Volume 38 Issue 2

Identification of the molecular structures of the oropharyngeal taste receptors

Bitter tasting plants are widely used for digestive disorders.^1-4 In 2000, researchers discovered the molecular structures of oropharyngeal taste buds, which changed our understanding of taste perception. Bitter, sweet and umami tastes are detected by G protein coupled receptors (GPCRs): TAS2R is responsible for bitter taste, T1R2+T1R3 for sweet taste, and T1R1+T1R3 for umami taste. The human genome contains one GPCR each for sweet and umami but encodes 25–30 GPCRs for bitter taste.^5,6 Note, besides the term TAS2R, bitter receptors may be referred to as T2R, Tas2R or Tas2r.

Researchers have identified agonists for 26 different TAS2Rs.^7,8 Some compounds can activate multiple TAS2Rs, others just one.⁷ The activation threshold of each TAS2R depends not only on the agonist but also varies between receptors.⁸

Furthermore, physiologically active TAS2Rs have been found throughout the gut,^9-12 as well as in the thyroid,¹³ reproductive tract, respiratory epithelium, urethra, skin, brain, heart, pancreas and blood cells.¹²

Oropharyngeal neural transmission

Within the oropharyngeal cavity, two perceptual systems exist: taste and somatosensory (chemesthesis). Taste identifies and distinguishes between bitter, salty, sour, sweet and umami (savoury) sensations. Chemesthesis involves the sensitivity of mucous membranes to compounds, resulting in the perceptions: irritation, pungency, cooling and warmth. Its receptors are stimulated by piquant substances, tannins, essential oils and ethanol.¹⁴

Both systems involve receptors connected to cranial nerves VI, VII, IX, and X.¹⁵ These nerves synapse in the nucleus tractus solitarius, with secondary neurons relaying information to the gustatory and somatosensory cortices.

The tastes bitter, salt, sour, sweet and umami can be distinguished because the neurons entering the gustatory cortex are dedicated neural pathways. Each taste has a single type of taste receptor, except bitter which has 26 different receptors. Although these 26 TAS2Rs produce a single perception of bitterness, bitter tastants have been reported to elicit a diverse range of cardiovascular responses.^16,17 These findings indicate the presence of multiple parallel neural pathways, perhaps 26, from the oropharyngeal TAS2Rs to the nucleus tractus solitarius, that is dedicated neural pathways. This pattern of signalling, whether partial or complete, retains information from individual TAS2Rs. Secondary neurons merge the signals from all 26 TAS2Rs to become the single sensation of bitterness.¹⁸

Many plants contain agonists of both systems. Aromatic bitters contain bitter compounds and essential oils while glucosinolates are both pungent and bitter.⁷

19th and 20th century paradigms

A new paradigm, based on TAS2Rs, is replacing the earlier paradigm rooted in Pavlov’s early 20th-century research. The 1920 Materia Medica stated: Pawlow’s researches show that the most powerful excitant of the flow of gastric juice is appetite, hence the sight of food which excites appetite excites gastric flow …. many drugs, e.g. bitters and aromatics, increase the gastric flow because they act on the gustatory nerves in the mouth, increasing appetite.¹⁹

In the first edition of Materia Medica (1892), prior to Pavlov’s findings, the impact of bitters on digestion was attributed to gastric nerve stimulation. This reflexly leads to dilatation of the gastric vessels and to an increase in these gastric and salivary secretions. In the stomach, bitters cause a feeling of hunger, an extra secretion of gastric juice, and greater vascular dilation.²⁰ Increased blood flow in the gut following meals is referred as postprandial hyperaemia. When the Pavlov-based paradigm dominated in the 20th century the concept of bitters eliciting postprandial hyperaemia was no longer in fashion.

Regarding bitters, the 1939 and 1963 (final) editions of Materia Medica claimed the action is entirely on the gustatory nerves and results in increased flow of saliva and gastric juice. If introduced into the stomach they have no such effect. The simple bitters have no general action. The pharmacological action of bitters in gastric secretions is noticeable in cachectic dogs, but not in healthy dogs. It is for conditions associated with the debility and anorexia that they have proved useful in clinical work.^21,22

Most late 20^th century and early 21^st century authors concur, bitters act by triggering cephalic phase reflex responses in the parasympathetic nerve system, restoring the appetite and boosting well-being.^23-31 These cephalic responses are manifested only when meals are taken and only when digestion is debilitated.

