Butyric acid

Butyric acid
Names
IUPAC name
Butanoic acid
Other names
Butyric acid, 1-Propanecarboxylic acid, Propanecarboxylic acid, C4:0 (Lipid numbers)
Identifiers
107-92-6 YesY
ChEBI CHEBI:30772 YesY
ChEMBL ChEMBL14227 YesY
ChemSpider 259 YesY
DrugBank DB03568 YesY
EC Number 203-532-3
1059
Jmol 3D model Interactive image
Interactive image
KEGG C00246 YesY
MeSH Butyric+acid
PubChem 264
RTECS number ES5425000
UNII 40UIR9Q29H YesY
UN number 2820
Properties
C
3H
7COOH
Molar mass 88.11 g·mol−1
Appearance Colorless liquid
Odor Unpleasant and obnoxious
Density 1.135 g/cm3 (−43 °C)[1]
0.9528 g/cm3 (25 °C)[2]
Melting point −5.1 °C (22.8 °F; 268.0 K)[2]
Boiling point 163.75 °C (326.75 °F; 436.90 K)[2]
Sublimes at −35 °C
ΔsublHo = 76 kJ/mol[3]
Miscible
Solubility Slightly soluble in CCl4[4]
Miscible with ethanol, ether
log P 0.79[4]
Vapor pressure 0.112 kPa (20 °C)[5]
0.74 kPa (50 °C)
9.62 kPa (100 °C)[3]
5.35·10−4 L·atm/mol[4]
Acidity (pKa) 4.82[4]
Thermal conductivity 1.46·105 W/m·K
1.398 (20 °C)[2]
Viscosity 1.814 cP (15 °C)[6]
1.426 cP (25 °C)[4]
Structure
Monoclinic (−43 °C)[1]
C2/m[1]
a = 8.01 Å, b = 6.82 Å, c = 10.14 Å[1]
α = 90°, β = 111.45°, γ = 90°
0.93 D (20 °C)[6]
Thermochemistry
178.6 J/mol·K[3][4]
222.2 J/mol·K[6]
−533.9 kJ/mol[3]
2183.5 kJ/mol[3]
Hazards
Safety data sheet External MSDS
GHS pictograms [7]
GHS signal word Danger
H314[7]
P280, P305+351+338, P310[7]
Xn C
R-phrases R20/21/22, R34, R36/37/38
S-phrases S26, S36, S45
NFPA 704
Flammability code 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g., diesel fuel Health code 3: Short exposure could cause serious temporary or residual injury. E.g., chlorine gas Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
2
3
0
Flash point 71 to 72 °C (160 to 162 °F; 344 to 345 K)[5][7]
440 °C (824 °F; 713 K)[7]
Explosive limits 2.2–13.4%[5]
Lethal dose or concentration (LD, LC):
2000 mg/kg (oral, rat)
Related compounds
Other anions
 Butyrate
Propionic acid
Acrylic acid
Succinic acid
Malic acid
Tartaric acid
Crotonic acid
Fumaric acid
Pentanoic acid
Related compounds
 1-Butanol
Butyraldehyde
Methyl butyrate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references

Butyric acid (from Greek βούτῡρον, meaning "butter"), also known under the systematic name butanoic acid, abbreviated BTA,[5] is a carboxylic acid with the structural formula CH3CH2CH2-COOH. Salts and esters of butyric acid are known as butyrates or butanoates. Butyric acid is found in milk, especially goat, sheep and buffalo milk, butter, parmesan cheese, and as a product of anaerobic fermentation (including in the colon and as body odor). It has an unpleasant smell and acrid taste, with a sweetish aftertaste similar to ether. It can be detected by mammals with good scent detection abilities such as dogs at 10 parts per billion, whereas humans can detect it in concentrations above 10 parts per million.

Butyric acid is present in, and is the main distinctive smell of, human vomit.[8]

Butyric acid was first observed in impure form in 1814 by the French chemist Michel Eugène Chevreul. 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 in Paris, France. Henri Braconnot, 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.[9] By 1817, he published some of his findings regarding the properties of butyric acid.[10] However, it was not until 1823 that he presented the properties of butyric acid in detail.[11] The name of butyric acid comes from the Latin word for butter, butyrum (or buturum), the substance in which butyric acid was first found.

