3-Indolepropionic acid (IPA), or indole-3-propionic acid, has been studied for its therapeutic value in the treatment of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. As of 2022 IPA shows potential in the treatment of this disease, though the therapeutic effect of IPA depends on dose and time of therapy initiation. Though promising in some historical clinical trials, IPA is not clinically listed as a useful therapeutic in managing Alzheimer's as of 2023. IPA is an even more potent scavenger of

hydroxyl radical The hydroxyl radical, •HO, is the neutral form of the hydroxide ion (HO–). Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are pr ...

s than

melatonin Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...

, the most potent scavenger of hydroxyl radicals that is synthesized by human enzymes. Similar to melatonin but unlike other antioxidants, it scavenges radicals without subsequently generating reactive and pro-oxidant intermediate compounds.

Occurrence

Biosynthesis in humans and cellular effects

This compound is endogenously produced by

human microbiota Human microbiota are microorganisms (bacteria, viruses, fungi and archaea) found in a specific environment. They can be found in the stomach, intestines, skin, genitals and other parts of the body. Various body parts have diverse microorganisms. S ...

and has only been detected ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' when the species '' Clostridium sporogenes'' is present in the gastrointestinal tract. , ''C. sporogenes'', which uses

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

to synthesize IPA, is the only species of bacteria known to synthesize IPA ''in vivo'' at levels which are subsequently detectable in the

blood plasma Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...

of the host. ''C. sporogenes'' produces IPA via a two step process. Tryptophanse (TnaA) first converts tryptophan into

indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...

. Tryptophan amino transferase (Tam1) then converts indole into IPA. ''

Peptostreptococcus ''Peptostreptococcus'' is a genus of anaerobic, Gram-positive, non-spore forming bacteria. The cells are small, spherical, and can occur in short chains, in pairs or individually. They typically move using cilia. ''Peptostreptococcus'' are slow- ...

'' species with a full ''fldAIBC'' gene cluster convert tryptophan into IPA and 3-indoleacrylic acid (IA) ''in vitro'' and protects against colitis in mice. IA differs from IPA only by a double bond and both enhance IL-10 secretion after LPS stimulation. However, IA does not reduce TNF production after LPS stimulation. It also activates the

NRF2 Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regu ...

antioxidant pathway and induces the expression of AhR target genes, unlike IPA.

Biosynthesis by soil microbes

IPA is structurally similar to the phytohormone

auxin Auxins (plural of auxin ) are a class of plant hormones (or plant-growth regulators) with some morphogen-like characteristics. Auxins play a cardinal role in coordination of many growth and behavioral processes in plant life cycles and are essent ...

(indole-3-acetic acid, IAA). Plants may encounter the substance when soil bacteria that produces IPA is present (''Clostridium'' is known to reside in soil). Like auxin, IPA increases the growth of lateral roots and root hairs. However, it seems to inhibit some auxin-related processes such as root gravitation, probably by interfering with the plant's own auxin signaling and/or transport.

Metabolism

IPA can be converted in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

kidneys In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retro ...

to 3-indoleacrylic acid, which is subsequently conjugated with glycine, forming indolylacryloyl glycine.

History

The neuroprotective, antioxidant, and anti-amyloid properties of IPA were first reported in 1999.

Research

A study that assessed the effects of broad-spectrum antibiotics – specifically

aminoglycosides Aminoglycoside is a medicinal chemistry, medicinal and bacteriology, bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside ...

fluoroquinolones Quinolone antibiotics constitute a large group of broad-spectrum antibiotic, broad-spectrum bacteriocidals that share a bicyclic molecule, bicyclic core structure related to the substance 4-Quinolone, 4-quinolone. They are used in human and ve ...

, and

tetracyclines Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of ''Streptomyces'' bacteria or produced semi-synthetically from those isolated compounds. ...

– on the metabolome of rats found that only

aminoglycoside Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...

s reduced plasma concentrations of IPA in rats. In 2017, elevated concentrations of IPA in human

were found to be correlated with a lower risk of

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

and higher consumption of

fiber Fiber (spelled fibre in British English; from ) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often inco ...

-rich foods. A separate study found that Roux-en-Y gastric bypass surgery increases the amount of IPA and indole sulfuric acid (ISA) in obese T2D patients. IPA is active ''in vitro'' against ''Mycobacterium tuberculosis'' and other ''Mycobacterium'' species. It works as an allosteric inhibitor of tryptophan biosynthesis.

References

{{DEFAULTSORT:Indolepropionic acid, 3- Antioxidants Indoles Propionic acids Auxins Biomolecules