The Austrian herbalist Rudolf Weiss disagreed, when bitters enter the gut muscle as well as nerve functions are stimulated. The appetite-inducing action of bitters is probable due to improved circulation in the abdominal organs. A bitter principle will powerfully stimulate gastric juice secretion. More importantly, bitters have a general tonic action … they increase the excitability of the sympathetic nervous system.³²

Some authors proposed that bitters elicited both cephalic and gut responses.^33,34 The European Medical Agency (EMA) report on gentian (Gentiana lutea) concluded pharmacological studies, in vitro and in vivo, indicate the stimulation of the gustatory nerves in the mouth and stimulating effects on the gastric, intestinal and biliary secretion. The specific mechanism of the mode of action of bitters is not finally known. Additionally, the data of an observational study [Wegner 1998] support the traditional use of the encapsulated bitters and show that the reflex effect stimulating the gustatory nerves in the mouth is not the only mechanism of action for bitters.³⁴

Dose recommendation discrepancies

One text recommends that dosage should be enough to promote a strong taste of bitterness … typically 5 to 10 drops of the 1:5 tincture … in 20ml water … 15 minutes before meals…and sipped slowly.²⁸ Table 1 lists the British Herbal Pharmacopoeia (BHP)³⁵ and EMA monograph single dose recommendations. Fluid preparations of gentian³⁶ and wormwood (Artemisia absinthium),³⁷ are prescribed 30 minutes before meals, for the temporary loss of appetite and after meals for mild dyspeptic/gastrointestinal disorders. Another bitter, hops (Humulus lupulus), is indicated for stress and sleep disorders.^{35, 38}

 

Table 1. European Medical Agency and British Herbal Pharmacopoeia recommended single dosages for preparations of gentian, wormwood and hops.

 

The BHP and EMA doses are inconsistent: tinctures and fluid extracts are given at similar doses. Additionally, a 2g infusion/decoction contains 40 times more plant material than the recommendation of 5 drops of a 1:5 tincture (0.05g).²⁸

Post-prandial hyperaemia

The effect of bitters on the autonomic system is usually attributed to vagal activation. This perspective is supported by research³⁹ presented in Rational Phytotherapy.⁴⁰ This study reported that bitters elicited reductions in heart rate and cardiac stroke volume. However, the statistical analysis was flawed, changes from baseline were analysed rather than comparisons of pre- and post-ingestion differences with water (control). A reassessment reported that the addition of bitters to water elicited no additional cardiac responses.⁴¹

Conceptually, the proposal that bitters elicit a decrease in blood circulation is inconsistent with digestive physiology. The cardiovascular system responds to feeding in two distinctly different phases. During anticipation and ingestion of food, cardiac output, heart rate, aortic pressure, and vascular resistance in various vascular beds are altered in a pattern that mimics an increase in sympathetic neural activity…Within 5–30 minutes after a meal, all cardiovascular responses to feeding subside except that blood flow to the digestive organs increases, while that to skeletal muscle decreases in resting animals.⁴²

Increased blood flow in the coeliac artery following food or drink consumption, known as postprandial hyperaemia, is essential for gastric accommodation. Gastric accommodation involves increased blood flow through the stomach wall musculature, to support the weight and volume of the ingested items and to bring them to body temperature. Gastric accommodation continues for approximately 15 minutes after the cessation of eating or drinking. Then, chyme begins to pass into the duodenum, referred to as gastric emptying,⁴³ which may continue for five hours or more.⁴⁴ During this intestinal phase of digestion, blood flow increases in the superior mesenteric artery, rising from fasting values of 500mL up to 1400mL per minute.⁴³ Postprandial hyperaemia is necessary for the production and release of the digestive juices, gut motility, absorption and removal of nutrients, and removal of metabolic wastes generated during the digestive processes.

