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Butyric acid
Skeletal structure of butyric acid
Skeletal structure of butyric acid
Flat structure of butyric acid
Flat structure of butyric acid
Space filling model of butyric acid
Space filling model of butyric acid
Names
Preferred IUPAC name
Butanoic acid[1]
Other names
Ethylacetic acid
1-Propanecarboxylic acid
Propylformic acid
C4:0 (Lipid numbers)
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.003.212 Edit this at Wikidata
EC Number
  • Butyric acid: 203-532-3
KEGG
MeSH Butyric+acid
RTECS number
  • Butyric acid: ES5425000
UNII
UN number 2820
  • InChI=1S/C4H8O2/c1-2-3-4(5)6/h2-3H2,1H3,(H,5,6) checkY
    Key: FERIUCNNQQJTOY-UHFFFAOYSA-N checkY
  • Butyric acid: InChI=1/C4H8O2/c1-2-3-4(5)6/h2-3H2,1H3,(H,5,6)
    Key: FERIUCNNQQJTOY-UHFFFAOYAP
  • Butyric acid: O=C(O)CCC
Properties
C
3H
7COOH
Molar mass 88.106 g·mol−1
Appearance Colorless liquid
Odor Unpleasant, similar to vomit or body odor
Density 1.135 g/cm3 (−43 °C)[2]
0.9528 g/cm3 (25 °C)[3]
Melting point −5.1 °C (22.8 °F; 268.0 K)[3]
Boiling point 163.75 °C (326.75 °F; 436.90 K)[3]
Sublimes at −35 °C
ΔsublHo = 76 kJ/mol[4]
Miscible
Solubility Miscible with ethanol, ether. Slightly soluble in CCl4
log P 0.79
Vapor pressure 0.112 kPa (20 °C)
0.74 kPa (50 °C)
9.62 kPa (100 °C)[4]
5.35·10−4 L·atm/mol
Acidity (pKa) 4.82
−55.10·10−6 cm3/mol
Thermal conductivity 1.46·105 W/m·K
1.398 (20 °C)[3]
Viscosity 1.814 cP (15 °C)[5]
1.426 cP (25 °C)
Structure
Monoclinic (−43 °C)[2]
C2/m[2]
a = 8.01 Å, b = 6.82 Å, c = 10.14 Å[2]
α = 90°, β = 111.45°, γ = 90°
0.93 D (20 °C)[5]
Thermochemistry
178.6 J/mol·K[4]
222.2 J/mol·K[5]
−533.9 kJ/mol[4]
2183.5 kJ/mol[4]
Hazards
GHS labelling:
GHS05: Corrosive[6]
Danger
H314[6]
P280, P305+P351+P338, P310[6]
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 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 fuelInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
3
2
0
Flash point 71 to 72 °C (160 to 162 °F; 344 to 345 K)[6]
440 °C (824 °F; 713 K)[6]
Explosive limits 2.2–13.4%
Lethal dose or concentration (LD, LC):
2000 mg/kg (oral, rat)
Safety data sheet (SDS) External MSDS
Related compounds
Propionic 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).

Butyric acid (/bjuːˈtɪrɪk/; from Ancient Greek: βούτῡρον, meaning "butter"), also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula CH3CH2CH2COOH. It is an oily, colorless liquid with an unpleasant odor. Isobutyric acid (2-methylpropanoic acid) is an isomer. Salts and esters 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[7] and an important component in the mammalian gut.

History

[edit]

Butyric acid was first observed in an 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, another 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.[8] By 1817, he published some of his findings regarding the properties of butyric acid and named it.[9] However, it was not until 1823 that he presented the properties of butyric acid in detail.[10] The name butyric acid comes from βούτῡρον, meaning "butter", the substance in which it was first found. The Latin name butyrum (or buturum) is similar.

Occurrence

[edit]

Triglycerides of butyric acid make up 3–4% of butter. When butter goes rancid, butyric acid is liberated from the glyceride by hydrolysis.[11] It is one of the fatty acid subgroup called short-chain fatty acids. Butyric acid is a typical carboxylic acid that reacts with bases and affects many metals.[12] It is found in animal fat and plant oils, bovine milk, breast milk, butter, parmesan cheese, body odor, vomit and as a product of anaerobic fermentation (including in the colon).[13] It has a taste somewhat like butter and an unpleasant odor. Mammals with good scent detection abilities, such as dogs, can detect it at 10 parts per billion, whereas humans can detect it only in concentrations above 10 parts per million. In food manufacturing, it is used as a flavoring agent.[14]

In humans, butyric acid is one of two primary endogenous agonists of human hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor.[15][16]

Butyric acid is present as its octyl ester in parsnip (Pastinaca sativa)[17] and in the seed of the ginkgo tree.[18]

Production

[edit]

Industrial

[edit]

In industry, butyric acid is produced by hydroformylation from propene and syngas, forming butyraldehyde, which is oxidised to the final product.[7]

H2 + CO + CH3CH=CH2 → CH3CH2CH2CHOoxidation→butyric acid

It can be separated from aqueous solutions by saturation with salts such as calcium chloride. The calcium salt, Ca(C4H7O2)2 · H2O, is less soluble in hot water than in cold.

Microbial biosynthesis

[edit]
One pathway for butyrate biosynthesis. Relevant enzymes: acetoacetyl-CoA thiolase, NAD- and NADP-dependent 3-hydroxybutyryl-CoA dehydrogenase, 3-hydroxybutyryl-CoA dehydratase, and NAD-dependent butyryl-CoA dehydrogenase.

Butyrate is produced by several fermentation processes performed by obligate anaerobic bacteria.[19] 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 oxidized into acetyl coenzyme A catalyzed by pyruvate:ferredoxin oxidoreductase. Two molecules of carbon dioxide (CO2) and two molecules of hydrogen (H2) are formed as waste products. Subsequently, ATP 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 + 2CO2 + 2H2

Other pathways to butyrate include succinate reduction and crotonate disproportionation.

Action Responsible 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

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:

  • acetoacetyl CoA → acetoacetate → acetone
  • acetoacetyl CoA → butyryl CoA → butyraldehyde → butanol

For commercial purposes Clostridium species are used preferably for butyric acid or butanol production. The most common species used for probiotics is the Clostridium butyricum.[20]

Fermentable fiber sources

[edit]

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.[13][21] One study found that resistant starch consistently produces more butyrate than other types of dietary fiber.[22] The production of SCFA from fibers in ruminant animals such as cattle is responsible for the butyrate content of milk and butter.[23]

Fructans are another source of prebiotic soluble dietary fibers which can be digested to produce butyrate.[24] 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),[25] 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.[26][27]

Chemical reactions

[edit]

Butyric acid reacts as a typical carboxylic acid: it can form amide, ester, anhydride, and chloride derivatives.[28] The latter, butyryl chloride, is commonly used as the intermediate to obtain the others.

