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A New Insight into Bitter Herbs – Kerry Bone

In the past it was thought bitters mainly acted

to stimulate the digestive processes of the

upper gastrointestinal tract by a reflex

initiated from the bitter taste buds on the

tongue. In other words, the interaction of the

bitter tasting phytochemicals in the herb with

receptors on the tongue stimulated nervous

impulses to the brain, which in turn initiated

facilitatory signals via the vagus nerve to the

upper digestive organs, especially the

stomach. Hence, tasting a bitter herb before

eating was essential to its activity and primed

the digestive process by stimulating the

release of gastric acid, digestive enzymes and

bile.

Since then, there have been several important

new discoveries. Firstly, we know much more

about the bitter taste receptors themselves. A

family of around 30 receptors (denoted as

TAS2R, previously T2R) has been identified.i

Most TAS2Rs are broadly tuned to each detect

a range of bitter substances, explaining how

we can recognise hundreds of bitter

compounds with only this limited set of

receptors. Also, some very bitter molecules

simultaneously stimulate more than one

receptor. For example, amarogentin from

gentian stimulates seven receptors: TAS2R1,

4, 39, 43, 46, 47 and 50. Absinthin from

wormwood stimulates four: TAS2R10, 14, 46

and 47.

ii This could explain why herbs like

gentian and wormwood are particularly good

at boosting digestion.

However, the most intriguing new discovery is

that bitter taste receptors are not restricted

to the mouth.iii There are numerous reports

of TAS2Rs being present further down in the

gut in certain cells lining the gastrointestinal

wall, including in the stomach. Cells with

these receptors appear to be wired to elicit an

aversive behavior, probably as a defensive

mechanism because many toxic chemicals are

bitter in taste.i As a result of this defensive

response of the digestive system, bitter taste

receptors in the gastrointestinal tract appear

to upregulate several metabolic and digestive

functions.

In particular, bitter receptors have been found

on enteroendocrine cells, the specialised

hormone-releasing cells of the upper digestive

tract.iv When stimulated, these cells release a

variety of gut hormones, but in particular

cholecystokinin (CCK) and glucagon-like

peptide 1 (GLP-1). CCK has numerous

important functions in the digestive tract: it

promotes secretion of pancreatic enzymes

and bile, slows down stomach emptying,

increases gastric digestive mixing and

For the education of healthcare professionals only

2

secretions, and creates a sense of fullness, so

you stop eating. GLP-1 also slows gastric

emptying and creates a sense of fullness, but

most importantly it stimulates the release of

insulin. In fact, there is a new class of diabetes

drugs (the gliptins) based on enhancing the

action of GLP-1. We now know that bitters

can stimulate the release of these important

hormones from enteroendocrine cells.

The new research above suggests that bitters

can create a sense of fullness (satiety) and

hence might actually help with weight loss.

How does this sit with the traditional notion

that bitters improve appetite? The answer is

there is no contradiction, because bitters only

seem to promote appetite when it is below

par.v

The discovery that bitter receptors occur

throughout the gastrointestinal tract and

appear to regulate a number of physiological

functions has the potential to change our

understanding of bitter herbs. Firstly, it means

that bitter herbs do not need to be tasted to

boost upper digestive function. While tasting

may be desirable for optimum effects, it is not

essential. In fact, clinical research on gentian

dating from 1998vi supports this concept, but

now we understand why. This means that

tablets or capsules containing bitter herbs will

be clinically active, although higher doses are

probably necessary. As noted above, support

for this concept of direct activity in the

stomach also comes from a multicentre,

uncontrolled study of gentian capsules

involving 205 patients.vi Patients took on

average about five capsules per day, each

containing 120 mg of a 5:1 dry extract of

gentian root, and achieved rapid and dramatic

relief of symptoms, including constipation,

flatulence, appetite loss, vomiting, heartburn,

abdominal pain and nausea. As early as 1956,

Wolf and Mack carried out an excellent study

on the direct action of various bitters on the

stomach of their patient Tom (who had an

occluded oesophagus and a gastric fistula),

with golden seal (Hydrastis canadensis)

proving to be the most potent direct-acting

bitter.

vii

Research has shown that the capacity to

sense bitterness varies from person to person.

Some people are highly sensitive and are

known as supertasters. Since the stimulation

of bitter receptors could exert a range of

important health benefits, could people who

have a low sensitivity to bitters be at a health

disadvantage? Epidemiological research

suggests this could be the case. In fact,

functional variants in bitter taste receptor

sensitivity have been linked to alcohol

dependency,viii adiposity,ix eating behavior

disinhibitionx

and high body-mass index

(BMI).

xi People with a lower bitter tasting

sensitivity exhibited the poorer health

measure.

