, summarized after Descamps-Solà et al.Human TAS2R44 (31), 47 (30), 48 (19, 23), 49 (20), and 50 (51) gene names are synonymous.*Human TAS2R with broad specificity. ?, no current data availability. [031]](https://europepmc.org/articles/PMC13201886/bin/nuag031f2.jpg.jpg "Click to view full size")
Expression profile of the bitter taste receptors (TAS2Rs) in the different regions of the human gastrointestinal tract, summarized after Descamps-Solà et al.Human TAS2R44 (31), 47 (30), 48 (19, 23), 49 (20), and 50 (51) gene names are synonymous.*Human TAS2R with broad specificity. ?, no current data availability. [031]
Bitter Receptor Activation and Carbohydrate Metabolism in Humans
The multitude of data suggests that beyond the 2 primary functions of the gastrointestinal TAS2R chemoreceptors (ie, recognition of bitter toxins in the upper gut and the bitter signaling crosstalk with microbiome in the distal portions of the tract), they also contribute to the luminal content sensing in the small intestine.More specifically, because plant-based foods are the only sources of both bitter-tasting phytochemicals and carbohydrates in human diets, our earlier studies hypothesized that a particular subset of the gastrointestinal TAS2Rs gained the function to prime or modulate the body carbohydrate metabolism in anticipation of carbohydrate loads associated with bitter plant foods.This can be achieved with a direct inhibition of glucose uptake in the jejunum, where TAS2Rs, the sodium-glucose cotransporter 1, and the fructose transporter SLC2A5 (GLUT5) colocalize,or with a possible indirect effect on the low-affinity basolateral monosaccharide transporter SLC2A2 (GLUT2) that enables sugar transfer from enterocytes into the bloodstream. At the same time, TAS2Rs also colocalize in the gastrointestinal enteroendocrine cells that express and secrete GLP-1,with direct effects on insulin secretion and improved postprandial glucose responses. This hypothesis provides a possible explanation why diverse, unrelated classes of nontoxic bitter phytochemicals rapidly modulate carbohydrate metabolism while not sharing a common chemical structure or pharmacophore.In addition to GLP-1 (22% of the response), the incretin-mediated insulin response is also dependent on the glucose-dependent insulinotropic polypeptide (44% of the response) and glucose itself (33% of the response),suggesting a vast underexplored area of metabolic regulation that could be harnessed for novel dietary interventions. 031 031 031 031 031 031
Cinchona bark (L.) is a bitter spice that yields alkaloid quinine found in a variety of modern drinks, including tonic water, gin cocktails, wine blends (eg, Dubonnet, Malaga Quina, Barolo Chinato), and soft drinks (eg, Irn-Bru, Paso de los Toros, Faxe Kondi). Quinine content in foods is limited to 83 mg Lin the United States and 100 mg Lin Europe.The hypoglycemic effect of quinine is known in association with the treatment of malariaand consuming gin-and-tonic cocktails.Intragastric administration of quinine at 275 and 600 mg to 15 healthy study participants decreased the glycemic response (area under the curve [AUC] = 120) to a nutrient drink by −9% to −14% (= .04) without slowing gastric emptying.Similarly, both intragastric and intraduodenal administration of 600 mg quinine to 14 healthy study participants prior to a nutrient drink decreased peak postprandial blood glucose by −11% to −14% (= .017).These effects were slightly more pronounced in female participants (−23.7%;< .05) and were also associated with increased plasma GLP-1, CCK, C-peptide, and insulin levels. Cinchona officinalis P P P –1 –1 031 031 031 031 031 031
Gentian root (L.) is a bitter herb that contains the secoiridoid glycosides amarogentin and gentiopicrin and is widely used in bitter preparations (eg, Suze, Salers, Aveze, Amaro, Angostura) and soft drinks (eg, Moxie). The aqueous extract of the root was coated with ethylcelluloseto provide 100 mg of secoiridoids to 20 healthy study participants; the result was a 30% decrease in energy intake (= .04), as well as a trend for a higher GLP-1 response.A 1:1:1 mixture of gentian root, cinchona bark, and chicory root in 600 mg capsules was tested in 31 overweight individuals consuming a 40% hypocaloric diet for 90 days. Prolonged satiety occurred, accompanied by a −5.9% decrease in fasting blood glucose (< .01) and −11.4% decrease in body weight (< .0001). Gentiana lutea P P P 031 031 031