Chemistry

Butyric acid is a fatty acid occurring in the form of esters in animal fats. The triglyceride of butyric acid makes up 3–4% of butter. When butter goes rancid, butyric acid is liberated from the glyceride by hydrolysis, leading to the unpleasant odor. It is an important member of the fatty acid subgroup called short-chain fatty acids. Butyric acid is a medium-strong acid that reacts with bases and strong oxidants, and attacks many metals.[12]

The acid is an oily, colorless liquid that is easily soluble in water, ethanol, and ether, and can be separated from an aqueous phase by saturation with salts such as calcium chloride. It is oxidized to carbon dioxide and acetic acid using potassium dichromate and sulfuric acid, while alkaline potassium permanganate oxidizes it to carbon dioxide. The calcium salt, Ca(C4H7O2)2·H2O, is less soluble in hot water than in cold.

Butyric acid has a structural isomer called isobutyric acid (2-methylpropanoic acid).

Safety

Personal protective equipment such as rubber or PVC gloves, protective eye goggles, and chemical-resistant clothing and shoes are used to minimize risks when handling butyric acid.

Inhalation of butyric acid may result in soreness of throat, coughing, a burning sensation, and laboured breathing. Ingestion of the acid may result in abdominal pain, shock, and collapse. Physical exposure to the acid may result in pain, blistering and skin burns, while exposure to the eyes may result in pain, severe deep burns and loss of vision.[12]

Production

It is industrially prepared by the fermentation of sugar or starch, brought about by the addition of putrefying cheese, with calcium carbonate added to neutralize the acids formed in the process. The butyric fermentation of starch is aided by the direct addition of Bacillus subtilis. Salts and esters of the acid are called butyrates or butanoates.

Butyric acid or fermentation butyric acid is also found as a hexyl ester hexyl butyrate in the oil of Heracleum giganteum (a type of hogweed) and as the octyl ester octyl butyrate in parsnip (Pastinaca sativa); it has also been noticed in skin flora and perspiration.

Uses

Butyric acid is used in the preparation of various butyrate esters. Low-molecular-weight esters of butyric acid, such as methyl butyrate, have mostly pleasant aromas or tastes. As a consequence, they are used as food and perfume additives. It is also used as an animal feed supplement due to the ability to reduce pathogenic bacterial colonization.[13] 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.[14] Many of the commercially available flavors used in carp (Cyprinus carpio) baits use butyric acid as their ester base; however, it is not clear whether fish are attracted by the butyric acid itself or the substances added to it. Butyric acid was, however, one of the few organic acids shown to be palatable for both tench and bitterling.[15]

The substance has also been used as a stink bomb by Sea Shepherd Conservation Society to disrupt Japanese whaling crews,[16] as well as by anti-abortion protesters to disrupt abortion clinics.[17]

Biochemistry

Biosynthesis

Butyrate is produced as end-product of a fermentation process solely performed by obligate anaerobic bacteria. Fermented Kombucha "tea" includes butyric acid as a result of the fermentation. This fermentation pathway was discovered by Louis Pasteur in 1861. Examples of butyrate-producing species of bacteria:

The pathway starts with the glycolytic cleavage of glucose to two molecules of pyruvate, as happens in most organisms. Pyruvate is then oxidized into acetyl coenzyme A using a unique mechanism that involves an enzyme system called pyruvate:ferredoxin oxidoreductase. Two molecules of carbon dioxide (CO2) and two molecules of elemental hydrogen (H2) are formed as waste products from the cell. Then,

ActionResponsible enzyme
Acetyl coenzyme A converts into acetoacetyl coenzyme A acetyl-CoA-acetyl transferase
Acetoacetyl coenzyme A converts into β-hydroxybutyryl CoA β-hydroxybutyryl-CoA dehydrogenase
β-hydroxybutyryl CoA converts into crotonyl CoA crotonase
Crotonyl CoA converts into butyryl CoA (CH3CH2CH2C=O-CoA) butyryl CoA dehydrogenase
A phosphate group replaces CoA to form butyryl phosphate phosphobutyrylase
The phosphate group joins ADP to form ATP and butyrate butyrate kinase

ATP is produced, as can be seen, 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.

