Urolithin A is a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

compound resulting from the transformation of

ellagitannins The ellagitannins are a diverse class of hydrolyzable tannins, a type of polyphenol formed primarily from the oxidative linkage of galloyl groups in 1,2,3,4,6-pentagalloyl glucose. Ellagitannins differ from gallotannins, in that their galloyl group ...

by the gut bacteria. It belongs to the class of organic compounds known as benzo-

coumarin Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by a lactone-like chain , forming a second six-membered h ...

s or dibenzo-α-

pyrone Pyrones or pyranones are a class of heterocyclic chemical compounds. They contain an unsaturated six-membered ring containing one oxygen atom and a ketone functional group. There are two isomers denoted as 2-pyrone and 4-pyrone. The 2-pyrone (or ...

s. Its precursors – ellagic acids and ellagitannins – are ubiquitous in nature, including edible plants, such as

pomegranates The pomegranate (''Punica granatum'') is a fruit-bearing deciduous shrub in the family Lythraceae, subfamily Punicoideae, that grows between tall. The pomegranate was originally described throughout the Mediterranean region. It was introduc ...

strawberries The garden strawberry (or simply strawberry; ''Fragaria × ananassa'') is a widely grown hybrid species of the genus '' Fragaria'', collectively known as the strawberries, which are cultivated worldwide for their fruit. The fruit is widely ap ...

raspberries The raspberry is the edible fruit of a multitude of plant species in the genus ''Rubus'' of the rose family, most of which are in the subgenus '' Idaeobatus''. The name also applies to these plants themselves. Raspberries are perennial with w ...

walnuts A walnut is the edible seed of a drupe of any tree of the genus ''Juglans'' (family Juglandaceae), particularly the Persian or English walnut, ''Juglans regia''. Although culinarily considered a "nut" and used as such, it is not a true bot ...

, and others. Since the 2000s, urolithin A has been the subject of preliminary studies regarding its possible biological effects. Urolithin A is not known to be found in any food source. Its

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

mostly depends on individual

microbiota Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found t ...

composition, as only some bacteria are able to convert ellagitannins into urolithins.

Chemistry

Urolithin A belongs to the class of

organic compounds In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The s ...

known as benzo-

s or dibenzo-α-

s. These are polycyclic

aromatic compound Aromatic compounds, also known as "mono- and polycyclic aromatic hydrocarbons", are organic compounds containing one or more aromatic rings. The parent member of aromatic compounds is benzene. The word "aromatic" originates from the past grouping ...

s containing a 1-

benzopyran Benzopyran is a polycyclic organic compound that results from the fusion of a benzene ring to a heterocyclic pyran ring. According to current IUPAC nomenclature, the name chromene used in previous recommendations is retained; however, systemati ...

moiety with a ketone group at the C2 carbon atom (1-benzopyran-2-one).

Biochemistry and metabolism

Pomegranate The pomegranate (''Punica granatum'') is a fruit-bearing deciduous shrub in the family Lythraceae, subfamily Punicoideae, that grows between tall. The pomegranate was originally described throughout the Mediterranean Basin, Mediterranean re ...

fruits,

are sources of

. Ellagitannins are

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

in the gut to release

ellagic acid Ellagic acid is a polyphenol found in numerous fruits and vegetables. It is the dilactone of hexahydroxydiphenic acid. Name The name comes from the French term ''acide ellagique'', from the word ''galle'' spelled backwards because it can be ob ...

, which is further processed by the gut

microflora Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found to ...

into urolithins through the loss of one of its two

lactone Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...

s and by successive removal of

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy g ...

s. While studies have shown that ''Gordonibacter urolithinfaciens'' and ''Gordonibacter pamelaeae'' play a role in the conversion of ellagic acids and ellagitannins into urolithin A, the microorganisms responsible for the complete transformation into the final urolithins are still unknown. The efficiency of the conversion of ellagitannins into urolithin A significantly varies in humans, and some individuals do not show any conversion. When synthesized and absorbed in the intestines, urolithin A enters the systemic circulation where it becomes available to tissues throughout the body where it is further subjected to additional chemical transformations (including

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosid ...

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

sulfation Sulfation is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected less directly. Regardless of the mechanism, the ...

, or a combination of them) within the

enterocytes Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its s ...

and

hepatocytes A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, b ...

. Urolithin A and its derivatives - urolithin A glucuronide and urolithin A sulfate being most abundant - release into the circulation, before being excreted in the urine.

Safety

''In vivo'' studies did not determine any

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

or specific

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...

s following dietary intake of urolithin A. Safety studies in elderly humans indicated urolithin A was well tolerated. In 2018, the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

listed urolithin A as a safe ingredient for food or

dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...

products having content in the range of 250 mg to one gram per serving.

Dietary sources

Urolithin A is not known to be found in any food but rather forms as the result of transformation of ellagic acids and ellagitannins by the gut microflora in humans. Sources of ellagitannins are: pomegranates, nuts, some berries (raspberries, strawberries, blackberries, cloudberries), tea,

muscadine ''Vitis rotundifolia'', or muscadine, is a grapevine species native to the southeastern and south-central United States. The growth range extends from Florida to New Jersey coast, and west to eastern Texas and Oklahoma. It has been extensively ...

grapes, many tropical fruits, and oak-aged wines (table below). The conversion of the ellagic acids into urolithin A depends on individual microflora composition and can vary significantly.

References

External links

* {{Phenol-Explorer, 1037
Urolithin A
at the

Human Metabolome Database The Human Metabolome Database (HMDB) is a comprehensive, high-quality, freely accessible, online database of small molecule metabolites found in the human body. Created by the Human Metabolome Project funded by Genome Canada. One of the first d ...