The new research also suggests a role for

bitter herbs in blood sugar control and

managing insulin resistance. In support of this,

94 patients with prediabetes exhibited

improvements in BMI, blood glucose control

and body fat when given just 16 to 48 mg/day

of isohumulones (hop bitter acids) as capsules

in a double blind, placebo-controlled clinical

trial.xii However, it is early days here and

more research is needed.

Blending bitters together will have more

clinical impact, as a wider range of bitter

receptors will be stimulated. This will help to

overcome the genetic variations in a person’s

capacity to taste and respond to bitters. For

example, a combination of gentian,

For the education of healthcare professionals only

3

wormwood and feverfew will stimulate 12 out of the known 29 human bitter taste receptors.

In a sense, with our modern dietary focus on

sweet, sour, savoury and salty foods, bitter

has become the neglected taste. The latest

research provides a compelling argument that

we can all benefit from adding back bitter

herbs and foods into our diet. Perhaps by

including bitterness in our diet we might avoid

bitterness in our life (in terms of physical

health)?

References

i Meyerhof W. Elucidation of mammalian

bitter taste. Rev Physiol Biochem Pharmacol

2005; 154: 37-72

ii Meyerhof W, Batram C, Kuhn C et al. The

molecular receptive ranges of human

TAS2R bitter taste receptors. Chem Senses

2010; 35(2): 157-170

iii Behrens M, Meyerhof W. Gustatory and

extragustatory functions of mammalian taste

receptors. Physiol Behav 2011; 105(1): 4-13

iv Valussi M. Functional foods with digestionenhancing properties. Int J Food Sci Nutr

2012; 63(Suppl 1): 82-89

v Mills SY, Bone KM. Chapter 2: “Principles

of herbal pharmacology” In: Principles and

Practice of Phytotherapy: Modern Herbal

Medicine. 1st Edition, Churchill

Livingstone, Edinburgh, 2000.

vi Wegener T. [Anwendung eines

Trockenextraktes Augentianae luteae radix

bei dyspeptischem Symptomkomplex]. Z

Phytother 1998; 19: 163-164

vii Wolf S, Mack M. Experimental study of the

action of bitters on the stomach of a

fistulous human subject Drug Standards

1956; 24(3): 98-101

viii Wang JC, Hinrichs AL, Bertelsen S et al.

Functional variants in TAS2R38 and

TAS2R16 influence alcohol consumption in

high-risk families of African-American

origin. Alcohol Clin Exp Res 2007; 31(2):

209-215

ix Tepper BJ, Koelliker Y, Zhao L et al.

Variation in the bitter-taste receptor gene

TAS2R38, and adiposity in a genetically

isolated population in Southern Italy.

Obesity (Silver Spring) 2008; 16(10): 2289-

2295

x Dotson CD, Shaw HL, Mitchell BD et al.

Variation in the gene TAS2R38 is

associated with the eating behavior

disinhibition in Old Order Amish women.

Appetite 2010; 54(1): 93-99

xi Feeney E, O'Brien S, Scannell A et al.

Genetic variation in taste perception: does it

have a role in healthy eating? Proc Nutr Soc

2011; 70(1): 135-143

xii Obara K, Mizutani M, Hitomi Y et al.

Isohumulones, the bitter component of beer,

improve hyperglycemia and decrease body

fat in Japanese subjects with prediabetes.

Clin Nutr 2009; 28(3): 278-284

This article, titled "A New Insight into Bitter Herbs," summarizes the updated understanding of how bitter herbs affect the body, moving beyond the traditional belief that they only work by stimulating taste buds on the tongue.

Key Points

• Beyond the Tongue: The most significant new finding is that bitter taste receptors (called TAS2Rs) are not limited to the mouth; they are also found in the stomach and intestines. This means that bitter herbs can have an effect even when consumed in capsule or tablet form, without being tasted.

• A Family of Receptors: Around 30 different bitter receptors have been identified, with each one able to detect a range of bitter substances. This explains how a relatively small number of receptors can recognize so many different bitter compounds.

• Stimulating Gut Hormones: When stimulated, the receptors in the gut trigger enteroendocrine cells to release hormones like cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1).

• Promoting Digestion and Satiety: The release of these hormones has multiple benefits. They:

  • Promote the secretion of pancreatic enzymes and bile.

  • Slow down stomach emptying.

  • Increase digestive mixing and secretions.

  • Create a sense of fullness (satiety), which could potentially aid in weight loss.

• Genetic Variation and Health: The article notes that people's sensitivity to bitterness varies. Individuals with a lower sensitivity to bitter tastes may be at a health disadvantage, with some studies linking this to conditions like alcohol dependency, obesity, and high BMI.

• Clinical Implications: The new research supports the idea that bitter herbs can be effective in tablet form and that blending multiple bitter herbs together can provide a more potent effect by stimulating a wider range of receptors. This could help overcome individual genetic variations in taste sensitivity.