Uses

[edit]

Butyric acid is used in the preparation of various butyrate esters. It is used to produce cellulose acetate butyrate (CAB), which is used in a wide variety of tools, paints, and coatings, and is more resistant to degradation than cellulose acetate.[29] CAB can degrade with exposure to heat and moisture, releasing butyric acid.[30]

Low-molecular-weight esters of butyric acid, such as methyl butyrate, have mostly pleasant aromas or tastes.[7] 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.[31] Many of the commercially available flavors used in carp (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 and bitterling.[32]

The substance has been used as a stink bomb by the Sea Shepherd Conservation Society to disrupt Japanese whaling crews.[33] The Dutch branch of Extinction Rebellion has used it as a chemical agent in a clothing store; several people who became unwell were treated on site by an ambulance crew.[34]

Pharmacology

[edit]
Human enzyme and GPCR binding[35][36]
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
HCA2 2.8 Agonist

Pharmacodynamics

[edit]

Butyric acid (pKa 4.82) is fully ionized at physiological pH, so its anion is the material that is mainly relevant in biological systems. It is one of two primary endogenous agonists of human hydroxycarboxylic acid receptor 2 (HCA2, also known as GPR109A), a Gi/o-coupled G protein-coupled receptor (GPCR),[15][16]

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 that facilitate the homeostatic control of energy balance; however, among the group of SCFAs, only butyrate is an agonist of HCA2.[37][38] It is also an HDAC inhibitor (specifically, HDAC1, HDAC2, HDAC3, and HDAC8),[35][36] a drug that inhibits the function of histone deacetylase enzymes, thereby favoring an acetylated state of histones in cells.[38]

Pharmacokinetics

[edit]

Butyrate that is produced in the colon through microbial fermentation of dietary fiber is primarily absorbed and metabolized by colonocytes and the liver[note 1] for the generation of ATP during energy metabolism; however, some butyrate is absorbed in the distal colon, which is not connected to the portal vein, thereby allowing for the systemic distribution of butyrate to multiple organ systems through the circulatory system.[38][39] Butyrate that has reached systemic circulation can readily cross the blood–brain barrier via monocarboxylate transporters (i.e., certain members of the SLC16A group of transporters).[40][41] Other transporters that mediate the passage of butyrate across lipid membranes include SLC5A8 (SMCT1), SLC27A1 (FATP1), and SLC27A4 (FATP4).[35][41]

Metabolism

[edit]

Butyric acid is metabolized by various human XM-ligases (ACSM1, ACSM2B, ASCM3, ACSM4, ACSM5, and ACSM6), also known as butyrate–CoA ligase.[42][43] The metabolite produced by this reaction is butyryl–CoA, and is produced as follows:[42]

Adenosine triphosphate + butyric acid + coenzyme A → adenosine monophosphate + pyrophosphate + butyryl-CoA

As a short-chain fatty acid, butyrate is metabolized by mitochondria as an energy (i.e., adenosine triphosphate or ATP) source through fatty acid metabolism.[38] In particular, it is an important energy source for cells lining the mammalian colon (colonocytes).[24] Without butyrates, colon cells undergo autophagy (i.e., self-digestion) and die.[44]

In humans, the butyrate precursor tributyrin, which is naturally present in butter, is metabolized by triacylglycerol lipase into dibutyrin and butyrate through the reaction:[45]

Tributyrin + H2O → dibutyrin + butyric acid

Biochemistry

[edit]

Butyrate has numerous effects on energy homeostasis in humans. These effects occur through its metabolism 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 HCA2).[37][46]

Mammalian gut

[edit]

Butyrate is essential to host immune homeostasis.[37] 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. 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[47] and type 1 diabetes.[48] Butyrate is also reduced in a diet low in dietary fiber, which can induce inflammation and have other adverse affects insofar as these short-chain fatty acids activate PPAR-γ.[49]

Decreased butyrate levels lead to a damaged or dysfunctional intestinal epithelial barrier.[50] Butyrate reduction has also been associated with Clostridioides difficile proliferation. Conversely, a high-fiber diet results in higher butyric acid concentration and inhibition of C. difficile growth.[51]

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.[52]

The odor of butyric acid, which emanates from the sebaceous follicles of all mammals, works on ticks as a signal.

Immunomodulation

[edit]

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: HCA2 (GPR109A), FFAR2 (GPR43), and FFAR3 (GPR41).[53]

Colonocytes

[edit]

Responsible for about 70% of energy from the colonocytes, butyric acid is a critical SCFA in colon homeostasis.[54] Short-chain fatty acids, which include butyric acid, are produced by beneficial colonic bacteria that feed on, or ferment prebiotics, supporting colonocytes by increasing energy conversion.[21]

Butyrate salts and esters

[edit]

The butanoate ion, C3H7COO−, is the conjugate base of butyric acid. It is the form found in biological systems at physiological pH. A butyric (or butanoic) compound is a carboxylate salt or ester of butyric acid.

Examples

[edit]

Salts

[edit]

Esters

[edit]

See also

[edit]

Notes

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Butyric acid

View on Grokipedia
from Grokipedia

Butyric acid, systematically named butanoic acid, is a straight-chain saturated carboxylic acid with the molecular formula C₄H₈O₂ and a molecular weight of 88.11 g/mol. It exists as a colorless, oily liquid at room temperature, boiling at 163.5 °C, with high solubility in water and most organic solvents, and is distinguished by its pungent, rancid odor reminiscent of spoiled butter. Naturally occurring as esters in animal fats, it constitutes 3–4% of butter's triglycerides, from which its common name derives (Latin butyrum for butter), and is also generated in the mammalian colon through microbial fermentation of undigested dietary fibers by gut bacteria such as Faecalibacterium prausnitzii. In biological contexts, butyric acid serves as the primary energy substrate for colonocytes, supporting intestinal barrier integrity, modulating inflammation, and influencing gene expression via histone deacetylase inhibition, thereby contributing to gut homeostasis and broader metabolic health. Industrially, it finds use in flavorings, fragrances, pharmaceuticals, and as a precursor in chemical synthesis, though its irritant properties necessitate careful handling.

Physical and Chemical Properties

Molecular Structure and Nomenclature

Butyric acid, with the systematic IUPAC name butanoic acid, is a straight-chain saturated fatty acid characterized by a four-carbon chain where one terminal methyl group is oxidized to a carboxyl functional group. Its molecular formula is C₄H₈O₂, and the condensed structural formula is CH₃CH₂CH₂COOH. The IUPAC nomenclature derives from the parent alkane butane, with the suffix "-oic acid" denoting the carboxylic acid group at the end of the chain, numbered starting from the carboxyl carbon as position 1. The common name "butyric acid" stems from the Latin butyrum (butter), reflecting its historical isolation from rancid butter and its prevalence in dairy fats. Other synonyms include n-butyric acid, ethylacetic acid, and propylformic acid, emphasizing its alkyl chain composition. Butyric acid possesses a structural isomer, isobutyric acid (systematically 2-methylpropanoic acid), which features a branched chain. In standard representation, the molecule exhibits a linear conformation in its neutral form, with the carboxyl group (-COOH) capable of existing in monomeric or dimeric states depending on the environment, influencing its spectroscopic properties. The IUPAC-recommended InChI notation is InChI=1S//c1-2-3-4(5)6/h2-3H2,1H3,(H,5,6), confirming its unbranched structure.