During postprandial hyperaemia, blood is diverted from the systemic circulation to the splanchnic arteries, which can lower blood pressure—a condition known as postprandial hypotension. To compensate, heart rate, stroke volume and cardiac output increase, yet blood pressure and peripheral resistance may still drop, even in healthy young adults.⁴⁵ In older adults, these compensatory mechanisms may fail, producing the symptoms: reduced appetite, meal avoidance, indigestion, headaches, nausea, fainting, falls, strokes and heart attacks. For elderly individuals and diabetics, eating poses cardiovascular risks and is linked to increased morbidity and mortality.^46,47

Bitters elicit cephalic phase responses in the cardiovascular system

Bitter tastants trigger cephalic phase cardiovascular responses in healthy adults without food intake. Fluid extracts of gentian (0.5g and 1.5g) and wormwood (1.5g) increase peripheral resistance,¹⁷ which acts to maintain systemic blood pressure. Notably, increases in peripheral resistance do not cause increased blood pressure because the baroreflex lowers heart rate to maintain pressure levels at the set-point.⁴⁸ Gentian and wormwood can help prevent postprandial hypotension by stabilising blood pressure and reducing cardiac workload.

At physiological doses bitter-tasting regular coffee (Coffea arabica) increases heart rate for at least 30 minutes, whereas the bitter quinides found in decaffeinated coffee do not elicit cardiovascular responses.⁴⁹ Caffeine added to decaffeinated coffee also increases heart rate.⁵⁰ Although a higher heart rate may result from either increased sympathetic activity or reduced vagal tone, the absence of changes in three sympathetically controlled parameters—cardiac contraction force, arterial compliance, and peripheral resistance—suggests that the autonomic response results from vagal withdrawal rather than sympathetic activation.⁴⁹ This mechanism, vagal withdrawal, likely explains why caffeine almost instantly triggers both mental and physiological arousal.

The diverse pattern of cardiovascular responses to different bitters indicates that there are multiple parallel neural pathways, possibly 26 pathways, from the bitter oropharyngeal receptors to the nucleus tractus solitarius of the medulla. At some stage, the secondary neuron pathways to the gustatory cortex merge to produce the single perception of bitterness.¹⁸ Thus, the perception of bitterness does not serve as an indicator for the specific cephalic phase responses triggered by individual bitter tastants. The concept of a “generalised bitter response” is misleading.

Bitters elicits cephalic phase responses in the intestines

Regular coffee elicits a cephalic phase response that increases bowel motility.⁵¹

Bitters in the stomach

Studies using HGT-1 cells, which mimic acid-secreting parietal cells, show that bitter compounds in wine (procyanidin B2, catechin, gallic acid), beer (bitter acids), and coffee (caffeine) stimulate acid secretion.^{10, 52}

Encapsulated caffeine (150mg) increases gastric acid secretion, however when delivered in solution the response is delayed.⁹ Encapsulated caffeine (133mg) reduces arterial compliance and raises diastolic blood pressure, but neither coffee (130mg caffeine) nor caffeine (133mg) in decaf coffee elicit these vascular responses.^49,50 These responses involve vagal signalling from the stomach to the nucleus tractus solitarius. The oropharyngeal response appears to attenuate the subsequent vagal responses elicited from stomach TAS2Rs.⁹

Bitters elicit CCK secretion and impact gastric emptying

The bitter compounds, denatonium benzoate and phenylthiocarbamide, induce CCK release by STC-1 enteroendocrine cells.⁵³ CCK produced by endocrine cells in the upper small intestine align chyme delivery with digestive capacity.⁵⁴

CCK regulates gastric emptying, promotes gallbladder contractions, and stimulates pancreatic enzyme release. It inhibits stomach acid secretion and reduces meal size without affecting satiety between meals.⁵⁵ Postprandial CCK plasma levels peak after 15 minutes and remain elevated for 3–5 hours. The half-life of CCK is 1–2 minutes.⁵⁵

Gastroparesis is caused by delayed stomach emptying, and can cause nausea, vomiting, early fullness, bloating, belching and abdominal pain. About one-third of people with functional dyspepsia have gastroparesis. It can affect eating habits, causing anorexia and weight loss.⁵⁶ Rapid gastric emptying produces similar symptoms, so the two conditions cannot be distinguished based on symptoms.⁵⁷

