Butyric acid (; from grc, βούτῡρον, meaning "butter"), also known under the systematic name butanoic acid, is a straight-chain
alkyl
In organic chemistry, an alkyl group is an alkane missing one hydrogen.
The term ''alkyl'' is intentionally unspecific to include many possible substitutions.
An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloalk ...
carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
with the
chemical formula
In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, ...
CH
3CH
2CH
2CO
2H. It is an oily, colorless liquid with an
unpleasant odor
An odor (American English) or odour (Commonwealth English; see spelling differences) is caused by one or more volatilized chemical compounds that are generally found in low concentrations that humans and animals can perceive via their sense ...
.
Isobutyric acid
Isobutyric acid, also known as 2-methylpropanoic acid or isobutanoic acid, is a carboxylic acid with structural formula ( CH3)2CH COOH. It is an isomer of ''n''- butyric acid. It is classified as a short-chain fatty acid. Deprotonation or esterif ...
(2-methylpropanoic acid) is an
isomer
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
Iso ...
.
Salts
In chemistry, a salt is a chemical compound consisting of an ionic assembly of positively charged cations and negatively charged anions, which results in a compound with no net electric charge. A common example is table salt, with positively cha ...
and
ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
s of butyric acid are known as butyrates or butanoates. The acid does not occur widely in nature, but its esters are widespread. It is a common industrial chemical
and an important component in the mammalian gut.
History
Butyric acid was first observed in impure form in 1814 by the French chemist
Michel Eugène Chevreul
Michel Eugène Chevreul (31 August 1786 – 9 April 1889) was a French chemist and centenarian whose work influenced several areas in science, medicine, and art. His early work with animal fats revolutionized soap and candle manufacturing and led ...
. By 1818, he had purified it sufficiently to characterize it. However, Chevreul did not publish his early research on butyric acid; instead, he deposited his findings in manuscript form with the secretary of the
Academy of Sciences
An academy of sciences is a type of learned society or academy (as special scientific institution) dedicated to sciences that may or may not be state funded. Some state funded academies are tuned into national or royal (in case of the Unite ...
in Paris, France.
Henri Braconnot
Henri Braconnot (29 May 1780 – 13 January 1855) was a French chemist and pharmacist.
He was born in Commercy, his father being a counsel at the local parliament. At the death of his father, in 1787, Henri began his instruction in an elementa ...
, a French chemist, was also researching the composition of butter and was publishing his findings, and this led to disputes about priority. As early as 1815, Chevreul claimed that he had found the substance responsible for the smell of butter. By 1817, he published some of his findings regarding the properties of butyric acid and named it. However, it was not until 1823 that he presented the properties of butyric acid in detail. The name butyric acid comes from grc, βούτῡρον, meaning "butter", the substance in which it was first found. The Latin name ''butyrum'' (or ''buturum'') is similar.
Occurrence
Triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...
s of butyric acid compose 3–4% of butter. When butter goes rancid, butyric acid is liberated from the glyceride by
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
. It is one of the fatty acid subgroup called
short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...
s. Butyric acid is a typical
carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
that reacts with bases and affects many metals.
[ICSC 1334 – Butyric acid](_blank)
Inchem.org (23 November 1998). Retrieved on 2020-10-27.
It is found in
animal fat
Animal fats and oils are lipids derived from animals: oils are liquid at room temperature, and fats are solid. Chemically, both fats and oils are composed of triglycerides. Although many animal parts and secretions may yield oil, in commercial p ...
and
plant oil
Plant oils or vegetable oils are oils derived from plant sources, as opposed to animal fats or petroleum. There are three primary types of plant oil, differing both the means of extracting the relevant parts of the plant, and in the nature of the ...
s,
bovine
Bovines (subfamily Bovinae) comprise a diverse group of 10 genera of medium to large-sized ungulates, including cattle, bison, African buffalo, water buffalos, and the four-horned and spiral-horned antelopes. The evolutionary relationship betwee ...
milk
Milk is a white liquid food produced by the mammary glands of mammals. It is the primary source of nutrition for young mammals (including breastfed human infants) before they are able to digestion, digest solid food. Immune factors and immune ...
,
breast milk
Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...
,
butter
Butter is a dairy product made from the fat and protein components of churned cream. It is a semi-solid emulsion at room temperature, consisting of approximately 80% butterfat. It is used at room temperature as a spread, melted as a condiment ...
,
parmesan cheese
Parmesan ( it, Parmigiano Reggiano; ) is an Italian hard, granular cheese produced from cows’ milk and aged at least 12 months.
It is named after two of the areas which produce it, the provinces
A province is almost always an administrat ...
,
body odor
Body odor or body odour (BO) is present in all animals and its intensity can be influenced by many factors (behavioral patterns, survival strategies). Body odor has a strong genetic basis, but can also be strongly influenced by various diseases ...
,
vomit
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteriti ...
, and as a product of anaerobic
fermentation
Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food ...
(including in the
colon).
It has a
taste
The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste (flavor). Taste is the perception produced or stimulated when a substance in the mouth reacts chemically with taste receptor ...
somewhat like butter and an unpleasant
odor
An odor (American English) or odour (English in the Commonwealth of Nations, Commonwealth English; American and British English spelling differences#-our, -or, see spelling differences) is caused by one or more volatilized chemical compounds ...
.
Mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
s with good scent detection abilities, such as
dog
The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the wolf. Also called the domestic dog, it is derived from the extinct Pleistocene wolf, and the modern wolf is the dog's nearest living relative. Do ...
s, can detect it at 10
parts per billion
In science and engineering, the parts-per notation is a set of pseudo-units to describe small values of miscellaneous dimensionless quantities, e.g. mole fraction or mass fraction. Since these fractions are quantity-per-quantity measures, they ...
, whereas
human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
s can detect it only in concentrations above 10
parts per million
In science and engineering, the parts-per notation is a set of pseudo-units to describe small values of miscellaneous dimensionless quantities, e.g. mole fraction or mass fraction. Since these fractions are quantity-per-quantity measures, they ...