Physical Characteristics

Butyric acid exists as a colorless to pale yellow oily liquid at standard and pressure, exhibiting a strong, penetrating rancid often described as reminiscent of vomit, rancid , or . Its is approximately 0.86 mmHg at 25 °C, contributing to its volatility and distinctive smell even at low concentrations. The compound has a melting point of −7.9 °C and a boiling point of 164 °C at 760 mmHg. Its is 0.96 g/cm³ relative to at 20 °C, with a more precise value of 0.9592 g/mL measured at the same . Butyric acid is fully miscible with , as well as with common organic solvents such as and , reflecting its polar functionality. The is 1.398 (nD20), and measures approximately 1.57 mPa·s at 20 °C. It possesses a of 72 °C (closed cup), indicating moderate flammability risks under certain conditions. These properties align with its classification as a short-chain , influencing its handling as a corrosive substance that reacts with metals and tissues.

Chemical Reactivity

Butyric acid displays the characteristic reactivity of short-chain aliphatic , primarily driven by the (-COOH). It acts as a with a pKa of approximately 4.82, undergoing proton donation in aqueous solutions to form the butyrate anion (CH₃CH₂CH₂COO⁻). This enables neutralization reactions with bases, producing and salts such as when reacted with : CH₃CH₂CH₂COOH + NaOH → CH₃CH₂CH₂COONa + H₂O. In esterification reactions, butyric acid condenses with alcohols under acidic catalysis (e.g., ) and heat to form esters and water, following the Fischer esterification mechanism. For example, with , it yields (CH₃CH₂CH₂COOCH₂CH₃), a compound with a fruity used in flavorings. The reaction is reversible and equilibrium-driven, often shifted toward ester formation by excess alcohol or removal of water. Butyric acid also forms other derivatives, including acid chlorides via reaction with (SOCl₂) to produce butanoyl chloride (CH₃CH₂CH₂COCl), which serves as an acylating agent in further syntheses. Butyric acid undergoes reduction to primary alcohols using strong reducing agents like lithium aluminum hydride (LiAlH₄) in , converting to butan-1-ol (CH₃CH₂CH₂CH₂OH) after . It is incompatible with strong oxidizing agents, potentially leading to vigorous or incandescent reactions; for instance, it reacts with above 212°F (100°C). Additionally, its alpha (CH₂ adjacent to the carboxyl) exhibits acidity, permitting to form enolates for reactions like alpha-halogenation or aldol condensations under basic conditions.

History

Discovery and Early Isolation

Butyric acid, derived from the Latin butyrum for , was first observed in impure form during the early through the analysis of animal fats. French chemist identified it in while studying the products of butter and other fats, noting a volatile, odorous component released upon acidification of soaps derived from these substances. Chevreul's systematic decomposition of fats via alkaline and subsequent acidification revealed short-chain acids, including butyric acid, distinguishing them from longer-chain fatty acids like stearic and oleic. By 1818, Chevreul had advanced the purification process, isolating butyric acid sufficiently to characterize its basic properties, such as its pungent and volatility, through and reaction with bases to form salts. His work involved repeated of salts of fatty acids from , confirming the presence of a low-molecular-weight, water-soluble acid unique to ruminant-derived fats like cow and . This early isolation laid foundational insights into the composition of natural fats, predating modern chromatographic techniques, though the exact molecular formula was not determined until later analyses. Chevreul's findings, published in his 1823 treatise on animal fats, emphasized empirical separation methods over speculative theories, establishing butyric acid as a distinct entity amid the era's limited analytical tools.

Industrial and Scientific Developments

The butyric acid-producing fermentation process was first scientifically described in 1861 by , who identified it as a key anaerobic involving bacteria such as species, laying foundational insights into microbial acid production. This discovery spurred early interest in fermentation for generation, though initial yields were low and processes unscalable without further optimization. By the early 20th century, industrial fermentation gained traction through the acetone-butanol-ethanol (ABE) process, developed in 1915 by using to meet British wartime demands for acetone and butanol; butyric acid formed as a critical intermediate in the pathway, with production peaking during the 1930s–1940s at facilities in the UK, US, and elsewhere before declining due to high costs and contamination risks. Post-World War II, economic shifts toward petroleum-derived chemicals supplanted fermentation, with butyric acid production transitioning to synthetic routes dominated by the catalyzed air oxidation of (n-butanal), itself derived from the of using and —a process first demonstrated industrially in the 1940s following Otto Roelen's 1938 invention of the oxo synthesis at Ruhrchemie. This method enabled large-scale, cost-effective output, reaching commercial maturity by the 1950s–1960s as from catalytic cracking became abundant, rendering fermentation uneconomical except for niche applications like extraction. Scientific advancements paralleled industrial evolution, with biochemical studies in the mid-20th century clarifying butyric acid's role in ruminant nutrition and preservation, while research from the onward revealed its function as a (HDAC) inhibitor, influencing and prompting investigations into anti-cancer and applications. Renewed focus on sustainable bioproduction emerged in the late 20th and early 21st centuries, driven by environmental concerns over petrochemical reliance; of strains like tyrobutyricum has since achieved titers exceeding 50 g/L in fed-batch fermentations using renewable feedstocks such as corn hydrolysates, though remains predominant due to superior scalability and purity.

Natural Occurrence and Biosynthesis

Sources in Nature

Butyric acid, also known as butanoic acid, occurs naturally as a short-chain in the fat of mammals, where it constitutes approximately 3 to 4 percent of the total fatty acids by weight. In cow's milk, the average content is about 4.4 percent, primarily in the form of triglycerides, resulting from microbial in the by bacteria such as species that convert dietary fibers into volatile fatty acids absorbed and incorporated into . This presence is higher in dairy products derived from ruminants compared to non-ruminant milks, reflecting the unique digestive physiology of animals like cows, sheep, and goats. Trace amounts are found in certain plant-derived essential oils and vegetable oils, including those from citronella (), (), (), (), Spanish anise, and , often as free acid or esters contributing to characteristic aromas. It also appears in animal fluids beyond , such as sweat and tissue fluids, as a metabolic byproduct of breakdown or microbial activity. These occurrences underscore butyric acid's role as an endogenous rather than a primary structural component in most natural matrices, with concentrations typically elevated in fermented or anaerobic biological environments.