Gastric emptying accounts for about 35% of the variation in peak postprandial blood glucose in healthy people and type-2 diabetics. Gastric emptying is frequently abnormal in diabetics, with gastroparesis affecting 30–50% of longstanding diabetics.⁵⁷

Drinking coffee, both regular and decaffeinated, increases CCK levels and gallbladder contractions,⁵⁸ but it does not influence the gastric emptying rates.⁵⁹

Hops contain bitter acids which stimulate CCK release in the rat duodenum.⁶⁰ In humans, a 500mg extract of hops (Amarasate), with 51.5% alpha- and 28.3% beta-acids, whether administered intragastrically or intraduodenally, increases plasma CCK and symptoms of nausea, bloating and an urge to vomit. Gastric emptying was not assessed.¹¹ This dose of 4 capsules is four times the EMA recommendation.³⁸ When administered at lower doses (100mg and 250mg) Amarasate has no effect on either CCK or gastric discomfort.⁶¹

When young adults consumed 18mg quinine hydrochloride intraduodenally, 60 minutes before a meal, CCK plasma levels increased and calorie intake decreased without gastric discomfort or delaying gastric emptying.⁶² When young men were administered 600mg of quinine hydrochloride, intragastrically and intraduodenally, the effects were similar: delayed gastric emptying, decreased plasma glucose, increased plasma CCK, insulin and GLP-1, without gastric discomfort.⁶³ For young women, an intraduodenal dose of 600mg increased CCK and delayed gastric emptying, whereas 300mg increased CCK but did not delay gastric emptying.⁶⁴ Administering 300mg intragastrically to young men did not affect gastric emptying.⁶⁵ However, both 300mg and 600mg given intraduodenally delayed gastric emptying in elderly diabetic men.⁶⁶ Since 30–50% of people with chronic diabetes experience gastroparesis,⁵⁷ this strategy for managing postprandial glycaemia may have limited application.

In Parkinson patients, gastric emptying and gastrointestinal symptoms improved after three months administration of the bitter decoction Rikkunshito (Atractylodis lanceae, Poria cocos, Panax ginseng, Pinellia ternata, Zingiber officinale, Citrus reticulata, Ziziphus jujuba, Glycyrrhiza glabra).⁶⁷ A review of 52 studies with 5472 patients found Rikkunshito reduced dyspepsia and increased gastric emptying.⁶⁸ Another review of 10 studies showed the bitter decoction Xiangshaliujun-zi — Astragalus mongholicus, Codonopsis pilosula, Atractylodis macrocephala, Poria cocus, Citrus reticulata, Wurfbania villosa, Ligusticum chuanxiong, Corydalis yanhusuo, Glycyrrhiza glabra and massa medicata fermentata (Persicaria hydropiper, Xanthium sibiricum, Artemisia annua, Prunus armeniaca, Phaseolus calcaratus, Triticum aestivum) —⁶⁹ restored gastric emptying and alleviated diabetic gastroparesis symptoms.⁷⁰ The positive effect of these bitter decoctions in cases of gastroparesis likely stems from increased postprandial hyperaemia rather than stimulation of TAS2Rs in the gut.⁷¹

Other herbs and alcoholic beverages elicit cephalic responses that modulate gastric emptying and may not involve intestinally produced CCK.⁷¹

The emerging TAS2R paradigm

TAS2Rs are functionally active within the oropharyngeal cavity, stomach and small intestine. The autonomic responses elicited by bitter compounds are complex, with individual agonists producing both generalised and characteristic responses. Oral presentations of caffeine increase heart rate,⁴⁹ gentian and wormwood increase peripheral resistance¹⁷ while coffee’s quinides do not elicit cardiovascular responses.⁴⁹

Oral exposure to caffeine alters responses elicited from stomach TAS2Rs^9,49 while solutions containing gentian and wormwood increase both peripheral resistance¹⁷ and gastric acid secretion.⁷²

The hypothesis that bitters elicit responses limited to enhancing vagal activity is not supported, rather bitters elicit a range of autonomic responses. Increased saliva and gastric acid secretions⁷² are associated with vagal activation, whereas increased peripheral resistance indicates increased sympathetic activity.¹⁷ Moreover, caffeine solutions elevate heart rate, an effect attributed to vagal withdrawal rather than augmentation of sympathetic tone.^9,49 Additionally, autonomic responses to bitters differ according to where the TAS2Rs are located.