• Blood Sugar Control: Early research also suggests that bitter compounds may play a role in managing blood sugar and insulin resistance.

more

Based on the previous article summary, here is a more detailed look into the key physiological mechanisms and clinical implications of bitter herbs.

The Gut-Brain Connection and the Vagus Nerve

The vagus nerve is the longest and most complex of the cranial nerves, acting as a two-way superhighway between the brain and the digestive system. The original understanding of bitter herbs centered on a vagal reflex:

1. Bitter compounds on the tongue activate taste receptors.

2. A signal is sent via the vagus nerve to the brain.

3. The brain then sends a return signal down the vagus nerve to the stomach, pancreas, and liver.

4. This signal stimulates the release of digestive acids, enzymes, and bile, "priming" the digestive process.

The new research adds a direct, local action to this process. By stimulating receptors directly in the gut, bitter compounds activate cells that release hormones, creating a powerful second layer of communication. This means bitters can influence digestion through both the classic vagal reflex from the mouth and a direct hormonal response in the gut.

Deeper Dive into Gut Hormones: CCK and GLP-1

The article highlights two crucial gut hormones released by enteroendocrine cells in response to bitter compounds:

• Cholecystokinin (CCK): Known as the "satiety hormone," CCK is a key regulator of digestion. It performs several vital functions:

  • Gallbladder Contraction: It stimulates the gallbladder to release bile, which is essential for breaking down fats.

  • Pancreatic Enzyme Release: It causes the pancreas to secrete digestive enzymes (amylase, lipase, and protease) to break down carbohydrates, fats, and proteins.

  • Stomach Emptying: CCK slows down the rate at which food leaves the stomach, prolonging the feeling of fullness and ensuring thorough digestion.

• Glucagon-Like Peptide-1 (GLP-1): This hormone is a major focus in modern medicine, particularly for diabetes and weight management. GLP-1:

  • Stimulates Insulin Secretion: It tells the pancreas to release insulin in a glucose-dependent manner, helping to control blood sugar levels after a meal.

  • Slows Gastric Emptying: Like CCK, it reduces the speed of food moving through the digestive system, contributing to a feeling of fullness.

  • Reduces Appetite: GLP-1 receptors in the brain signal satiety, which can lead to reduced food intake.

This hormonal pathway is why bitters can both improve digestion and promote a sense of fullness, explaining how they can be useful for both stimulating a poor appetite and supporting healthy weight management.

Clinical Takeaways and Modern Applications

The new understanding that bitter herbs act directly in the gut has significant clinical implications:

• Capsule and Tablet Form: Bitter herbs do not need to be tasted to be effective. This validates the use of encapsulated or tableted bitter formulas for patients who dislike the taste or for whom the oral reflex is not sufficient.

• Genetic Variation: Since bitter sensitivity varies from person to person, blending multiple bitter herbs can be a more effective strategy. This approach stimulates a wider range of bitter receptors, increasing the likelihood of a therapeutic response, especially in individuals with low bitter sensitivity.

• Metabolic Health: The link between bitter receptors and the release of GLP-1 suggests a potential new role for bitter herbs in managing insulin resistance and blood sugar control, although more research is needed in this area.

great. please look further into which herbs and bitters have which compounds to react with the bitter receptors

The research on the interaction between specific bitter compounds and TAS2R receptors is a rapidly developing field. While it's complex, a number of key interactions have been identified, confirming that specific bitter phytochemicals activate distinct, and often multiple, receptors.

Here is a breakdown of some of the known relationships between bitter herbs, their active compounds, and the TAS2R receptors they activate.

1. Gentian (Gentiana lutea)

• Compound: Amarogentin and Gentiopicrin

• Receptors: Amarogentin is a particularly potent bitter compound. It has been shown to activate a broad range of receptors, including:

  • TAS2R1

  • TAS2R4

  • TAS2R39

  • TAS2R43

  • TAS2R46

  • TAS2R47

  • TAS2R50

• Significance: The ability of amarogentin to stimulate so many receptors is likely why gentian is considered one of the most effective and powerful bitter tonics for digestion.

2. Wormwood (Artemisia absinthium)

• Compound: Absinthin

• Receptors: Absinthin is a key sesquiterpene lactone that activates a specific set of receptors, including:

  • TAS2R10

  • TAS2R14

  • TAS2R46

  • TAS2R47

• Significance: The activation of TAS2R46 by absinthin is notable, as this receptor has also been found in extra-oral tissues like airway smooth muscle, suggesting a potential broader physiological role beyond just digestion.

3. Rue (Ruta graveolens)

• Compound: Skimmianine and Furanocoumarins

• Receptors:

  • Skimmianine is an alkaloid that acts as a specific agonist for TAS2R14.