Microbial Biosynthesis Pathways

Microbial biosynthesis of butyric acid primarily occurs through anaerobic fermentation pathways in bacteria, converting carbohydrates or amino acids into butyrate as an end product. The most prevalent route is the acetyl-coenzyme A (acetyl-CoA) pathway, utilized by a significant portion of butyrate-producing bacteria in environments like the human gut microbiome, where it accounts for the majority of butyrate synthesis from dietary fibers. In this pathway, pyruvate derived from glycolysis is oxidatively decarboxylated to acetyl-CoA by pyruvate:ferredoxin oxidoreductase, followed by condensation of two acetyl-CoA molecules into acetoacetyl-CoA via thiolase (thiolase/β-ketothiolase). Subsequent reduction to (R)-3-hydroxybutyryl-CoA by 3-hydroxybutyryl-CoA dehydrogenase, dehydration to crotonyl-CoA by crotonase, and reduction to butyryl-CoA by butyryl-CoA dehydrogenase complete the chain elongation. The final dephosphorylation to butyrate occurs via one of two mechanisms: the butyrate kinase pathway, involving phosphotransbutyrylase and butyrate kinase to generate ATP, or the CoA-transferase pathway, utilizing butyryl-CoA:acetate CoA-transferase to exchange with acetate, producing butyrate and acetyl-CoA without net ATP gain from that step. This pathway predominates in Firmicutes such as species (e.g., and Clostridium tyrobutyricum) and gut commensals like Faecalibacterium prausnitzii and Roseburia spp., enabling efficient of hexoses and pentoses under anaerobic conditions. In C. tyrobutyricum, glucose yields butyrate with a molar ratio of approximately 0.5-0.7 mol butyrate per mol glucose, alongside byproducts like , CO₂, and H₂, reflecting the pathway's balance via ferredoxin-linked oxidoreductases. Alternative pathways include amino acid degradation routes: the pathway via 2,3-aminomutase and subsequent β-ketoadipate reduction; the 4-aminobutyrate (GABA) pathway through and chain shortening; and the glutarate pathway via or to glutaryl-CoA then . These are less common, present in fewer bacterial genomes (typically <5% in gut metagenomes), and often serve as supplementary routes in diverse microbial consortia. In mixed microbial communities, such as those in the colon, pathway selection influences yield and efficiency; for instance, the CoA-transferase route enhances butyrate production when acetate is abundant, as seen in fiber-fermenting consortia. Genomic analyses of human fecal metagenomes reveal that 19-39% of bacterial genomes encode at least one butyrate synthesis pathway, with acetyl-CoA dominance correlating to higher butyrate output from resistant starches and non-digestible oligosaccharides. These pathways underscore the role of strict anaerobes in sustaining microbial ecosystems, though yields vary with substrate availability and pH, typically peaking at neutral conditions in Clostridium spp.

Production Methods

Industrial Synthesis

The primary industrial synthesis of butyric acid employs a two-step process derived from petrochemical feedstocks, specifically propylene obtained from crude oil refining. The initial hydroformylation (oxo synthesis) step involves the reaction of propylene with synthesis gas—a stoichiometric mixture of carbon monoxide and hydrogen—typically at elevated temperatures (120–180°C) and pressures (10–30 MPa) using soluble catalysts such as cobalt carbonyl complexes or rhodium-phosphine systems to selectively form n-butyraldehyde as the predominant product, alongside minor amounts of isobutyraldehyde. In the subsequent oxidation step, n-butyraldehyde is catalytically or non-catalytically oxidized in the liquid phase with air or pure oxygen at moderate temperatures (around 50–100°C), achieving high conversions exceeding 99% and butyric acid selectivities over 95% under optimized conditions, with water often produced as a byproduct. This route leverages the abundance and low cost of , rendering chemical synthesis economically dominant over alternatives for large-scale production. Alternative chemical pathways, such as direct hydrocarboxylation of propylene with carbon monoxide and water under nickel catalysis or oxidation of n-butane, exist but are less prevalent due to lower selectivity, higher energy demands, or catalyst deactivation issues compared to the hydroformylation-oxidation sequence. Global production via these methods supports applications in solvents, fragrances, and chemical intermediates, with annual output estimated in thousands of metric tons, though exact figures vary by market fluctuations in petrochemical prices.

Fermentation-Based Production

Fermentation-based production of butyric acid relies on anaerobic bacterial metabolism, primarily by Clostridium species such as C. butyricum, which convert carbohydrates into butyrate through the acetyl-CoA to butyryl-CoA pathway under strict anaerobiosis. Substrates commonly include glucose, xylose, or lignocellulosic biomass hydrolysates like those from sweet sorghum or rice straw, enabling utilization of renewable feedstocks. In batch fermentations optimized at pH 6.5, C. butyricum achieves butyric acid titers of 12.25 g/L with cell yields around 3.65 g/L dry weight. Fed-batch strategies enhance productivity, yielding up to 16.74 g/L—a 36.65% improvement over batch—by controlled substrate feeding to mitigate inhibition. Higher titers, such as 57.9 g/L from xylose at pH 6.3, have been reported with yields of 0.38–0.59 g/g substrate and productivities up to 3.19 g/L/h, though these require integrated extraction to counter product toxicity. Challenges include low final concentrations (typically <20 g/L in unextracted broths) due to end-product inhibition and metabolic shifts toward solvents like acetone-butanol-ethanol in solventogenic clostridia, limiting economic viability compared to petrochemical synthesis. Yields from biomass hydrolysates vary, often reaching 0.37 g/g xylose in engineered strains, but require pretreatment to overcome inhibitors like furfural. Recent advances involve strain engineering (e.g., overexpression of key enzymes like butyryl-CoA dehydrogenase) and process innovations such as bio-augmentation with C. butyricum in mixed cultures or psychrophilic conditions to selectively boost butyrate over other volatile fatty acids. Extractive fermentation using solvents or membranes, or consolidated bioprocessing with cellulolytic clostridia, aims to improve titers beyond 50 g/L for industrial scalability. Despite progress, fermentation remains non-competitive for bulk production as of 2024, with focus on niche bio-based applications.

Dietary and Biotechnological Sources

Butyric acid is present in various dietary sources, primarily as esters like tributyrin within the fat fractions of dairy products. Butter, derived from milk fat, contains approximately 3–4% butyric acid by weight, making it the richest direct food source. Hard cheeses such as and certain goat cheeses provide 1–1.8 g of butyric acid per 100 g, while overall dairy fats include about 5% of saturated fatty acids as butyric acid or its derivatives. Lesser amounts occur in red meat and fermented vegetables like sauerkraut, though concentrations are typically below 1% of total lipids. These levels reflect the acid's origin in ruminant milk fat, where it arises from microbial fermentation in the animal's gut. Biotechnological production of butyric acid relies on anaerobic fermentation by acetogenic bacteria, with Clostridium species dominating due to their high yields and tolerances. Clostridium tyrobutyricum is a primary strain, converting substrates like glucose, xylose, or glycerol into butyric acid via the butyl pathway, achieving concentrations up to 20–30 g/L in optimized bioreactors. Other clostridia, such as C. butyricum, offer similar efficiencies but require neutral pH control to mitigate acid inhibition. Recent strategies include co-culturing with Bacillus species to enhance sucrose utilization and yields, or engineering strains for solventogenic shifts, targeting industrial scalability beyond chemical synthesis. Probiotic Lactobacillus plantarum strains have shown preliminary butyric acid production from plant-based media, though at lower titers than clostridia. These methods leverage renewable biomass feedstocks, contrasting petroleum-derived routes, with ongoing research focusing on inhibitor-resistant mutants for economic viability.