Some bitters activate one TAS2R, while quinine activates nine.⁷ Tannins, such as gallic acid, stimulate both taste and somatosensory receptors, so bitter plants do not elicit a single uniform response.

The discovery that gentian and wormwood increase peripheral resistance is significant. Furthermore, this effect is independent of food intake. Following a meal, this response promotes postprandial hyperaemia and reduces the load on the heart; however, these benefits are only noticeable when postprandial hyperaemia is inadequate and symptoms are present. This explains why bitters are said to have a positive effect only in cases of digestive weakness.^22,73

The discovery that bitters increase CCK, by stimulating duodenal TAS2Rs, provides a mechanism clarifying how bitters increase gall bladder and pancreatic secretions which previously was attributed to cephalic responses.⁷⁴

The existence of multiple dose-response curves can account for the wide range of recommended doses for gentian, hops and wormwood (Table 1). Doses in the range 50–200mg elicit responses that prime the digestive organs and increase stomach acid,⁷² while doses of 500–1500mg are required to elicit increased peripheral resistance.¹⁷ These curves likely differ between bitters, for example 500mg of gentian elicited increased peripheral resistance whereas 500mg of wormwood did not, even though they have the same bitterness values.⁷⁵ This finding suggests that bitterness values are not directly related to thresholds of TAS2R dose-response curves.

Little is known of the dose-response curves for the stomach and intestinal TAS2Rs or whether vagal transmissions from the gut use labelled-line or across-fibre pathways. Furthermore, it is unclear to what extent bitter agonists elicit paracrine releases.⁷⁶

Although some authors caution that excessive intake of bitters leads to gastric discomfort and nausea,^73,74,77 symptoms associated with gastroparesis,⁵⁶ the EMA monographs^36-38 do not report gastric discomfort and nausea as being an issue, at the recommended doses.

Regarding the timing of administration, gentian and wormwood tinctures taken 5 minutes before meals are sufficient to increase the flows of saliva and gastric acid without affecting gastric emptying.⁷² It is unlikely that this dose increases peripheral resistance, just as it is unlikely that the administration of 1–2g bitter solutions 30 minutes before food will affect peripheral resistance in the postprandial period. Tincture doses may be taken 15–30 minutes before or immediately prior to meals, while 1–2g doses in solution may be taken immediately prior to meals, during or after meals. In cases of dyspepsia or postprandial hypotension, 1–2g doses in solution after meals with additional doses taken as required. Ten minutes should be allowed for capsule disintegration, disintegration time for tablets varies and should be listed on the label.

Some bitters, at physiological doses, activate TAS2Rs in the duodenum eliciting the release of CCK, but it is unclear whether physiological doses produce delayed gastric emptying in humans.

Limitations

The impact of bitters on the autonomic system has only been investigated by a few studies and has involved only several plants. Most investigations have focused on young, healthy adults without digestive issues and the relevance of these findings for target populations is unclear. An individual’s regular diet may influence the microbiota and the expression of TAS2Rs in the gut.⁷⁸ The meal constituents used in studies may also influence outcomes. Additionally, genetic factors influence TAS2R thresholds.⁷⁹ Lastly, it should be kept in mind that some studies lacked placebo controls.^67,72

Conclusion

Modulation of the autonomic nervous system elicited by bitter tastants is more extensive than previously realised. Following the identification of the molecular structures of TAS2Rs, several studies have investigated bitter herbs. These investigations have uncovered novel mechanisms of action, which validate the traditional usage of bitters,⁸⁰ and are consistent with a protective role in the digestive process.⁷³ Such research serves as a foundation for future studies and presents new rationales for treatments, for example, postprandial hypotension and gastroparesis.

Conflict of interest

The author declares no conflicts of interest.

Funding

The author received no funding for this study.

Author(s)

Michael K McMullen PhD
53 rue Blanquerie, 11300 Limoux, France
Email dr.michael.mcmullen@hotmail.se

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