. In
food manufacturing
Food processing is the transformation of agricultural products into food, or of one form of food into other forms. Food processing includes many forms of processing foods, from grinding grain to make raw flour to home cooking to complex ind ...
, it is used as a
flavoring agent
A flavoring (or flavouring), also known as flavor (or flavour) or flavorant, is a food additive used to improve the taste or smell of food. It changes the perceptual impression of food as determined primarily by the chemoreceptors of the gustat ...
.
In humans, butyric acid is one of two primary
endogenous agonist
In pharmacology, an endogenous agonist for a particular receptor is a compound naturally produced by the body which binds to and activates that receptor. For example, the primary endogenous agonist for serotonin receptors is serotonin, and the ...
s of human
hydroxycarboxylic acid receptor 2
Hydroxycarboxylic acid receptor 2 (HCA2), also known as niacin receptor 1 (NIACR1) and GPR109A, is a protein which in humans is encoded by the ''HCAR2'' gene. HCA2, like the other hydroxycarboxylic acid receptors HCA1, HCA1 and HCA3, HCA3, is a Gi ...
(HCA
2), a
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
.
Butyric acid is present as its
octyl ester in
parsnip
The parsnip (''Pastinaca sativa'') is a root vegetable closely related to carrot and parsley, all belonging to the flowering plant family Apiaceae. It is a biennial plant usually grown as an annual. Its long taproot has cream-colored skin an ...
(''Pastinaca sativa'') and in the seed of the
ginkgo tree
''Ginkgo biloba'', commonly known as ginkgo or gingko ( ), also known as the maidenhair tree, is a species of tree native to China. It is the last living species in the order Ginkgoales, which first appeared over 290 million years ago. Fossils ...
.
Production
Industrial
In industry, butyric acid is produced by
hydroformylation
Hydroformylation, also known as oxo synthesis or oxo process, is an industrial process for the production of aldehydes from alkenes. This chemical reaction entails the net addition of a formyl group (CHO) and a hydrogen atom to a carbon-carbon d ...
from
propene
Propylene, also known as propene, is an unsaturated organic compound with the chemical formula CH3CH=CH2. It has one double bond, and is the second simplest member of the alkene class of hydrocarbons. It is a colorless gas with a faint petrole ...
and
syngas
Syngas, or synthesis gas, is a mixture of hydrogen and carbon monoxide, in various ratios. The gas often contains some carbon dioxide and methane. It is principly used for producing ammonia or methanol. Syngas is combustible and can be used as ...
, forming
butyraldehyde
Butyraldehyde, also known as butanal, is an organic compound with the formula CH3(CH2)2CHO. This compound is the aldehyde derivative of butane. It is a colorless flammable liquid with an unpleasant smell. It is miscible with most organic solvents. ...
, which is
oxidised
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
to the final product.
[
:H2 + CO + CH3CH=CH2 → CH3CH2CH2CHO → butyric acid
It can be separated from aqueous solutions by saturation with salts such as ]calcium chloride
Calcium chloride is an inorganic compound, a salt with the chemical formula . It is a white crystalline solid at room temperature, and it is highly soluble in water. It can be created by neutralising hydrochloric acid with calcium hydroxide.
Ca ...
. The calcium salt, Ca(C4H7O2)2·H2O, is less soluble in hot water than in cold.
Microbial biosynthesis
Butyrate is produced by several fermentation processes performed by obligate {{wiktionary, obligate
As an adjective, obligate means "by necessity" (antonym ''facultative'') and is used mainly in biology in phrases such as:
* Obligate aerobe, an organism that cannot survive without oxygen
* Obligate anaerobe, an organism that ...
anaerobic
Anaerobic means "living, active, occurring, or existing in the absence of free oxygen", as opposed to aerobic which means "living, active, or occurring only in the presence of oxygen." Anaerobic may also refer to:
* Anaerobic adhesive, a bonding a ...
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
. This fermentation pathway was discovered by Louis Pasteur
Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist and microbiologist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization, the latter of which was named afte ...
in 1861. Examples of butyrate-producing species
In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate s ...
of bacteria:
*''Clostridium butyricum
''Clostridium butyricum'' is a strictly anaerobic organism, anaerobic endospore-forming Gram-positive butyric acid–producing bacillus subsisting by means of fermentation (biochemistry), fermentation using an intracellularly accumulated amylope ...
''
*''Clostridium kluyveri
''Clostridium kluyveri'' (CLOKL) is an anaerobic, motile, gram-positive bacterium. It is named after the Dutch microbiologist Albert Kluyver
Albert Jan Kluyver ForMemRS (June 3, 1888 – May 14, 1956) was a Dutch microbiologist and biochem ...
''
*''Clostridium pasteurianum
''Clostridium pasteurianum'' (previously known as ''Clostridium pastorianum'') is a bacterium discovered in 1890 by the Russian microbiologist Sergei Winogradsky. It was the first free living (non-symbiotic) micro-organism discovered that could ...
''
*''Faecalibacterium prausnitzii
''Faecalibacterium'' is a genus of bacteria. Its sole known species, ''Faecalibacterium prausnitzii'' is gram-positive, mesophilic, rod-shaped, anaerobic and is one of the most abundant and important commensal bacteria of the human gut microbiota ...
''
*''Fusobacterium nucleatum
''Fusobacterium nucleatum'' is a Gram negative, anaerobic oral bacterium, commensal to the human oral cavity, that plays a role in periodontal disease. This organism is commonly recovered from different monocultured microbial and mixed infection ...
''
*''Butyrivibrio fibrisolvens''
*''Eubacterium limosum''
The pathway starts with the glycolytic
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
cleavage of glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
to two molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
s of pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
, as happens in most organisms. Pyruvate is oxidized
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
into acetyl coenzyme A
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
catalyzed by pyruvate:ferredoxin oxidoreductase. Two molecules of carbon dioxide
Carbon dioxide (chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is transpar ...