Hops flower (L.) is a bitter herb rich in α acids (humulone, α-lupulic acid) commonly used as a bittering agent in beer. The 100 mg and 250 mg capsules containing 51.5% α acids were given to 30 healthy, fasted study participants and resulted in a 10% reduction (< .05) in the self-reported hunger scores.In another study, capsules containing 8-48 mg of isohumulones were given to 94 individuals with prediabetes daily for 4 months and resulted in a −4.6% reduction in fasting blood glucose (< .05) and a −0.3% reduction in hemoglobin A1c (< .01).Similar findings were observed for the model bitter substance, denatonium benzoate, after its intragastric infusion in healthy female study participants. Humulus lupulus P P P 031 031 031
POLYPHENOLS, SMALL PHENOLIC ACID METABOLITES, AND BITTER RECEPTORS
The multitude of studies also point to the fact that bitter polyphenols in herbs and spices can also improve glucose tolerance by stimulating gastrointestinal hormone secretion, although many of the studies focused primarily on coffee chlorogenic acids,tea catechins,and blackcurrant anthocyaninswithout a direct connotation to their interactions with the gastrointestinal bitter receptors. The realization that many polyphenols and their metabolites taste bitter to a certain degree was largely obscured by the fact that this bitterness is highly variable and depends on their glycosylation status, changes in hydroxylation and methylation profiles, as well as the degree of polymerization. At some point, condensation and/or polymerization reactions in polyphenols shift the perception of bitterness toward astringency, which does not depend on direct interactions with bitter receptors but instead relies on formation of stable complexes with proteins that convey a drying or puckering sensation. 031 031 031
This perception has changed in the recent years as the information about interactions of different phenolic compounds with the individual TAS2Rs started to accumulate in cell cultureand preclinical modelsand appeared in databases, such as BitterDB,dedicated to bitter ligands and the associated bitter-taste receptors. It was also used in machine learning–based prediction tools for identifying putative ligand-TAS2R interactions, such as BitterX.The current prediction algorithms routinely achieve 76%-82% accuracy, which allows for the effective modeling of large bitter-compound libraries. 031 031 031 031 031
Anthocyanins
A substantial number of herbs and spices are rich in anthocyanins, including blackcurrants (L.), roselle (L.), kokum (Chois.), and dark varieties of basil (L.) and perilla ((L.) Britton). The parental structures of anthocyanin glucosides had a high potency score for putative activation of up to 11 human TAS2Rs (Table 2). These scores diminished as the parent structures were degraded into small phenolic acids and their metabolites, accompanied by shifts in the predicted TAS2R activation profiles. The final phenolic breakdown products formed immediately prior to mineralizationwere predicted to virtually not be recognized by the human TAS2Rs (). Ribes nigrum Hibiscus sabdariffa Garcinia indica Ocimum basilicum Perilla frutescens 031 Table 2
| hT2R 2 | 1 | 3 | 4 | 5 | 7 | 8 | 9 | 10 3 | 13 | 14 3 | 16 | 38 | 39 | 40 | 41 | 42 | 43 3 | 44 3 | 45 | 46 3 | 47 | 48 | 49 | 50 | 60 | PS 4 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| C-GA | 75 | 73 | 72 | 65 | 57 | 76 | 61 | 67 | 60 | 62 | 57 | 319 | ||||||||||||||
| C-R | 78 | 75 | 65 | 61 | 52 | 69 | 60 | 60 | 57 | 54 | 60 | 304 | ||||||||||||||
| C-G | 75 | 67 | 71 | 65 | 51 | 74 | 60 | 66 | 59 | 61 | 54 | 309 | ||||||||||||||
| C | 62 | 62 | 73 | 78 | 58 | 63 | 95 | |||||||||||||||||||
| CA | 67 | 53 | 71 | 66 | 59 | 63 | ||||||||||||||||||||
| FA | 68 | 54 | 60 | 72 | 70 | 58 | 54 | 122 | ||||||||||||||||||