Home Production Methods

Small-scale or home production of butyric acid from butter is possible but hazardous and strongly discouraged outside controlled laboratory environments. One method involves saponification of butter with sodium hydroxide (NaOH) to form sodium butyrate and other salts, followed by acidification with a strong acid (e.g., sulfuric or hydrochloric acid) to release free butyric acid. This approach exploits the 2–4% butyric acid content in butter triglycerides. An alternative involves anaerobically fermenting butter in a sealed container to promote bacterial production of the acid, analogous to the natural liberation of butyric acid during rancidity through hydrolysis. Butyric acid is highly corrosive and toxic, causing severe skin burns, eye damage, and respiratory irritation; it is readily absorbed through skin and has a highly persistent, penetrating odor reminiscent of vomit or rancid cheese detectable at very low concentrations (odor threshold as low as 0.001 mg/m³). The processes entail risks from caustic chemicals, acid splattering, corrosive fumes, severe irritation, and burns. Professional laboratory conditions with appropriate safety equipment (fume hood, gloves, goggles, protective clothing, respiratory protection) are essential. DIY attempts are not advised due to these significant hazards.

Industrial and Commercial Applications

Use in Animal Feed and Agriculture

Butyric acid and its salts, such as , are supplemented in animal feeds primarily to enhance gastrointestinal health, improve nutrient absorption, and boost growth performance in livestock species including poultry, swine, and cattle. These short-chain fatty acids lower intestinal pH, exhibit antimicrobial effects against pathogens like Salmonella and Clostridium perfringens, and serve as an energy source for enterocytes, thereby strengthening the gut barrier and modulating the microbiome. Supplementation levels typically range from 0.5% to 3% of the diet, often in coated forms to ensure targeted release in the lower gut and minimize volatility or rapid metabolism in the rumen or stomach. In poultry production, butyric acid supplementation has been shown to increase body weight gain and improve feed conversion ratios by up to 5-10% in broilers, while enhancing egg production and shell quality in layers through better mucus layer integrity and reduced osteoporosis risk. Studies indicate it promotes villus height and crypt depth in the jejunum, leading to higher digestibility of proteins and fats, with apparent metabolizable energy gains observed at doses of 0.2-0.5% coated butyric acid. It also reduces reliance on antibiotics by inhibiting harmful bacterial overgrowth, aligning with regulatory bans on growth promoters in regions like the since 2006. For swine, particularly weaned piglets, sodium butyrate at 0.3-1% dietary inclusion elevates lactobacillus populations and lactic acid levels in the gut, mitigating post-weaning diarrhea and improving average daily gain by 10-15% through anti-inflammatory effects and enhanced barrier function. In ruminants like calves and dairy cows, supplementation supports rumen development and lactation performance; for instance, 3% sodium butyrate in calf starters reduced feed intake variability while increasing body weight and β-hydroxybutyric acid levels indicative of improved ketogenesis, and in lactating cows, it boosted milk yield via better mammary gland development and nutrient partitioning. Agriculturally, butyric acid derivatives aid in weaning stress alleviation across species, with coated formulations showing superior efficacy in maintaining intestinal integrity under heat stress or low-protein diets, potentially reducing mortality rates by 20-30% in challenged herds. Market analyses project growing adoption due to antibiotic reduction mandates, with global butyric acid for animal feed demand rising amid evidence of sustained productivity gains without residue concerns in meat or milk. However, excessive levels can suppress voluntary feed intake in sensitive animals, necessitating precise dosing based on species and life stage.

Other Chemical and Manufacturing Uses

Butyric acid serves as a key precursor in the synthesis of cellulose acetate butyrate (CAB), a thermoplastic polymer valued for its toughness, clarity, and resistance to weathering. CAB plastics, produced by partial esterification of cellulose with butyric and acetic acids, find applications in tool handles, paints, coatings, and ophthalmic lenses due to enhanced flexibility and abrasion resistance compared to cellulose acetate alone. Industrial production of CAB typically involves controlled butyric acid ratios to achieve desired viscosity and mechanical properties, with global demand tied to the broader cellulosic plastics market exceeding 100,000 metric tons annually as of 2010 data. Esters derived from butyric acid, such as ethyl butyrate and butyl butyrate, are manufactured via acid-catalyzed esterification and used as solvents, plasticizers, and intermediates in chemical synthesis. These esters contribute to the production of synthetic lubricants and resins, where butyric acid's volatility aids in formulating low-viscosity products for industrial coatings. In fragrance and flavor manufacturing, butyric acid undergoes esterification to yield compounds imparting buttery or fruity notes, with annual production volumes supporting the perfume industry's estimated 2,000 metric tons of short-chain fatty acid derivatives. Butyric acid also functions as a pH regulator and buffering agent in chemical manufacturing processes, including water treatment formulations and laboratory reagents, leveraging its carboxylic acid dissociation constant (pKa ≈ 4.82) for precise acidity control. Its role extends to polymer additives, where it enhances hydrolysis resistance in biodegradable polyesters, though scale remains smaller than CAB applications.

Biological Functions

Role in the Mammalian Gut Microbiome

Butyric acid serves as a key metabolite produced by the mammalian gut microbiota, primarily through anaerobic fermentation of dietary fibers and resistant starches in the colon. Anaerobic bacteria convert undigested carbohydrates into short-chain fatty acids (SCFAs), with butyrate comprising approximately 15-23% of total SCFAs at concentrations ranging from 10 to 25 mM in the human colon, following a typical molar ratio of acetate:propionate:butyrate of 60:20:20. This production occurs via two primary pathways: the butyryl-CoA:acetate CoA-transferase (but) route, which utilizes acetate from cross-feeding bacteria, and the butyrate kinase (buk) pathway, both relying on enzymes that assemble acetyl-CoA units into butyrate. Minor contributions arise from amino acid fermentation, such as glutamate or lysine degradation, though carbohydrate sources predominate. Prominent butyrate-producing taxa, representing 10-20% of the total gut microbiota (estimated at ~38 × 10¹² cells), include Faecalibacterium prausnitzii (abundance up to 5-17.6% in fecal samples), Eubacterium rectale (up to 13%), Roseburia intestinalis (0.9-5%), and various Clostridium species within the Firmicutes phylum. These anaerobes thrive in the oxygen-poor colonic lumen, where they degrade complex polysaccharides like xylan or inulin, often engaging in syntrophic relationships—such as consuming acetate or lactate produced by upstream fermenters like Bifidobacterium—to yield butyrate. Deficiencies in these producers correlate with dysbiosis, as observed in conditions like inflammatory bowel disease, where reduced butyrate output disrupts microbial equilibrium. Butyrate producers actively shape microbiome composition by secreting antimicrobial peptides (e.g., cathelicidins, reuterin) that inhibit pathogens like Salmonella, while fostering commensal diversity through metabolite cross-talk and niche stabilization. By stimulating mitochondrial oxygen consumption in adjacent epithelial cells, butyrate maintains the hypoxic environment essential for obligate anaerobes, preventing aerobic competitor overgrowth and preserving community structure. Exogenous butyrate supplementation, as shown in rodent models, enhances SCFA-producing taxa and reduces pathobiont proliferation, indicating a regulatory feedback where butyrate concentrations (e.g., 10-20 mM) modulate bacterial growth and inhibit inflammation-promoting species. This microbial modulation underscores butyrate's role in sustaining a resilient, fiber-dependent ecosystem, with empirical data from germ-free animal studies confirming its absence leads to altered microbiota assembly upon colonization.