(CO2) and two molecules of hydrogen
Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, an ...
(H2) are formed as waste products. Subsequently, is produced in the last step of the fermentation. Three molecules of ATP are produced for each glucose molecule, a relatively high yield. The balanced equation for this fermentation is
:C6H12O6 → C4H8O2 + 2 CO2 + 2 H2
Other pathways to butyrate include succinate reduction and crotonate disproportionation.
Several species form acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscib ...
and ''n''-butanol in an alternative pathway, which starts as butyrate fermentation. Some of these species are:
*''Clostridium acetobutylicum
''Clostridium acetobutylicum'', American Type Culture Collection, ATCC 824, is a commercially valuable bacterium sometimes called the "Weizmann Organism", after Jewish Russian-born biochemist Chaim Weizmann. A senior lecturer at the University o ...
'', the most prominent acetone and butanol producer, used also in industry
*''Clostridium beijerinckii
''Clostridium beijerinckii'' is a gram positive, rod shaped, motile bacterium of the genus ''Clostridium''. It has been isolated from feces and soil. Produces oval to subterminal spores. it is named after Martinus Beijerinck who is a Dutch bacte ...
''
*''Clostridium tetanomorphum
''Clostridium'' is a genus of obligate anaerobe, anaerobic, Gram-positive bacteria. Species of ''Clostridium'' inhabit soils and the intestinal tract of animals, including humans. This genus includes several significant human pathogens, includin ...
''
*''Clostridium aurantibutyricum
''Clostridium aurantibutyricum'' is a species of bacteria in the genus ''Clostridium
''Clostridium'' is a genus of anaerobic, Gram-positive bacteria. Species of ''Clostridium'' inhabit soils and the intestinal tract of animals, including hum ...
''
These bacteria begin with butyrate fermentation, as described above, but, when the pH drops below 5, they switch into butanol and acetone production to prevent further lowering of the pH. Two molecules of butanol are formed for each molecule of acetone.
The change in the pathway occurs after acetoacetyl CoA formation. This intermediate then takes two possible pathways:
*acetoacetyl CoA → acetoacetate → acetone
*acetoacetyl CoA → butyryl CoA → butyraldehyde → butanol
Fermentable fiber sources
Highly-fermentable fiber residues, such as those from resistant starch
Resistant starch (RS) is starch, including its degradation products, that escapes from digestion in the small intestine of healthy individuals. Resistant starch occurs naturally in foods, but it can also be added as part of dried raw foods, or use ...
, oat bran
Bran, also known as miller's bran, is the hard outer layers of cereal grain. It consists of the combined aleurone and pericarp. Corn (maize) bran also includes the pedicel (tip cap). Along with germ, it is an integral part of whole grains, a ...
, pectin
Pectin ( grc, πηκτικός ': "congealed" and "curdled") is a heteropolysaccharide, a structural acid contained in the primary lamella, in the middle lamella, and in the cell walls of terrestrial plants. The principal, chemical component of ...
, and guar
The guar or cluster bean, with the botanical name ''Cyamopsis tetragonoloba'', is an annual legume and the source of guar gum. It is also known as gavar, gawar, or guvar bean.
The origin of ''Cyamopsis tetragonoloba'' is unknown, since it has ...
are transformed by colonic bacteria into short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...
s (SCFA) including butyrate, producing more SCFA than less fermentable fibers such as cellulose
Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of β(1→4) linked D-glucose units. Cellulose is an important structural component of the primary cell wall ...
s. One study found that resistant starch consistently produces more butyrate than other types of dietary fiber
Dietary fiber (in British English fibre) or roughage is the portion of plant-derived food that cannot be completely broken down by human digestive enzymes. Dietary fibers are diverse in chemical composition, and can be grouped generally by the ...
. The production of SCFA from fibers in ruminant
Ruminants (suborder Ruminantia) are ungulate, hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by Enteric fermentation, fermenting it in a specialized stomach prior to digestion, principally ...
animals such as cattle is responsible for the butyrate content of milk and butter.[
Fructans are another source of prebiotic soluble dietary fibers which can be digested to produce butyrate.] They are often found in the soluble fibers of foods which are high in sulfur
Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formula ...
, such as the allium
''Allium'' is a genus of monocotyledonous flowering plants that includes hundreds of species, including the cultivated onion, garlic, scallion, shallot, leek, and chives. The generic name ''Allium'' is the Latin word for garlic,Gledhill, Davi ...
and cruciferous vegetables
Cruciferous vegetables are vegetables of the family Brassicaceae (also called Cruciferae) with many genera, species, and cultivars being raised for food production such as cauliflower, cabbage, kale, garden cress, bok choy, broccoli, Brussels spr ...
. Sources of fructans include wheat
Wheat is a grass widely cultivated for its seed, a cereal grain that is a worldwide staple food. The many species of wheat together make up the genus ''Triticum'' ; the most widely grown is common wheat (''T. aestivum''). The archaeologi ...
(although some wheat strains such as spelt
Spelt (''Triticum spelta''), also known as dinkel wheat or hulled wheat, is a species of wheat that has been cultivated since approximately 5000 BC.
Spelt was an important staple food in parts of Europe from the Bronze Age to medieval times. No ...
contain lower amounts), rye
Rye (''Secale cereale'') is a grass grown extensively as a grain, a cover crop and a forage crop. It is a member of the wheat tribe (Triticeae) and is closely related to both wheat (''Triticum'') and barley (genus ''Hordeum''). Rye grain is u ...
, barley
Barley (''Hordeum vulgare''), a member of the grass family, is a major cereal grain grown in temperate climates globally. It was one of the first cultivated grains, particularly in Eurasia as early as 10,000 years ago. Globally 70% of barley pr ...
, onion
An onion (''Allium cepa'' L., from Latin ''cepa'' meaning "onion"), also known as the bulb onion or common onion, is a vegetable that is the most widely cultivated species of the genus ''Allium''. The shallot is a botanical variety of the onion ...