| DHC | 67 | 53 | 69 | 67 | 53 | 53 | 87 | |||||||||||||||||||
| DHF | 67 | 57 | 69 | 69 | 55 | 56 | 90 | |||||||||||||||||||
| COA | 59 | 69 | 59 | 69 | 41 | |||||||||||||||||||||
| PCA | 57 | 55 | 9 | |||||||||||||||||||||||
| VA | 59 | 57 | 52 | 53 | 35 | |||||||||||||||||||||
| PAA | 68 | 78 | 76 | 66 | 64 | 55 | 58 | 130 | ||||||||||||||||||
| HVA | 64 | 52 | 71 | 66 | 54 | 52 | 86 | |||||||||||||||||||
| HBA | 73 | 53 | 59 | 77 | 69 | 56 | 93 | |||||||||||||||||||
| BA | 72 | 77 | 74 | 68 | 66 | 54 | 99 | |||||||||||||||||||
| PHG | 60 | 51 | 9 | |||||||||||||||||||||||
| PG | 51 | 2 | ||||||||||||||||||||||||
| CAT | 60 | 59 | 60 | 57 | 38 |
Proanthocyanidins
The proanthocyanidins are another group of polyphenols abundant in herbs and spices, particular in cinnamon ((L.) J.Presl) and cocoa powder (L.). However, proanthocyanidins are found in these powders in an average degree of polymerization that ranges from 4 to 10, with monomers and dimers present only at the level of 5%-10% of the mixture. The thresholded weighted potency scores of these compounds suggest they do not interact with TAS2Rs at the level of trimers and above. Similar to anthocyanins, small phenolic metabolites generated from proanthocyanidin breakdown had diminished capacity to activate TAS2Rs (). This observation may explain why large doses of cinnamon are necessary to observe its effects on postprandial glycemia levels in humans (a nonsignificant −36% reduction in AUC of 0-180), and why these observations remain inconsistent among the different studies. Cinnamomum cassia Theobroma cacao Table 3 031
| hT2R 6 | 1 | 3 | 4 | 5 | 7 | 8 | 9 | 10 7 | 13 | 14 7 | 16 | 38 | 39 | 40 | 41 | 42 | 43 7 | 44 7 | 45 | 46 7 | 47 | 48 | 49 | 50 | 60 | PS |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| E1 5 | 0 | |||||||||||||||||||||||||
| D1 5 | 51 | 2 | ||||||||||||||||||||||||
| C1 5 | 0 | |||||||||||||||||||||||||
| B1 | 74 | 77 | 72 | 56 | 74 | 71 | 58 | 63 | 56 | 53 | 57 | 313 | ||||||||||||||
| A1 | 73 | 75 | 69 | 51 | 67 | 63 | 51 | 62 | 61 | 56 | 58 | 302 | ||||||||||||||
| CT | 64 | 59 | 72 | 54 | 72 | 63 | 59 | 124 | ||||||||||||||||||
| ECT | 64 | 58 | 71 | 52 | 73 | 62 | 91 | |||||||||||||||||||
| VAL | 55 | 63 | 63 | 75 | 62 | 59 | 57 | 51 | 155 | |||||||||||||||||
| HAA | 60 | 68 | 52 | 54 | 37 | |||||||||||||||||||||
| EGC | 59 | 57 | 68 | 72 | 55 | 55 | 88 | |||||||||||||||||||
| GCG | 64 | 67 | 71 | 77 | 51 | 65 | 55 | 126 | ||||||||||||||||||
| GA | 93 | 98 | 96 | 87 | 94 | 94 |
Other Phenolic Compounds
Spices and herbs also contain a particularly abundant variety of flavonols (quercetin, kaempferol, myricetin) and flavones (apigenin, luteolin), among flavonoid components. These flavonoids interact with TAS2Rs similar to anthocyanins in that the respective di- and monoglucosides are perceived as more bitter, and their predicted bitterness decreases as these structures are metabolized (). Table 4
Lower postprandial glycemia was confirmed in clinical studies after consumption of fenugreek (L.),amla (L.),basil (L.),and turmeric (Linn.),among others. In combination studies with healthy volunteers who consumed 150 mg of coffee chlorogenic acid and 540 mg of green tea catechols, the acute beneficial effects on postprandial glucose (−5.4%; AUC = 0-240;< .05), insulin, and incretin responses to a high-fat and high-carbohydrate cookie meals were also observed.The TAS2R-related molecular mechanisms behind these effects were also evaluated in cell culture for other glycosylated secondary metabolites, such as steviol glycosides,secoiridoid glycosides,glucosinolates,and sesquiterpene lactones.These findings indicate consuming herbs and spices that contain polyphenols capable of activating TAS2Rs may stimulate the release of incretin hormones from specialized cells in the gastrointestinal tract, trigger insulin secretion, and ultimately reduce postprandial blood glucose levels within a few hours after a meal. Trigonella foenum-graecum Phyllanthus emblica O. tenuiflorum Curcuma longa P 031 031 031 031 031 031 031 031 031