Energy Metabolism in Colonocytes

Butyrate, the ionized form of butyric acid, serves as the primary energy substrate for colonocytes, the epithelial cells lining the mammalian colon, supplying approximately 70-80% of their ATP requirements through mitochondrial beta-oxidation. Upon reaching the colonic lumen via microbial fermentation of dietary fibers, butyrate is rapidly absorbed by colonocytes via monocarboxylate transporters such as MCT1 (encoded by SLC16A1), achieving near-complete uptake with 95% of luminal butyrate metabolized locally rather than passing to the systemic circulation. Within colonocytes, butyrate undergoes activation to butyryl-CoA by acyl-CoA synthetases, followed by sequential beta-oxidation in the mitochondria, yielding two molecules of acetyl-CoA per butyrate molecule; this acetyl-CoA then enters the tricarboxylic acid (TCA) cycle, driving oxidative phosphorylation to generate ATP. This pathway is preferentially utilized over glucose oxidation, as colonocytes exhibit a metabolic preference for fatty acids, with butyrate oxidation accounting for the majority of oxygen consumption in differentiated cells, thereby maintaining low luminal oxygen levels (<1% O₂) essential for anaerobic microbiota.00226-3) In germ-free models, absence of butyrate leads to impaired mitochondrial respiration and increased autophagy in colonocytes, which is restored upon butyrate supplementation, underscoring its causal role in epithelial energy homeostasis. Defects in butyrate beta-oxidation, observed in conditions like inflammatory bowel disease, correlate with reduced ATP production and epithelial dysfunction, as evidenced by diminished enzyme activities in the oxidation pathway in affected mucosa. Quantitatively, butyrate metabolism contributes 5-15% to total human caloric needs via colonocyte utilization, highlighting its broader systemic implications beyond local energy provision. This reliance on butyrate oxidation also influences crypt architecture, with higher rates in differentiated upper crypt cells compared to proliferative basal regions, linking energy status to epithelial renewal.

Immunomodulatory Effects

Butyrate exerts immunomodulatory effects primarily in the gastrointestinal tract, where it influences immune cell differentiation, cytokine production, and inflammatory signaling to maintain mucosal homeostasis. As a short-chain fatty acid derived from microbial fermentation of dietary fibers, butyrate inhibits histone deacetylases (HDACs), leading to hyperacetylation of histones and non-histone proteins, which alters gene expression in immune cells. This HDAC inhibition suppresses NF-κB pathway activation, reducing transcription of pro-inflammatory genes. Additionally, butyrate activates G protein-coupled receptors (GPCRs) such as GPR109A on immune and epithelial cells, further promoting anti-inflammatory responses. In T cells, butyrate enhances extrathymic differentiation of Foxp3+ regulatory T cells (Tregs) by upregulating Foxp3 expression and promoting histone H3 acetylation at the Foxp3 locus, as demonstrated in murine models where luminal butyrate levels of 1-10 mM correlated with increased colonic Treg populations. This effect counters pro-inflammatory Th17 cell differentiation, balancing adaptive immunity against pathogens while preventing autoimmunity. In innate immune cells, butyrate attenuates macrophage responses to lipopolysaccharide (LPS) by decreasing secretion of interleukin-6 (IL-6), IL-12p40, and nitric oxide, with these outcomes dependent on HDAC activity. Dendritic cells exposed to butyrate exhibit reduced IL-12 and interferon-gamma (IFN-γ) production alongside elevated IL-10, fostering a tolerogenic phenotype that supports Treg induction. These local effects extend systemically, as butyrate strengthens intestinal barrier integrity by upregulating tight junction proteins like occludin and zonula occludens-1, thereby limiting translocation of pro-inflammatory microbial products. In experimental colitis models, oral butyrate administration (e.g., 100-200 mM sodium butyrate enemas) ameliorated inflammation by modulating NLRP3 inflammasome activity and reducing IL-17 and tumor necrosis factor-alpha (TNF-α) levels, highlighting its role in resolving acute immune responses. However, high concentrations (>10 mM) may impair protective immunity, such as by suppressing follicular helper T cell differentiation via HDAC inhibition, underscoring dose-dependent duality in immune .

Pharmacological and Therapeutic Aspects

Pharmacodynamics

Butyric acid, primarily in its dissociated butyrate form at physiological , acts as a potent inhibitor of class I and II histone deacetylases (HDACs), enzymes that remove acetyl groups from , thereby promoting chromatin condensation and transcriptional repression. By inhibiting HDACs, butyrate induces hyperacetylation of H3 and H4, which loosens structure, enhances accessibility of transcription factors to DNA, and upregulates genes involved in cell differentiation, , and arrest, particularly in rapidly proliferating cells such as colon cancer cells. This mechanism has been demonstrated , where millimolar concentrations of (a common butyrate salt) arrest cells in the via p21WAF1/CIP1 induction and trigger caspase-dependent through downregulation of anti-apoptotic proteins. Beyond HDAC inhibition, butyrate serves as an agonist for G-protein-coupled receptors GPR41 (FFAR3) and GPR43 (FFAR2), which are expressed on immune cells, enterocytes, and adipocytes. Activation of these receptors couples to Gi/o proteins, inhibiting adenylyl cyclase and reducing cyclic AMP levels, which modulates downstream signaling to suppress nuclear factor-κB (NF-κB) activation and proinflammatory cytokine production, including interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF-α). This contributes to anti-inflammatory effects in the gastrointestinal tract and systemic circulation, as evidenced by reduced endothelial inflammation and lowered arterial blood pressure via vagus nerve-mediated pathways in animal models. Butyrate also influences innate and adaptive immunity by promoting regulatory T-cell (Treg) differentiation through acetylation and inhibiting phosphorylation, which curbs interferon-γ-driven Th1 responses and T-cell . At higher doses, it exhibits broader cytostatic effects independent of HDACs, potentially via mitochondrial modulation or direct interference with in hypoxic tumor environments, though these require further mechanistic validation . Concentrations achieving these effects (typically 0.5–5 mM) align with luminal gut levels from microbial but exceed plasma levels (∼0.1–1 μM), highlighting context-dependent influenced by local delivery.