, garlic
Garlic (''Allium sativum'') is a species of bulbous flowering plant in the genus ''Allium''. Its close relatives include the onion, shallot, leek, chive, Allium fistulosum, Welsh onion and Allium chinense, Chinese onion. It is native to South A ...
, Jerusalem
Jerusalem (; he, יְרוּשָׁלַיִם ; ar, القُدس ) (combining the Biblical and common usage Arabic names); grc, Ἱερουσαλήμ/Ἰεροσόλυμα, Hierousalḗm/Hierosóluma; hy, Երուսաղեմ, Erusałēm. i ...
and globe artichoke
The globe artichoke (''Cynara cardunculus'' var. ''scolymus'' ),Rottenberg, A., and D. Zohary, 1996: "The wild ancestry of the cultivated artichoke." Genet. Res. Crop Evol. 43, 53–58. also known by the names French artichoke and green articho ...
, asparagus
Asparagus, or garden asparagus, folk name sparrow grass, scientific name ''Asparagus officinalis'', is a perennial flowering plant species in the genus ''Asparagus''. Its young shoots are used as a spring vegetable.
It was once classified in ...
, beetroot
The beetroot is the taproot portion of a beet plant, usually known in North America as beets while the vegetable is referred to as beetroot in British English, and also known as the table beet, garden beet, red beet, dinner beet or golden beet ...
, chicory
Common chicory ('' Cichorium intybus'') is a somewhat woody, perennial herbaceous plant of the family Asteraceae, usually with bright blue flowers, rarely white or pink. Native to the Old World, it has been introduced to North America and Austra ...
, dandelion leaves, leek
The leek is a vegetable, a cultivar of ''Allium ampeloprasum'', the broadleaf wild leek ( syn. ''Allium porrum''). The edible part of the plant is a bundle of leaf sheaths that is sometimes erroneously called a stem or stalk. The genus ''Alli ...
, radicchio
Radicchio ( or ; ) is a perennial cultivated form of leaf chicory (''Cichorium intybus'', Asteraceae) sometimes known as Italian chicory because of its common use in Italian cuisine. It is grown as a leaf vegetable and usually has colorful white ...
, the white part of spring onion
Scallions (also known as spring onions or green onions) are vegetables derived from various species in the genus ''Allium''. Scallions generally have a milder taste than most onions and their close relatives include garlic, shallot, leek, chi ...
, broccoli
Broccoli (''Brassica oleracea'' var. ''italica'') is an edible green plant in the cabbage family (family Brassicaceae, genus ''Brassica'') whose large flowering head, stalk and small associated leaves are eaten as a vegetable. Broccoli is cl ...
, brussels sprouts
The Brussels sprout is a member of the Gemmifera cultivar group of cabbages (''Brassica oleracea''), grown for its edible buds. The leaf vegetables are typically 1.5–4.0 cm (0.6–1.6 in) in diameter and resemble miniature cabbages ...
, cabbage
Cabbage, comprising several cultivars of ''Brassica oleracea'', is a leafy green, red (purple), or white (pale green) biennial plant grown as an annual vegetable crop for its dense-leaved heads. It is descended from the wild cabbage ( ''B.&nb ...
, fennel
Fennel (''Foeniculum vulgare'') is a flowering plant species in the carrot family. It is a hardy, perennial herb with yellow flowers and feathery leaves. It is indigenous to the shores of the Mediterranean but has become widely naturalized ...
and prebiotics
Prebiotics are compounds in food that induce the growth or activity of beneficial microorganisms such as bacteria and fungi. The most common example is in the gastrointestinal tract, where prebiotics can alter the composition of organisms in the ...
, such as fructooligosaccharides ( FOS), oligofructose
Fructooligosaccharides (FOS) also sometimes called oligofructose or oligofructan, are oligosaccharide fructans, used as an alternative sweetener. FOS exhibits sweetness levels between 30 and 50 percent of sugar in commercially prepared syrups. It o ...
, and inulin
Inulins are a group of naturally occurring polysaccharides produced by many types of plants, industrially most often extracted from chicory. The inulins belong to a class of dietary fibers known as fructans. Inulin is used by some plants as a mea ...
.
Reactions
Butyric acid reacts as a typical carboxylic acid: it can form amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
, ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
, anhydride
An organic acid anhydride is an acid anhydride that is an organic compound. An acid anhydride is a compound that has two acyl groups bonded to the same oxygen atom. A common type of organic acid anhydride is a carboxylic anhydride, where the pa ...
, and chloride
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
derivatives. The latter, butyryl chloride
Butyryl chloride is an organic compound with the chemical formula CH3CH2CH2C(O)Cl. It is a colorless liquid with a pungent odor. Butyryl chloride is soluble in aprotic organic solvents, but it reacts readily with water and alcohols. It is usual ...
, is commonly used as the intermediate to obtain the others.
Uses
Butyric acid is used in the preparation of various butyrate esters. It is used to produce cellulose acetate butyrate Cellulose acetate butyrate (CAB) is a mixed ester thermoplastic derivative of cellulose acetate that contains both acetate and butyrate
The conjugate acids are in :Carboxylic acids.
{{Commons category, Carboxylate ions, Carboxylate anions
Carbo ...
(CAB), which is used in a wide variety of tools, paints, and coatings, and is more resistant to degradation than cellulose acetate
In biochemistry, cellulose acetate refers to any acetate ester of cellulose, usually cellulose diacetate. It was first prepared in 1865. A bioplastic, cellulose acetate is used as a film base in photography, as a component in some coatings, and ...
. CAB can degrade with exposure to heat and moisture, releasing butyric acid.
Low-molecular-weight esters of butyric acid, such as methyl butyrate
Methyl butyrate, also known under the systematic name methyl butanoate, is the methyl ester of butyric acid. Like most esters, it has a fruity odor, in this case resembling apples or pineapples. At room temperature, it is a colorless liquid with ...