Several species form acetone and n-butanol in an alternative pathway, which starts as butyrate fermentation. Some of these species are:

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:

Highly-fermentable fiber residues, such as those from resistant starch, oat bran, pectin, and guar are transformed by colonic bacteria into short-chain fatty acids (SCFA) including butyrate, producing more SCFA than less fermentable fibers such as celluloses.[18] One study found that resistant starch consistently produces more butyrate than other types of dietary fiber.[19] The production of SCFA from fibers in ruminant animals such as cattle is responsible for the butyrate content of milk and butter.[20]

Fructans are another source of prebiotic soluble dietary fibers. They are often found in the soluble fibers of foods which are high in sulfur, such as the Allium and Cruciferous vegetables. Sources of fructans include wheat (although some wheat strains such as spelt contain lower amounts),[21] rye, barley, onion, garlic, Jerusalem and globe artichoke, asparagus, beetroot, chicory, dandelion leaves, leek, radicchio, the white part of spring onion, broccoli, brussels sprouts, cabbage, fennel and prebiotics such as fructooligosaccharides (FOS), oligofructose and inulin.[22][23] While many of these foods lack in butyrate production compared to resistant starch, they do have a number of benefits. They generally possess a low glycemic index which appeals well to diabetics. They also appeal to those on the ketogenic diet who benefit from beta-Hydroxybutyric acid, which is a HDAC inhibitor which can cross the blood brain barrier and be used as fuel in the mitochondria of brain cells.[24] Other HDAC inhibitors in these butyrate producing foods are sulforaphane,[25] which has promise in inhibiting human breast cancer cells.[26] Sulforaphane has also been shown to promote hair growth in mice,[27] it contains compounds which prevent ulcers,[28] and helps with cognitive function in rats.[29] It is good to note that sulforaphane in broccoli is destroyed if prepared improperly.[30] Diallyl disulfide found in the fructans containing garlic has been shown to reduce chemical toxicity and carcinogenesis in rodents,[31] and shows synergestic benefits with butyrate when it comes to inhibiting the growth of human cancer tumor cells in the colon.[32]

Pharmacology

Pharmacodynamics

Human enzyme and GPCR binding[33][34]
Inhibited enzyme IC50 (nM) Entry note
HDAC1 16,000
HDAC2 12,000
HDAC3 9,000
HDAC4 2,000,000 Lower bound
HDAC5 2,000,000 Lower bound
HDAC6 2,000,000 Lower bound
HDAC7 2,000,000 Lower bound
HDAC8 15,000
HDAC9 2,000,000 Lower bound
CA1 511,000
CA2 1,032,000
GPCR target pEC50 Entry note
FFAR2 2.9–4.6 Full agonist
FFAR3 3.8–4.9 Full agonist
NIACR1 missing data Full agonist

Like other short chain fatty acids (SCFAs), butyrate is an agonist at the free fatty acid receptors FFAR2 and FFAR3, which function as nutrient sensors which help regulate energy balance; unlike the other SCFAs, butyrate is also an agonist of niacin receptor 1. Butyric acid is also an HDAC inhibitor (specifically, HDAC1, HDAC2, HDAC3, and HDAC8), a drug that inhibits the function of histone deacetylase enzymes, thereby favoring an acetylated state of histones in cells. Acetylated histones have a lower affinity for DNA than nonacetylated histones, due to the neutralization of electrostatic charge interactions. In general, it is thought that transcription factors will be unable to access regions where histones are tightly associated with DNA (i.e., nonacetylated, 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.

Metabolism

Butyric acid is metabolized by various human XM-ligases (ACSM1, ACSM2B, ASCM3, ACSM4, ACSM5, and ACSM6), also known as butyrate–CoA ligase.[8] The metabolite produced by this reaction is butyryl–CoA, and is produced as follows:[8]

Adenosine triphosphate + Butyric acid + Coenzyme A → Adenosine monophosphate + Pyrophosphate + Butyryl-CoA

As a short chain fatty acid, butyrate is utilized by mitochondria as an energy (i.e., adenosine triphosphate or ATP) source through fatty acid metabolism.

In humans, the butyrate prodrug tributyrin is metabolized by triacylglycerol lipase into dibutyrin and butyrate through the reaction:[35]

Tributyrin + H20 = Dibutyrin + Butyrate

Research

Peripheral therapeutic effects

Butyrate is known to have numerous beneficial effects in humans on energy homeostasis and related diseases (diabetes and obesity), inflammation, and immune function (e.g., it has pronounced antimicrobial and anticarcinogenic effects).[36][37] These effects are all known to occur through its utilization by mitochondria to generate ATP during fatty acid metabolism or through one or more of its histone-modifying enzyme targets (i.e., the class I histone deacetylases) and G-protein coupled receptor targets (i.e., FFAR2, FFAR3, and NIACR1).[36]

Immunomodulation and inflammation

Butyrate's effects on the immune system are mediated through the inhibition of class I histone deacetylases and activation of its G-protein coupled receptor targets: NIACR1 (GPR109A), FFAR2 (GPR43), and FFAR3 (GPR41).[38][39] Among the short-chain fatty acids, butyrate is the most potent promoter of intestinal regulatory T cells in vitro and the only one among the group which is an NIACR1 ligand;[39] 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 and colorectal cancer.