Pharmacokinetics and Metabolism

Butyric acid, primarily encountered as its conjugate base butyrate in physiological contexts, is absorbed mainly in the colon following microbial of dietary fibers. Absorption occurs via mechanisms, including monocarboxylate transporters MCT1 and MCT4, as well as the sodium-coupled monocarboxylate transporter SLC5A8 (SMCT1), with minor contributions from passive diffusion across the colonic epithelium. Approximately 95% of absorbed butyrate is utilized locally by colonocytes, limiting systemic exposure. In the systemic circulation, butyrate exhibits rapid distribution but low plasma concentrations due to efficient local . levels in humans average around 18 µmol/L, rising to 14–64 µmol/L in postprandial or postmortem samples, while peripheral concentrations are approximately 20% of portal levels. Pharmacokinetic studies of administered butyrate salts (e.g., sodium or butyrate) in humans reveal a biphasic elimination profile, with an initial of 0.5 minutes reflecting accelerated clearance and a secondary of 13.7 minutes. Plasma is generally short, around 6 minutes, underscoring rapid tissue and . Metabolism of butyrate proceeds primarily through mitochondrial β-oxidation, yielding that enters the tricarboxylic acid (TCA) cycle to generate ATP. In colonocytes, this pathway supplies up to 70% of cellular energy requirements, with butyrate also serving as a substrate for of , , and . Systemically, any circulating butyrate is swiftly oxidized in the liver, , and other tissues via similar β-oxidation, resulting in near-complete conversion to and with minimal unmetabolized . Fecal accounts for about 10% of unabsorbed butyrate, which can increase with high-fiber diets enhancing microbial production. This efficient metabolic handling contributes to butyrate's role as a localized signaling molecule rather than a sustained circulating .

Clinical Evidence for Health Effects

Butyrate contributes to weight loss through mechanisms including improved insulin sensitivity and blood sugar control that reduce fat storage, decreased inflammation linked to obesity, modulation of appetite hormones to enhance satiety, and modest increases in energy expenditure via brown adipose tissue activation. Obese individuals frequently exhibit lower levels of butyrate-producing gut bacteria, with interventions elevating butyrate associated with improved weight management outcomes. A randomized published in 2022 evaluated oral supplementation (20 mg/kg/day for 6 months) in children and adolescents aged 5-17 years with , finding significant reductions in BMI z-score (-0.15 vs. -0.01 in group), waist circumference, and fat mass, alongside improvements in insulin sensitivity and composition. Additionally, a 2024 randomized controlled trial demonstrated that resistant starch supplementation (40 g/day for 8 weeks) in adults with excess body weight led to an average weight loss of 2.8 kg and improved insulin sensitivity, associated with increases in butyrate-producing gut bacteria such as Bifidobacterium adolescentis and Ruminococcus bromii. Animal studies consistently show that butyrate prevents weight gain in high-fat diet models. Similar metabolic benefits were observed in preliminary studies, where butyrate modulated glucose , though larger trials are needed to confirm effects in adults. In (IBD), evidence is mixed. A 2024 study in patients with active (UC) reported that short-chain fatty acid-butyrate supplementation reduced inflammatory biomarkers such as and calprotectin, while upregulating circadian-clock genes associated with mucosal healing. Conversely, in vitro analysis of primary epithelial monolayers from UC patients showed butyrate failed to protect against inflammation-induced barrier dysfunction and potentially exacerbated permeability loss. For , supplementation (dose not specified in abstract) significantly improved clinical remission rates, reduced disease activity scores, and enhanced quality-of-life metrics in a cohort reported at the 2024 European Crohn's and Colitis Organisation congress. A trial combining with also alleviated abdominal symptoms like and pain in irritable bowel syndrome-like conditions, attributed to HDAC inhibition and gut restoration. Cardiovascular effects appear context-dependent. A 2024 randomized trial in hypertensive adults found 4 weeks of oral butyrate (300 mg/day) increased daytime systolic by 5.2 mmHg and diastolic by 3.1 mmHg compared to , suggesting potential adverse impacts in this population. Reviews of note animal-derived anti-hypertensive mechanisms via G-protein-coupled receptor signaling, but human clinical data remain limited and inconsistent. For and other malignancies, clinical evidence is sparse and largely preclinical; butyrate's HDAC-inhibitory properties show anti-proliferative effects in cell lines, but no large-scale trials demonstrate therapeutic or . Overall, while small-scale studies indicate potential benefits in metabolic and select gastrointestinal contexts, contradictory findings—particularly on and —underscore the need for robust, large randomized controlled trials to establish causality and optimal dosing, as current evidence often derives from underpowered or short-term interventions.

Controversies and Limitations

Double-Edged Effects in Metabolism and Obesity

Butyric acid, as butyrate, exhibits context-dependent effects on and , with evidence of both protective and potentially obesogenic influences. While numerous demonstrate that butyrate supplementation mitigates high-fat diet-induced , , and adiposity by enhancing mitochondrial function and expenditure, observational data reveal elevated fecal butyrate concentrations in and individuals compared to lean controls, suggesting a possible association with obesogenic states. However, obese individuals frequently exhibit reduced abundances of key butyrate-producing bacteria, such as Faecalibacterium prausnitzii, in their gut microbiota, potentially impairing beneficial signaling pathways despite elevated fecal levels in some cohorts. Interventions to boost butyrate production, via dietary precursors like resistant starch or direct supplementation, correlate with improved weight management in select human studies, including average weight reductions of 2.8 kg over 8 weeks and enhanced insulin sensitivity, as well as BMI decreases in pediatric populations, though outcomes vary by individual microbiome composition, host factors, and require further large-scale trials to clarify causality and context-dependency. This discrepancy may arise from butyrate's as an substrate and signaling ; when primarily metabolized for harvest by and host tissues, it can increase dietary caloric yield and assimilation, contributing to fat storage rather than oxidation. Mechanistically, butyrate can promote by enhancing differentiation and accumulation in preadipocytes, as observed in studies of obese models where it modulated fat cell conversion positively. Furthermore, butyrate facilitates synthesis from or via pathways like β-hydroxy-β-methylglutaryl-CoA, potentially exacerbating in energy-replete conditions. In developmental contexts, maternal butyrate exposure has been linked to increased offspring body weight, , and intramuscular fat deposition in animal models, indicating transgenerational metabolic programming risks. These pro-obesogenic effects contrast with butyrate's inhibitory actions on deacetylases and of G-protein-coupled receptors (e.g., GPR41/43), which typically favor and insulin-sensitizing outcomes, underscoring its double-edged nature dependent on dosage, microbial context, and host metabolic status. Human data remain limited and correlative, with higher short-chain fatty acid levels—including butyrate—in obese populations potentially reflecting dysbiotic that prioritize extraction over beneficial signaling, though causal links require further intervention trials to disentangle. Overall, while butyrate's net metabolic impact leans beneficial in controlled supplementation, its capacity to augment availability highlights risks in obesogenic environments where substrate utilization predominates over regulatory functions.