, have mostly pleasant aromas or tastes.[ As a consequence, they are used as food and perfume additives. It is an approved food flavoring in the EU FLAVIS database (number 08.005).
Due to its powerful odor, it has also been used as a fishing bait additive. Many of the commercially available flavors used in ]carp
Carp are various species of oily freshwater fish from the family Cyprinidae, a very large group of fish native to Europe and Asia. While carp is consumed in many parts of the world, they are generally considered an invasive species in parts of ...
(''Cyprinus carpio'') baits use butyric acid as their ester base. It is not clear whether fish are attracted by the butyric acid itself or the substances added to it. Butyric acid was one of the few organic acids shown to be palatable for both tench
The tench or doctor fish (''Tinca tinca'') is a fresh- and brackish-water fish of the order Cypriniformes found throughout Eurasia from Western Europe including the British Isles east into Asia as far as the Ob and Yenisei Rivers. It is also ...
and bitterling
The bitterling-like cyprinids form the cyprinid subfamily Acheilognathinae. This subfamily contains four genera, although the Khanka spiny bitterling is often placed in ''Acheilognathus'', and at least 71 described species to date. Over half of th ...
. The substance has been used as a stink bomb
A stink bomb, sometimes called a stinkpot, is a device designed to create an unpleasant smell. They range in effectiveness from being used as simple pranks to military grade malodorants or riot control chemical agents.
History
A stink bomb ...
by Sea Shepherd Conservation Society
The Sea Shepherd Conservation Society (SSCS) is a non-profit, marine conservation activism organization based in Friday Harbor, Washington, Friday Harbor on San Juan Island, Washington, in the United States. Sea Shepherd employs direct action t ...
to disrupt Japanese whaling
Whaling is the process of hunting of whales for their usable products such as meat and blubber, which can be turned into a type of oil that became increasingly important in the Industrial Revolution.
It was practiced as an organized industry ...
crews.
Pharmacology
Pharmacodynamics
Butyric acid (pKa 4.82) is fully ionized
Ionization, or Ionisation is the process by which an atom or a molecule acquires a negative or positive charge by gaining or losing electrons, often in conjunction with other chemical changes. The resulting electrically charged atom or molecule ...
at physiological pH
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical a ...
, so its anion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
is the material that is mainly relevant in biological systems.
It is one of two primary endogenous agonist
In pharmacology, an endogenous agonist for a particular receptor is a compound naturally produced by the body which binds to and activates that receptor. For example, the primary endogenous agonist for serotonin receptors is serotonin, and the ...
s of human hydroxycarboxylic acid receptor 2
Hydroxycarboxylic acid receptor 2 (HCA2), also known as niacin receptor 1 (NIACR1) and GPR109A, is a protein which in humans is encoded by the ''HCAR2'' gene. HCA2, like the other hydroxycarboxylic acid receptors HCA1, HCA1 and HCA3, HCA3, is a Gi ...
(HCA2, aka GPR109A), a G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
(GPCR),
Like other short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...
s (SCFAs), butyrate is an agonist at the free fatty acid receptor
The free fatty acid receptor is a G-protein coupled receptor which binds free fatty acids. There are four variants of the receptor, each encoded by a separate gene ( FFAR1, FFAR2, FFAR3, FFAR4). Preliminary findings suggest that FFAR2 and FF ...
s FFAR2
Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor encoded by the ''FFAR2'' gene.
Expression
''FFAR2'' mRNA is expressed in adipose tissue, pancreas, spleen, lymph nodes, bone marrow, and peripheral blood mononuclear cells. ''FFAR2 ...
and FFAR3
Free fatty acid receptor 3 (FFA3) is a G-protein coupled receptor that in humans is encoded by the ''FFAR3'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity.. ...
, which function as nutrient sensors that facilitate the homeostatic control of energy balance In biology, energy homeostasis, or the homeostatic control of energy balance, is a biological process that involves the coordinated homeostatic regulation of food intake (energy inflow) and energy expenditure (energy outflow). The human brain, parti ...
; however, among the group of SCFAs, only butyrate is an agonist of HCA2. It is also an HDAC inhibitor
Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases.
HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are be ...
(specifically, HDAC1, HDAC2, HDAC3, and HDAC8), a drug that inhibits the function of histone deacetylase
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
enzymes, thereby favoring an acetylated state of histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
s in cells. Histone acetylation loosens the structure of chromatin
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
by reducing the electrostatic
Electrostatics is a branch of physics that studies electric charges at rest (static electricity).
Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for amber ...
attraction between histones and DNA. In general, it is thought that transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
will be unable to access regions where histones are tightly associated with DNA (i.e., non-acetylated, e.g., heterochromatin). Therefore, butyric acid is thought to enhance the transcriptional activity at promoters, which are typically silenced or downregulated due to histone deacetylase activity.
Pharmacokinetics
Butyrate that is produced in the colon through microbial fermentation of dietary fiber is primarily absorbed and metabolized by colonocytes and the liver for the generation of ATP during energy metabolism; however, some butyrate is absorbed in the distal colon
The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being rem ...
, which is not connected to the portal vein, thereby allowing for the systemic distribution of butyrate to multiple organ systems through the circulatory system. Butyrate that has reached systemic circulation can readily cross the blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
via monocarboxylate transporter The monocarboxylate transporters, or MCTs, are a family of proton-linked
plasma membrane transporters that carry molecules having one carboxylate group (monocarboxylates), such as lactate, pyruvate, and ketones across biological membranes. MCTs ...
s (i.e., certain members of the SLC16A group of transporters). Other transporters that mediate the passage of butyrate across lipid membranes include SLC5A8
Sodium-coupled monocarboxylate transporter 1 is a protein that in humans is encoded by the ''SLC5A8'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." mean ...
(SMCT1), SLC27A1 (FATP1), and SLC27A4
Long-chain fatty acid transport protein 4 is a protein that in humans is encoded by the ''SLC27A4'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ...
(FATP4).