Butyrate has established antimicrobial properties in humans which are mediated through the antimicrobial peptide, LL-37, which it induces via HDAC inhibition on histone H3.[38][40][41] Butyrate increases gene expression of FOXP3 (the transcription regulator for Tregs) and promotes colonic Tregs through the inhibition of class I histone deacetylases;[38][39] through these actions, it increases the expression of interleukin 10, an anti-inflammatory cytokine.[38][39] Butyrate also suppresses colonic inflammation by inhibiting the IFN-γ–STAT1 signaling pathways, which is mediated partially through histone deacetylase inhibition. While transient IFN-γ signaling is generally associated with normal host immune response, 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 on the T cell surface.[42] It is thus suggested that Butyrate enhances apoptosis of T cells in the colonic tissue and thereby eliminates the source of inflammation (IFN-γ production).[42]

Similar to other NIACR1 agonists, butyrate also produces marked anti-inflammatory effects in a variety of tissues, including the brain, gastrointestinal tract, skin, and vascular tissue.[43][44][45][46] Butyrate binding at FFAR3 induces neuropeptide Y release and promotes the functional homeostasis of colonic mucosa and the enteric immune system.[47]

Butyric acid is important as an energy (ATP) source for cells lining the mammalian colon (colonocytes). Without butyric acid for energy, colon cells undergo autophagy (i.e., self-digestion).[48]

Cancer

Butyrate produces different effects in healthy and cancerous cells; this is known as the "butyrate paradox". In particular, butyrate inhibits colonic tumor cells and promotes healthy colonic epithelial cells;[49] but the signaling mechanism is not well understood.[50] A review suggested the chemopreventive benefits of butyrate depend in part on amount, time of exposure with respect to the tumorigenic process, and the type of fat in the diet.[18] The production of volatile fatty acids such as butyrate from fermentable fibers may contribute to the role of dietary fiber in colon cancer.[18] Short-chain fatty acids, which include butyric acid, are produced by beneficial colonic bacteria (probiotics) that feed on, or ferment prebiotics, which are plant products that contain adequate amounts of dietary fiber. These short-chain fatty acids benefit the colonocytes (cells of the colon) by increasing energy production and cell proliferation, and may protect against colon cancer.[51]

Conversely, some researchers have sought to eliminate butyrate and consider it a potential cancer driver.[52] Studies in mice indicate it drives transformation of MSH2-deficient colon epithelial cells.[53] It is important to note that these are related to a gene deficiency. Niacin, beta-hydroxybutyrate and curcumin may be effective adjunct treatments if genetic issues are present.[54]

Diabetes

A review on the relationship between the microbiome and diabetes asserted that butyrate can induce "profound immunometabolic effects" in animal models of and humans with type 2 diabetes;[37] it also noted a relationship between the presence of obesity or diabetes and a state of marked dysbiosis in a host, which is not yet completely understood.[37] While acknowledging that there is strong evidence for the use of butyrate in such disorders, the review called for more research into the pathophysiology (i.e., biomolecular mechanisms) of these diseases, so as to improve therapeutic approaches to these diseases.[37]

Neuroepigenetic effects

Addiction

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
The signaling cascade involved in psychostimulant addiction
The image above contains clickable links
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[55][56] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[57][58][59] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[58] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[60] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[61][62] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[61][62]

The observation of large number of downregulated genes after methamphetamine withdrawal is consistent with previous results showing that methamphetamine can cause increased expression of histone deacetylases (HDACs) in the nucleus accumbens and the dorsal striatum. Butyric acid is a HDAC inhibitor.[63] HDACs are enzymes that can cause histone deacetylation and repression of gene expression. HDACs are important regulators of synaptic formation, synaptic plasticity, and long-term memory formation. Several HDACs also appear to play significant roles in various models of drug abuse and addiction.[64] It has been shown that local knockout of HDAC1, as well as chronic and continuous infusion of MS-275, a pharmacological inhibitor highly selective in vitro for HDAC1, in NAc suppressed cocaine-induced locomotor sensitization in mice.[65] HDAC3 inhibitor RGFP966 has been shown to facilitate extinction of cocaine-seeking behavior and prevent reinstatement of cocaine conditioned place preference in mice.[66] Histone deacetylase inhibitors have been shown to decrease cocaine but not sucrose self-administration in rats.[67] The beneficial bacteria which ferment probiotics and prebiotics to produce butyric acid have been shown to regulate behavior by means of the vagus nerve.[68]