| hT2R 8 | 1 | 3 | 4 | 5 | 7 | 8 | 9 | 10 9 | 13 | 14 9 | 16 | 38 | 39 | 40 | 41 | 42 | 43 9 | 44 9 | 45 | 46 9 | 47 | 48 | 49 | 50 | 60 | PS |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| QR | 78 | 72 | 62 | 52 | 68 | 57 | 53 | 53 | 158 | |||||||||||||||||
| QG | 76 | 64 | 68 | 58 | 72 | 57 | 62 | 53 | 55 | 203 | ||||||||||||||||
| Q | 57 | 66 | 73 | 76 | 55 | 62 | 93 | |||||||||||||||||||
| API | 73 | 71 | 69 | 58 | 52 | 70 | 58 | 62 | 57 | 58 | 57 | 301 | ||||||||||||||
| AG | 54 | 68 | 57 | 75 | 60 | 78 | 59 | 64 | 57 | 206 | ||||||||||||||||
| A | 62 | 57 | 77 | 81 | 61 | 56 | 95 |
REDISCOVERING BITTER IN MODERN DIETS
Consistent with the human studies we have described, both ancestral and modern higher-quality diets are expected to be intrinsically more bitter, because they tend to include a greater diversity of plant-based foods rich in secondary metabolites. Encouraging the consumption of bitter foods or adding the desired bitterness to foods in the form of spices and herbs may help recondition taste preferences, especially in populations habituated to hyperpalatable, highly processed foods.They can be used as a means to re-expose and potentially recalibrate taste preferences in populations accustomed to highly processed foods. Over time, this could contribute to greater dietary variety, improved nutrient density, and enhanced metabolic resilience.Therefore, promoting acceptance of bitterness may be a powerful strategy to shift eating behaviors toward healthier, more sustainable diets. 031 031
This statement also extends to modern cultivars of spices, herbs, and grains that were selectively bred for milder flavors, often at the expense of their original bitter and astringent phytochemical profiles.As a result, many of these cultivars may have reduced concentrations of bioactive compounds that contribute to metabolic health. Reintroducing or preserving the bitter traits of traditional varieties could enhance both the functional and nutritional value of these dietary staples. This is substantiated by observing the rates of glucose uptake in the intestinal cells after exposure to digests from the Agriculture and Food Research Initiative Collaborative Oat Research Enterprise oat worldwide diversity panel with different levels of bitter-tasting secondary metabolites (). 031 Figure 3
These observations imply that the reduction of bitter phytochemicals during crop domestication may have inadvertently diminished natural glucose-regulating mechanisms and adaptive hormonal responses that optimize nutrient handling. An alternative approach to achieve similar dietary effects is incorporating select spices and herbs into foods and beverages as a practical way to reintroduce beneficial bitterness into modern diets. Unlike purified metabolites, spices and herbs deliver these phytochemicals in complex, fiber-rich or oil-based matricesthat facilitate delayed release in the gastrointestinal tract, unless left to cook for a long time. Reintroducing these traditional flavors also aligns with a broader movement toward functional, health-promoting diets. 031
Fluorescent 2-NBDG glucose uptake in the STC-1 intestinal cell model after exposure to aqueous oat digests from the 109 and Food Research Initiative Collaborative Oat Research Enterprise phenotypic oats panel. Cells were incubated with treatments for 2 hours, presented with 2-NBDG for 30 minutes, and fluorescence was quantified at excitation/emission of 465/540 nm.
CONCLUSION
The widespread distribution of TAS2Rs throughout the gastrointestinal tract highlights their multifunctional roles beyond taste, including site-specific effects on nutrient absorption and microbiome interactions. Activation of gastrointestinal TAS2Rs by plant-derived bitter compounds stimulates the release of key hormones such as GLP-1 and CCK, promoting better glucose regulation, insulin secretion, and appetite control. Thus, rediscovering and reintegrating bitter flavors from common spices and herbs into modern diets offer a promising strategy to improve metabolic health and dietary quality. Broadening dietary exposure to bitter phytochemicals could represent a simple yet powerful step toward more resilient and health-promoting food systems.