Metabolism
Butyric acid is metabolized by various human XM-ligases (ACSM1, ACSM2B, ASCM3, ACSM4, ACSM5, and ACSM6), also known as butyrate–CoA ligase. The metabolite produced by this reaction is butyryl–CoA
Butyryl-coenzyme A (or butyryl-CoA) is the coenzyme A-containing derivative of butyric acid. It is acted upon by butyryl-CoA dehydrogenase and an intermediary compound of ABE fermentation.
Butyryl-CoA is a precursor to and converted from crotonyl- ...
, and is produced as follows:
:Adenosine triphosphate + butyric acid + coenzyme A → adenosine monophosphate + pyrophosphate + butyryl-CoA
As a short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...
, butyrate is metabolized by mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
as an energy (i.e., adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
or ATP) source through fatty acid metabolism
Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes ...
. In particular, it is an important energy source for cells lining the mammalian colon (colonocytes).[ Without butyrates, colon cells undergo ]autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
(i.e., self-digestion) and die.
In humans, the butyrate precursor tributyrin
Tributyrin is a triglyceride naturally present in butter. It is an ester composed of butyric acid and glycerol. Among other things, it is used as an ingredient in making margarine. It is present in butter and can be described as a liquid fat wi ...
, which is naturally present in butter, is metabolized by triacylglycerol lipase
The enzyme Triacylglycerol lipase (also Triglyceride lipase, EC 3.1.1.3;systematic name triacylglycerol acylhydrolase) catalyses the hydrolysis of ester linkages of triglycerides:
: triacylglycerol + H2O diacylglycerol + a carboxylate
These l ...
into dibutyrin and butyrate through the reaction:
:Tributyrin + H2O → dibutyrin + butyric acid
Biochemistry
Butyrate has numerous effects on energy homeostasis In biology, energy homeostasis, or the homeostatic control of energy balance, is a biological process that involves the coordinated homeostatic regulation of food intake (energy inflow) and energy expenditure (energy outflow). The human brain, parti ...
and related diseases (diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
and obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
), inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, and immune function
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
(e.g., it has pronounced antimicrobial
An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ar ...
and anticarcinogenic An anticarcinogen (also known as a carcinopreventive agent) is a substance that counteracts the effects of a carcinogen or inhibits the development of cancer. Anticarcinogens are different from anticarcinoma agents (also known as anticancer or ant ...
effects) in humans. These effects occur through its metabolism by mitochondria to generate during fatty acid metabolism
Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes ...
or through one or more of its histone-modifying enzyme
Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core hi ...
targets (i.e., the class I histone deacetylases) and G-protein coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...
targets (i.e., FFAR2
Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor encoded by the ''FFAR2'' gene.
Expression
''FFAR2'' mRNA is expressed in adipose tissue, pancreas, spleen, lymph nodes, bone marrow, and peripheral blood mononuclear cells. ''FFAR2 ...
, FFAR3
Free fatty acid receptor 3 (FFA3) is a G-protein coupled receptor that in humans is encoded by the ''FFAR3'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity.. ...
, and HCA2).
In the mammalian gut
Butyrate is essential to host immune homeostasis. Although the role and importance of butyrate in the gut is not fully understood, many researchers argue that a depletion of butyrate-producing bacteria in patients with several vasculitic conditions is essential to the pathogenesis of these disorders. A depletion of butyrate in the gut is typically caused by an absence or depletion of butyrate-producing-bacteria (BPB). This depletion in BPB leads to microbial dysbiosis
Dysbiosis (also called dysbacteriosis) is characterized by a disruption to the microbiome resulting in an imbalance in the microbiota, changes in their functional composition and metabolic activities, or a shift in their local distribution. For ex ...
. This is characterized by an overall low biodiversity and a depletion of key butyrate-producing members. Butyrate is an essential microbial metabolite with a vital role as a modulator of proper immune function in the host. It has been shown that children lacking in BPB are more susceptible to allergic disease and Type 1 Diabetes. Butyrate is also reduced in a diet low in fiber
Fiber or fibre (from la, fibra, links=no) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often incorporate ...
which can induce inflammation and have other adverse affects insofar as these short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...
s activate PPAR-γ.
Butyrate exerts a key role for the maintenance of immune homeostasis both locally (in the gut) and systemically (via circulating butyrate). It has been shown to promote the differentiation of regulatory T cell
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...
s. In particular, circulating butyrate prompts the generation of extrathymic regulatory T cells. The low-levels of butyrate in human subjects could favor reduced regulatory T cell-mediated control, thus promoting a powerful immuno-pathological T-cell response. On the other hand, gut butyrate has been reported to inhibit local pro-inflammatory cytokines. The absence or depletion of these BPB in the gut could therefore be a possible aide in the overly-active inflammatory response. Butyrate in the gut also protects the integrity of the intestinal epithelial barrier. Decreased butyrate levels therefore lead to a damaged or dysfunctional intestinal epithelial barrier.
In a 2013 research study conducted by Furusawa et al., microbe-derived butyrate was found to be essential in inducing the differentiation of colonic regulatory T cells in mice. This is of great importance and possibly relevant to the pathogenesis and vasculitis associated with many inflammatory diseases because regulatory T cells have a central role in the suppression of inflammatory and allergic responses. In several research studies, it has been demonstrated that butyrate induced the differentiation of regulatory T cells in vitro and in vivo. The anti-inflammatory capacity of butyrate has been extensively analyzed and supported by many studies. It has been found that microorganism-produced butyrate expedites the production of regulatory T cells, although the specific mechanism by which it does so unclear. More recently, it has been shown that butyrate plays an essential and direct role in modulating gene expression of cytotoxic T-cells. Butyrate also has an anti-inflammatory effect on neutrophils, reducing their migration to wounds. This effect is mediated via the receptor HCA1
In the gut microbiomes found in the class Mammalia, omnivores and herbivores have butyrate-producing bacterial communities dominated by the butyryl-CoA:acetate CoA-transferase pathway, whereas carnivores have butyrate-producing bacterial communities dominated by the butyrate kinase pathway.