Risks and Criticisms of Supplementation

Butyrate supplementation, typically administered as salts like to mitigate the corrosiveness of pure butyric acid, has been associated with primarily gastrointestinal side effects, including , , , , and cramping, especially at higher doses exceeding physiological levels produced by gut . These effects arise from butyrate's osmotic activity in the gut and potential to alter microbial dynamics, with recommendations to start at lower doses (e.g., 150-300 mg daily) to minimize discomfort. Clinical trials in humans report adverse events as mild and transient, such as and in 2 out of 40 pediatric participants during a 6-month intervention for at 20 mg/kg/day, resolving without discontinuation. Safety assessments of butyric acid-rich triglyceride oils establish a (NOAEL) of 4650 mg/kg/day in models, suggesting broad tolerability in humans at supplemental doses up to several grams daily, though long-term data beyond 6-12 months remain limited. Excessive doses may disrupt intestinal barrier integrity or induce inflammatory responses in susceptible individuals, as observed in preclinical models where high concentrations negated protective effects against ethanol-induced damage. Criticisms of butyrate supplementation center on its double-edged physiological role, where benefits in healthy epithelia contrast with potential harm in pathological states; for instance, as a preferred source for colonocytes, butyrate can fuel proliferation in cells exhibiting a Warburg-like , potentially accelerating tumor progression despite HDAC-inhibitory anti-cancer effects at lower concentrations. Its impact on is similarly contested, with some evidence suggesting promotion of harvest and fat storage via gut-brain signaling, challenging claims of universal metabolic benefit. Limited in supplement formulations (e.g., release profiles affecting colonic delivery) and reliance on short-term trials raise concerns over efficacy reproducibility and undetected chronic risks, underscoring the need for caution in populations with malignancies or metabolic dysregulation.

Evaluation of Overstated Health Claims

Claims that butyric acid or its salts serve as a for conditions ranging from to neurodegenerative diseases often rely on extrapolations from and studies, where butyrate exhibits HDAC inhibition, effects, and epithelial support at concentrations of 0.5-5 mM, but trials frequently yield inconsistent or modest outcomes due to poor colonic delivery of oral supplements and inter-individual variability in . For instance, while animal models show butyrate reducing diet-induced weight gain via increased energy expenditure and gut hormone modulation, human observational data link elevated fecal , including butyrate, to higher through enhanced energy harvest from indigestible carbohydrates, rendering anti-obesity claims premature without large randomized controlled trials confirming net benefits. Supplementation efficacy is further overstated in marketing for broad-spectrum gut repair, as is rapidly absorbed in the proximal gut, achieving luminal levels below therapeutic thresholds in the colon where most benefits are hypothesized; specialized formulations like show promise in small studies for increasing distal delivery, yet a 2024 trial reported only subtle shifts in biomarkers without clinically meaningful symptom relief in non-diseased cohorts. In , meta-analyses of adjunctive butyrate enemas indicate short-term mucosal improvements in subsets, but oral routes fail to replicate these in , with risks of adverse effects like elevated systolic observed in patients receiving 4 g daily doses. Neurological and anticancer assertions, such as butyrate alleviating "brain fog" via the gut-brain axis or universally preventing colorectal tumors, lack substantiation beyond associative ; while butyrate promotes differentiation in HDAC-sensitive lines, resistant clones utilize it as fuel for proliferation, and intervention trials report no survival extensions despite elevated fecal levels correlating with progression-free intervals in select solid tumors. These discrepancies highlight reliance on preclinical hype, where high-dose effects (e.g., >5 mM inducing barrier disruption) are ignored, and endogenous production via fermentable fibers remains superior to isolated supplementation for sustainable health modulation without unintended metabolic shifts like in .

Butyrate Salts

Butyrate salts are ionic compounds derived from butyric acid (CH₃CH₂CH₂COOH) through neutralization with metal hydroxides or carbonates, yielding anions such as butanoate (CH₃CH₂CH₂COO⁻) paired with cations like sodium (Na⁺), calcium (Ca²⁺), magnesium (Mg²⁺), or potassium (K⁺). These salts enhance the delivery of butyrate in biological and industrial contexts due to improved water solubility over the free acid, which has limited solubility (approximately 6 g/100 mL at 20°C) and a pungent odor that limits direct use. Sodium butyrate (CH₃CH₂CH₂COONa) is the most common, exhibiting high aqueous (over 80 g/100 mL at ) and rapid dissociation to release active butyrate ions. It is produced industrially via fermentation-derived butyric acid neutralization and serves as a (HDAC) inhibitor in pharmaceutical formulations, with in vitro studies confirming its inhibition of class I and II HDACs at micromolar concentrations, influencing related to cell differentiation and . Calcium butyrate ((CH₃CH₂CH₂COO)₂Ca), conversely, offers lower (around 1-2 g/100 mL) but greater stability in acidic environments like the , reducing premature degradation and enabling sustained release in the intestines; this property supports its preference in some nutritional supplements despite potential sodium intake concerns with the sodium variant. In animal , butyrate salts function as feed additives to promote gastrointestinal development and modulate . For instance, supplementation with coated in piglet diets (0.5-1 g/kg) has been shown to increase villus height, reduce pathogen loads like , and improve average daily gain by 5-10% in controlled trials, attributed to butyrate's role in lowering intestinal pH and enhancing integrity. Calcium-magnesium butyrate variants provide similar benefits with added , though efficacy depends on to protect against or gastric . Human applications leverage these salts for targeted butyrate delivery, bypassing dietary fiber fermentation variability. Sodium butyrate supplementation (300-600 mg/day) alleviated and improved in patients in a 2022 randomized, double-blind trial involving 66 adults over 6 weeks, with symptom scores dropping by 20-30% versus . However, broader clinical evidence remains preliminary, with most benefits inferred from animal models or data, and long-term safety profiles requiring further validation beyond short-term tolerability.

Esters and Other Derivatives

Esters of butyric acid are formed through esterification reactions with alcohols, yielding compounds with characteristic fruity or buttery aromas that are widely utilized in the food, beverage, and fragrance sectors. , a colorless volatile , imparts a pineapple-like scent and is employed in artificial production, perfumery, and flavorings for and e-cigarettes. Butyl butyrate similarly provides sweet, pineapple-banana notes and serves as a flavor additive in beverages, cosmetics, and perfumes, as well as a in coatings due to its low toxicity and blending properties. Tributyrin, the ester of butyric acid with , occurs naturally in and functions as a that hydrolyzes in the intestine to release butyrate, supporting applications in nutritional supplements for gut barrier integrity and microbial modulation. Beyond simple alkyl esters, polymeric derivatives such as (CAB) incorporate butyrate groups into cellulose chains, resulting in a material with enhanced UV stability, low moisture absorption, and toughness for use in lacquers, films, and ophthalmic tools. Other reactive derivatives include butyryl chloride, an intermediate that acylates nucleophiles in , particularly for pharmaceuticals, agrochemicals, and pesticides.

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