  • Furanocoumarins activate a different set of receptors: TAS2R10, TAS2R14, and TAS2R49.

• Significance: This demonstrates how a single plant can contain multiple compounds that interact with a variety of bitter receptors, creating a more comprehensive effect.

4. Other Bitter Compounds and Their Receptors

• Flavonoids: Many flavonoids and isoflavonoids, commonly found in a wide variety of plants, have an undesirable bitter taste. Studies have shown they can activate receptors like TAS2R14 and TAS2R39. For example, (-)-epicatechin activates TAS2R4, TAS2R5, and TAS2R39.

• Quinine: This well-known bitter alkaloid, from cinchona bark, has been shown to interact with multiple receptors, including TAS2R4, TAS2R7, TAS2R10, TAS2R39, and TAS2R46.

• Isohumulones: These hop bitter acids, found in beer, have been shown to improve blood glucose control and decrease body fat in clinical trials, suggesting they act on bitter receptors in the gut to influence metabolic processes, though the specific receptors are still being researched.

perfect. please list actual edible/drinkable forms of these healing bitters and link to tradtional uses

Certainly. The healing properties of these bitters have been used for centuries, often in forms that made their intensely bitter taste palatable. Here are some of the most common edible and drinkable forms, along with their traditional uses.

1. Gentian (Gentiana lutea)

• Edible/Drinkable Forms: Gentian is one of the most widely used bitter roots in the beverage industry. You can find it in:

  • Herbal Tea: A simple infusion of the dried root.

  • Liqueurs and Aperitifs: It is a key ingredient in many European aperitifs and digestive liqueurs, such as Suze, Aperol, and various "Amaros."

  • Bitters: It is a foundational ingredient in cocktail bitters like Angostura Bitters and Peychaud's Bitters.

  • Traditional Schnapps: In the Alps, it is used to make a digestive brandy called "Enzian."

• Traditional Uses:

  • Digestive Aid: Historically, gentian has been a primary remedy for digestive issues, including poor appetite, indigestion, flatulence, and stomach weakness. The bitter compounds were believed to "prime" the digestive system for a meal.

  • Fever Reducer: It was traditionally used to treat fevers and was even used as a substitute for quinine in some cases.

  • General Tonic: In folk medicine, it was seen as a general tonic to strengthen the body and support liver and gallbladder function.

2. Wormwood (Artemisia absinthium)

• Edible/Drinkable Forms:

  • Absinthe: The most famous use of wormwood, this spirit is defined by its characteristic bitter flavor.

  • Vermouth: This fortified wine is flavored with wormwood and other botanicals. The name "vermouth" is derived from the German word for wormwood, Wermut.

  • Teas: Wormwood can be prepared as a strong, bitter tea for medicinal purposes.

  • Tinctures and Capsules: Due to its intense bitterness, it is often consumed in these forms today to avoid the taste.

• Traditional Uses:

  • Antiparasitic: The name "wormwood" comes from its traditional use as an anthelmintic, a remedy to expel intestinal worms.

  • Appetite Stimulant: It was used to stimulate a flagging appetite and treat indigestion.

  • Liver and Gallbladder Support: Like many bitters, it was traditionally used to promote bile flow and support liver health.

3. Rue (Ruta graveolens)

• Edible/Drinkable Forms:

  • Condiment/Spice: The leaves are used sparingly as a seasoning in some traditional Mediterranean and Ethiopian cuisines, particularly in dishes with a strong flavor.

  • Grappa: In Italy, a sprig of rue is sometimes added to bottles of grappa (a type of brandy) to impart a bitter flavor.

  • Herbal Tea: It can be brewed as a tea, though it is consumed with caution due to its potent nature.

• Traditional Uses:

  • Digestive Aid: Rue was historically used for digestive issues, gas, and stomach cramps.

  • Nervous System Support: It was considered a nervine, used to treat nervous headaches, anxiety, and heart palpitations.

  • External Uses: Due to its compounds, it was used topically for skin conditions and inflammation. Historically, it was also used to repel insects.

4. Cinchona Bark (Cinchona officinalis)

• Edible/Drinkable Forms:

  • Tonic Water: The key ingredient is quinine, a bitter compound extracted from cinchona bark. Tonic water was originally created as a way to make quinine palatable for British soldiers in colonial India.

  • Bitter Liqueurs and Aperitifs: It is used as a bittering agent in products like Campari, Barolo Chinato, and some vermouths.

• Traditional Uses:

  • Malaria Treatment: Cinchona bark's most famous and significant traditional use is as a potent antimalarial. Quinine was the first effective treatment for the disease.

  • Fever Reduction: Beyond malaria, it was used for a variety of fevers.

  • Leg Cramps: It was also traditionally used to treat leg cramps and is still sometimes used for this purpose today.

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