Immunomodulation and inflammation
Butyrate's effects on the immune system are mediated through the inhibition of class I histone deacetylase
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
s and activation of its G-protein coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...
targets: HCA2 (GPR109A), FFAR2
Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor encoded by the ''FFAR2'' gene.
Expression
''FFAR2'' mRNA is expressed in adipose tissue, pancreas, spleen, lymph nodes, bone marrow, and peripheral blood mononuclear cells. ''FFAR2 ...
(GPR43), and FFAR3
Free fatty acid receptor 3 (FFA3) is a G-protein coupled receptor that in humans is encoded by the ''FFAR3'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity.. ...
(GPR41). Among the short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...
s, butyrate is the most potent promoter of intestinal regulatory T cells ''in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' and the only one among the group that is an HCA2 ligand. It has been shown to be a critical mediator of the colonic inflammatory response. It possesses both preventive and therapeutic potential to counteract inflammation-mediated ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...
and colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
.
Butyrate has established antimicrobial properties in humans that are mediated through the antimicrobial peptide
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for an ...
LL-37
Cathelicidin antimicrobial peptide (CAMP) is a polypeptide that is primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes (PMNs); in humans, the ''CAMP'' gene encodes the peptide precursor CAP-18 (18 kDa), which is proce ...
, which it induces via HDAC
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
inhibition on histone H3.
Table 3: Select human antimicrobial peptides and their proposed targets
br
Table 4: Some known factors that induce antimicrobial peptide expression
/ref> In vitro, butyrate increases gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
of FOXP3
FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of reg ...
(the transcription regulator
In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from al ...
for ) and promotes colonic regulatory T cell
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...
s (Tregs) through the inhibition of class I histone deacetylases
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
; through these actions, it increases the expression of interleukin 10
Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti- inflammatory cytokine. In humans, interleukin 10 is encoded by the ''IL10'' gene. IL-10 signals through a receptor complex consisting of two IL-10 ...
, an anti-inflammatory cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
.
Figure 1: Microbial-derived molecules promote colonic Treg differentiation.
/ref> Butyrate also suppresses colonic inflammation by inhibiting the IFN-γ
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
–STAT1
Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family.
Function
All STAT molecules are phosphorylated by receptor associa ...
signaling pathways, which is mediated partially through histone deacetylase inhibition. While transient IFN-γ signaling is generally associated with normal host immune response
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...
, chronic IFN-γ signaling is often associated with chronic inflammation. It has been shown that butyrate inhibits activity of HDAC1 that is bound to the Fas gene promoter in T cells, resulting in hyperacetylation of the Fas promoter and up-regulation of Fas receptor
The Fas receptor, also known as Fas, FasR, apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the ''FAS'' gene. Fas ...
on the T-cell surface.
Similar to other HCA2 agonists studied, butyrate also produces marked anti-inflammatory effects in a variety of tissues, including the brain, gastrointestinal tract, skin, and vascular tissue
Vascular tissue is a complex conducting tissue, formed of more than one cell type, found in vascular plants. The primary components of vascular tissue are the xylem and phloem. These two tissues transport fluid and nutrients internally. There ...
. Butyrate binding at FFAR3 induces neuropeptide Y
Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the ma ...
release and promotes the functional homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
of colonic mucosa and the enteric immune system.
Cancer
Butyrate has been shown to be a critical mediator of the colonic inflammatory response. It is responsible for about 70% of energy from the colonocytes, being a critical SCFA in colon homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
. Butyrate possesses both preventive and therapeutic potential to counteract inflammation-mediated ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...
(UC) and colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
. It produces different effects in healthy and cancerous cells: this is known as the "butyrate paradox". In particular, butyrate inhibits colonic tumor cells and stimulates proliferation of healthy colonic epithelial cells. The explanation why butyrate is an energy source for normal colonocytes and induces apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
in colon cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel mo ...
cells, is the Warburg effect in cancer cells, which leads to butyrate not being properly metabolized. This phenomenon leads to the accumulation of butyrate in the nucleus, acting as a histone deacetylase
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
(HDAC) inhibitor. One mechanism underlying butyrate function in suppression of colonic inflammation is inhibition of the IFN-γ
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
/STAT1
Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family.
Function
All STAT molecules are phosphorylated by receptor associa ...
signalling pathways. It has been shown that butyrate inhibits activity of HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...
that is bound to the Fas gene promoter in T cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
, resulting in hyperacetylation of the Fas promoter and upregulation of Fas receptor on the T cell surface. It is thus suggested that butyrate enhances apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
of T cells in the colonic tissue and thereby eliminates the source of inflammation (IFN-γ production). Butyrate inhibits angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
by inactivating Sp1 transcription factor
Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene.
Function
The protein encoded by this gene is a zinc finger transcription factor that binds to GC-rich motifs of many promote ...
activity and downregulating vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
.
In summary, the production of volatile fatty acids Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...
such as butyrate from fermentable fibers may contribute to the role of dietary fiber in colon cancer. Short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...
s, which include butyric acid, are produced by beneficial colonic bacteria (probiotics
Probiotics are live microorganisms promoted with claims that they provide health benefits when consumed, generally by improving or restoring the gut microbiota. Probiotics are considered generally safe to consume, but may cause bacteria-host i ...
) that feed on, or ferment prebiotics, which are plant products that contain dietary fiber. These short-chain fatty acids benefit the colonocytes by increasing energy production, and may protect against colon cancer by inhibiting cell proliferation.
Conversely, some researchers have sought to eliminate butyrate and consider it a potential cancer driver. Studies in mice indicate it drives transformation of MSH2-deficient colon epithelial cells.
Potential treatments from butyrate restoration
Owing to the importance of butyrate as an inflammatory regulator and immune system contributor, butyrate depletions could be a key factor influencing the pathogenesis of many vasculitic conditions. It is thus essential to maintain healthy levels of butyrate in the gut. Fecal microbiota transplants
Fecal microbiota transplant (FMT), also known as a stool transplant, is the process of transferring fecal bacteria and other microbes from a healthy individual into another individual. FMT is an effective treatment for Clostridioides difficile ...