Cognitive deficits and memory

Studies in rodents have found that the environment exerts an influence on epigenetic changes related to cognition, in terms of learning and memory;[69] environmental enrichment correlated with increased histone acetylation, and verification by administering histone deacetylase inhibitors induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories.[70][71] Research has also linked learning and long-term memory formation to reversible epigenetic changes in the hippocampus and cortex in animals with normal-functioning, non-damaged brains.[71][72] In human studies, post-mortem brains from Alzheimer's patients show increased histone de-acetylase levels.[73][74]

See also

References

 This article incorporates text from a publication now in the public domain: Chisholm, Hugh, ed. (1911). "Butyric Acid". Encyclopædia Britannica (11th ed.). Cambridge University Press. 

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  36. 1 2 Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I (2015). "Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation". Nutrients 7 (4): 2839–49. doi:10.3390/nu7042839. PMC 4425176. PMID 25875123. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues.
  37. 1 2 3 4 Tilg H, Moschen AR (September 2014). "Microbiota and diabetes: an evolving relationship". Gut 63 (9): 1513–1521. doi:10.1136/gutjnl-2014-306928. PMID 24833634. Recent studies have suggested that gut bacteria play a fundamental role in diseases such as obesity, diabetes and cardiovascular disease. Data are accumulating in animal models and humans suggesting that obesity and type 2 diabetes (T2D) are associated with a profound dysbiosis. First human metagenome-wide association studies demonstrated highly significant correlations of specific intestinal bacteria, certain bacterial genes and respective metabolic pathways with T2D. Importantly, especially butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii concentrations were lower in T2D subjects. This supports the increasing evidence, that butyrate and other short-chain fatty acids are able to exert profound immunometabolic effects.
  38. 1 2 3 4 Wang G (2014). "Human antimicrobial peptides and proteins". Pharmaceuticals (Basel) 7 (5): 545–94. doi:10.3390/ph7050545. PMC 4035769. PMID 24828484. The establishment of a link between light therapy, vitamin D and human cathelicidin LL-37 expression provides a completely different way for infection treatment. Instead of treating patients with traditional antibiotics, doctors may be able to use light or vitamin D [291,292]. Indeed using narrow-band UV B light, the level of vitamin D was increased in psoriasis patients (psoriasis is a common autoimmune disease on skin) [293]. In addition, other small molecules such as butyrate can induce LL-37 expression [294]. Components from Traditional Chinese Medicine may regulate the AMP expression as well [295]. These factors may induce the expression of a single peptide or multiple AMPs [296]. It is also possible that certain factors can work together to induce AMP expression. While cyclic AMP and butyrate synergistically stimulate the expression of chicken β-defensin 9 [297], 4-phenylbutyrate (PBA) and 1,25-dihydroxyvitamin D3 (or lactose) can induce AMP gene expression synergistically [294,298]. It appears that stimulation of LL-37 expression by histone deacetylase (HDAC) inhibitors is cell dependent. Trichostatin and sodium butyrate increased the peptide expression in human NCI-H292 airway epithelial cells but not in the primary cultures of normal nasal epithelial cells [299]. However, the induction of the human LL-37 expression may not be a general approach for bacterial clearance. During Salmonella enterica infection of human monocyte-derived macrophages, LL-37 is neither induced nor required for bacterial clearance [300].
    Table 3: Select human antimicrobial peptides and their proposed targets
    Table 4: Some known factors that induce antimicrobial peptide expression