(to restore BPB and symbiosis
Symbiosis (from Greek , , "living together", from , , "together", and , bíōsis, "living") is any type of a close and long-term biological interaction between two different biological organisms, be it mutualistic, commensalistic, or parasit ...
in the gut) could be effective by replenishing butyrate levels. In this treatment, a healthy individual donates their stool to be transplanted into an individual with dysbiosis. A less-invasive treatment option is the administration of butyrate—as oral supplements or enemas—which has been shown to be very effective in terminating symptoms of inflammation with minimal-to-no side-effects. In a study where patients with ulcerative colitis were treated with butyrate enemas, inflammation decreased significantly, and bleeding ceased completely after butyrate provision.
Addiction
Butyric acid is an inhibitor that is selective for class I HDACs in humans. HDACs are histone-modifying enzyme
Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core hi ...
s that can cause histone deacetylation and repression of gene expression. HDACs are important regulators of synaptic formation, synaptic plasticity
In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuit ...
, and long-term memory
Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to short-term and working memory, which persist for only about 18 to 30 seconds. Long-t ...
formation. Class I HDACs are known to be involved in mediating the development of an addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...
. Butyric acid and other HDAC inhibitors have been used in preclinical research to assess the transcriptional, neural, and behavioral effects of HDAC inhibition in animals addicted to drugs.
Butyrate salts and esters
The butyrate or butanoate ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
, C3 H7C OO−, is the conjugate base
A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...
of butyric acid. It is the form found in biological systems at physiological pH
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical a ...
. A butyric (or butanoic) compound is a carboxylate salt
In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge.
Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylate ...
or ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
of butyric acid.
Examples
Salts
* Sodium butyrate
Sodium butyrate is a compound with formula Na(C3H7COO). It is the sodium salt of butyric acid. It has various effects on cultured mammalian cells including inhibition of proliferation, induction of differentiation and induction or repression of ...
Esters
* Butyl butyrate
Butyl butyrate, or butyl butanoate, is an organic compound that is an ester formed by the condensation of butyric acid and ''n''-butanol. It is a clear, colorless liquid that is insoluble in water, but miscible with ethanol and diethyl ether. It ...
* Butyryl-CoA
Butyryl-coenzyme A (or butyryl-CoA) is the coenzyme A-containing derivative of butyric acid. It is acted upon by butyryl-CoA dehydrogenase and an intermediary compound of ABE fermentation.
Butyryl-CoA is a precursor to and converted from crotonyl- ...
* Cellulose acetate butyrate Cellulose acetate butyrate (CAB) is a mixed ester thermoplastic derivative of cellulose acetate that contains both acetate and butyrate
The conjugate acids are in :Carboxylic acids.
{{Commons category, Carboxylate ions, Carboxylate anions
Carbo ...
(aircraft dope)
* Estradiol benzoate butyrate
Estradiol benzoate butyrate (EBB), sold under the brand names Neolutin N, Redimen, Soluna, and Unijab and formerly known under the developmental code name Unimens, is an estrogen medication which is used in hormonal birth control for women. It is ...
* Ethyl butyrate
Ethyl butyrate, also known as ethyl butanoate, or butyric ether, is an ester with the chemical formula CH3CH2CH2COOCH2CH3. It is soluble in propylene glycol, paraffin oil, and kerosene. It has a fruity odor, similar to pineapple, and is a key in ...
* Methyl butyrate
Methyl butyrate, also known under the systematic name methyl butanoate, is the methyl ester of butyric acid. Like most esters, it has a fruity odor, in this case resembling apples or pineapples. At room temperature, it is a colorless liquid with ...
* Pentyl butyrate
* Tributyrin
Tributyrin is a triglyceride naturally present in butter. It is an ester composed of butyric acid and glycerol. Among other things, it is used as an ingredient in making margarine. It is present in butter and can be described as a liquid fat wi ...
See also
* List of saturated fatty acids
See also
*List of unsaturated fatty acids
*Carboxylic acid
**List of carboxylic acids
*Dicarboxylic acid
{{DEFAULTSORT:List Of Saturated Fatty Acids
Saturated Fatty Acids
A saturated fat is a type of fat in which the fatty acid chains ...
* Histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
** Histone-modifying enzyme
Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core hi ...
*** Histone acetylase
*** Histone deacetylase
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
* Hydroxybutyric acid
Hydroxybutyric acid is a group of four-carbon organic compounds that have both hydroxyl and carboxylic acid functional groups. They can be viewed as derivatives of butyric acid. The carboxylate anion and the esters of hydroxybutyric acids are kno ...
s
** α-Hydroxybutyric acid
2-Hydroxybutyric acid, also known as ''alpha''-hydroxybutyrate and α-hydroxybutyrate, is a hydroxybutyric acid with the hydroxyl group on the carbon adjacent to the carboxyl. It is a chiral compound having two enantiomers, D-2-hydroxybutyric aci ...
** β-Hydroxybutyric acid
β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxyb ...
** γ-Hydroxybutyric acid
''gamma''-Hydroxybutyric acid (or γ-hydroxybutyric acid (GHB), also known as 4-hydroxybutanoic acid) is a naturally occurring neurotransmitter and a depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brain areas. ...
* β-Methylbutyric acid
** β-Hydroxy β-methylbutyric acid
β-Hydroxy β-methylbutyric acid (HMB), otherwise known as its conjugate base, , is a naturally produced substance in humans that is used as a dietary supplement and as an ingredient in certain medical foods that are intended to promote wou ...
Notes
References
External links
NIST Standard Reference Data for butanoic acid
{{DEFAULTSORT:Butyric Acid
GABA analogues
Flavors
Alkanoic acids
Fatty acids
Foul-smelling chemicals
Biomolecules
Histone deacetylase inhibitors