  39. 1 2 3 4 Hoeppli RE, Wu D, Cook L, Levings MK (February 2015). "The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome". Front Immunol 6: 61. doi:10.3389/fimmu.2015.00061. PMC 4332351. PMID 25741338. Specific species that have been recognized by their high levels of butyrate production include Faecalibacterium prausnitzii and the cluster IV and XIVa of genus Clostridium ... Administration of acetate, propionate, and butyrate in drinking water mimics the effect of Clostridium colonization in germ-free mice, resulting in an elevated Treg frequency in the colonic lamina propria and increased IL-10 production by these Tregs (180, 182). Of the three main SCFAs, butyrate has been found to be the most potent inducer of colonic Tregs. Mice fed a diet enriched in butyrylated starches have more colonic Tregs than those fed a diet containing propinylated or acetylated starches (181). Arpaia et al. tested an array of SCFAs purified from commensal bacteria and confirmed butyrate was the strongest SCFA-inducer of Tregs in vitro (180). Mechanistically, it has been proposed that butyrate, and possibly propionate, promote Tregs through inhibiting histone deacetylase (HDAC), causing increased acetylation of histone H3 in the Foxp3 CNS1 region, and thereby enhancing FOXP3 expression (180, 181). Short-chain fatty acids partially mediate their effects through G-protein coupled receptors (GPR), including GPR41, GPR43, and GPR109A. GPR41 and GPR43 are stimulated by all three major SCFAs (191), whereas GPR109A only interacts with butyrate (192).
    Figure 1: Microbial-derived molecules promote colonic Treg differentiation.
  40. ↑ Yonezawa H, Osaki T, Hanawa T, Kurata S, Zaman C, Woo TD, Takahashi M, Matsubara S, Kawakami H, Ochiai K, Kamiya S (2012). "Destructive effects of butyrate on the cell envelope of Helicobacter pylori". J. Med. Microbiol. 61 (Pt 4): 582–9. doi:10.1099/jmm.0.039040-0. PMID 22194341.
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  43. ↑ Offermanns S, Schwaninger M (2015). "Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation". Trends Mol Med 21 (4): 245–255. doi:10.1016/j.molmed.2015.02.002. PMID 25766751. Neuroinflammatory cells express HCA2, a receptor for the endogenous neuroprotective ketone body β-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation.
  44. ↑ Chai JT, Digby JE, Choudhury RP (May 2013). "GPR109A and vascular inflammation". Curr Atheroscler Rep 15 (5): 325. doi:10.1007/s11883-013-0325-9. PMC 3631117. PMID 23526298. As GPR109A's primary pharmacological ligand in clinical use, niacin has been used for over 50 years in the treatment of cardiovascular disease, mainly due to its favourable effects on plasma lipoproteins. However, it has become apparent that niacin also possesses lipoprotein-independent effects that influence inflammatory pathways mediated through GPR109A.
  45. ↑ Graff EC, Fang H, Wanders D, Judd RL (February 2016). "Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2". Metab. Clin. Exp. 65 (2): 102–113. doi:10.1016/j.metabol.2015.10.001. PMID 26773933. HCA2 is highly expressed on immune cells, including macrophages, monocytes, neutrophils and dermal dendritic cells, among other cell types. ... Recent studies demonstrate that HCA2 mediates profound anti-inflammatory effects in a variety of tissues, indicating that HCA2 may be an important therapeutic target for treating inflammatory disease processes.
  46. ↑ Wakade C, Chong R (December 2014). "A novel treatment target for Parkinson's disease". J. Neurol. Sci. 347 (1-2): 34–38. doi:10.1016/j.jns.2014.10.024. PMID 25455298. GPR109A and its agonists are known to exert anti-inflammatory actions in the skin, gut and retina.
  47. ↑ Farzi A, Reichmann F, Holzer P (2015). "The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour". Acta Physiol (Oxf) 213 (3): 603–27. doi:10.1111/apha.12445. PMC 4353849. PMID 25545642. In the context of this review it is particularly worth noting that short chain fatty acids such as butyrate, which the colonic microbiota generates by fermentation of otherwise indigestible dietary fibre (Cherbut et al. 1998), stimulate L cells to release PYY via the G-protein coupled receptor Gpr41 (Samuel et al. 2008). In this way, short chain fatty acids can indirectly attenuate gastrointestinal motility as well as electrolyte and water secretion (Cox 2007b). More importantly, short chain fatty acids exert homeostatic actions on the function of the colonic mucosa and immune system (Hamer et al. 2008, Tazoe et al. 2008, Guilloteau et al. 2010, Macia et al. 2012a, Smith et al. 2013). Whether PYY plays a role in these effects of short chain fatty acids awaits to be investigated, but may be envisaged from the finding that PYY promotes mucosal cell differentiation (Hallden & Aponte 1997).
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