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Int. J. Mol. Sci. 2022, 23, 1222. https://doi.org/10.3390/ijms23031222 www.mdpi.com/journal/ijms
Review
Biological Effects of Indole-3-Propionic Acid, a Gut
Microbiota-Derived Metabolite, and Its Precursor Tryptophan
in Mammals’ Health and Disease
Piotr Konopelski * and Izabella Mogilnicka
Laboratory of the Centre for Preclinical Research, Department of Experimental Physiology and
Pathophysiology, Medical University of Warsaw, 02-091 Warsaw, Poland; izabellamogilnicka@gmail.com
* Correspondence: piotr.konopelski@wum.edu.pl; Tel.: +48-22-57-20-734
Abstract: Actions of symbiotic gut microbiota are in dynamic balance with the host’s organism to
maintain homeostasis. Many different factors have an impact on this relationship, including bacte-
rial metabolites. Several substrates for their synthesis have been established, including tryptophan,
an exogenous amino acid. Many biological processes are influenced by the action of tryptophan and
its endogenous metabolites, serotonin, and melatonin. Recent research findings also provide evi-
dence that gut bacteria-derived metabolites of tryptophan share the biological effects of their pre-
cursor. Thus, this review aims to investigate the biological actions of indole-3-propionic acid (IPA),
a gut microbiota-derived metabolite of tryptophan. We searched PUBMED and Google Scholar da-
tabases to identify pre-clinical and clinical studies evaluating the impact of IPA on the health and
pathophysiology of the immune, nervous, gastrointestinal and cardiovascular system in mammals.
IPA exhibits a similar impact on the energetic balance and cardiovascular system to its precursor,
tryptophan. Additionally, IPA has a positive impact on a cellular level, by preventing oxidative
stress injury, lipoperoxidation and inhibiting synthesis of proinflammatory cytokines. Its synthesis
can be diminished in the presence of different risk factors of atherosclerosis. On the other hand,
protective factors, such as the introduction of a Mediterranean diet, tend to increase its plasma con-
centration. IPA seems to be a promising new target, linking gut health with the cardiovascular sys-
tem.
Keywords: gut microbiota; indole-3-propionic acid; oxidative stress; cardiovascular system
1. Introduction
Over the past two decades, research interest on the interactions between diet, gut
microbiota and their host organism has grown. The findings bring new information on
the correlation between the activity of symbiotic gut microbiota and the pathophysiology
of lifestyle diseases, including obesity [1], diabetes [2] and hypertension [3,4]. Initially,
research focused mainly on the role of short-chain fatty acids (SCFAs) [3,5] and carnitine-
derived metabolites [6–8]. The new data suggest that tryptophan, the essential amino acid,
can also be metabolized by microbiota, leading to the synthesis of biologically active
group of indoles [9]. So far, research projects on bacterial metabolism of tryptophan fo-
cused mainly on actions of indole [10,11], and its liver metabolite, indoxyl sulfate (IS)
[12,13]. Indole decreases intestinal inflammation and has positive impact on gastrointes-
tinal and liver homeostasis [10,14]. On the other hand, IS can be classified as uremic toxin,
as its concentration increases significantly in chronic kidney disease [9,15]. IS is proposed
to be one of the factors linking kidney dysfunction with an increased risk of developing
cardiovascular disease [12,16,17].
Citation: Konopelski, P.; Mogilnicka,
I. Biological Effects of Indole-3-
Propionic Acid, a Gut
Microbiota-Derived Metabolite, and
Its Precursor Tryptophan in
Mammals’ Health and Disease. Int. J.
M
ol. Sci. 2022, 23, 1222.
https://doi.org/10.3390/ijms23031222
Academic Editor: Burkhard
Poeggeler
Received: 16 December 2021
Accepted: 19 January 2022
Published: 22 January 2022
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional
claims in published maps and institu-
tional affiliations.
Copyright: © 2022 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (http://crea-
tivecommons.org/licenses/by/4.0/).
Int. J. Mol. Sci. 2022, 23, 1222 2 of 21
Until now, the biological actions of indole-3-propionic acid (IPA), another microbiota
derived metabolite of tryptophan, have not been properly reviewed in the scientific liter-
ature. A review of articles summarizing the impact of tryptophan metabolism on cardio-
vascular system homeostasis has recently been published, however; the main focus of that
paper was kynurenine- and the serotonin pathway [18]. The aim of our study is to provide
a comprehensive review of the physiological roles of IPA, and changes in its synthesis in
neurological, gastrointestinal and cardiovascular diseases. Scientific papers evaluating the
biological effects of this metabolite have multiplied greatly over the past few years [19–
22]. IPA has a protective role on a cellular and tissue level, by limiting inflammation [23],
lipid peroxidation [24], and the formation of free radicals [25]. Additionally, IPA affects
the function of the immune [22], nervous [26], gastrointestinal [27] and cardiovascular
system [19], and its synthesis decreases significantly in several pathogenic states and dis-
eases, including colitis [28], diabetes [29], and obesity [30]. The novelty of this review is
that we assess the available evidence on biological effects of IPA and emphasize its poten-
tial therapeutic applications.
2. Gut Microbiota
The close relationship between host and symbiotic gut microbiota has gained scien-
tific interest over the past few decades. It has been observed that this relationship is bidi-
rectional and symbiotic, with both participants benefiting from this union. The host pro-
vides a specific niche, supplies nutrients and optimal conditions for the bacteria to grow.
The role of gut microbiota in mammalian health goes beyond the synthesis of vitamins
[31] and is associated with many biochemical pathways and the synthesis of specific me-
tabolites that can be absorbed into the circulation [32]. Gut bacteria participate in the
breakdown of haemoglobin through their ability to transform bilirubin into stercobilino-
gen, enabling elimination of the latter in faeces [33]. Additionally, gut bacteria metabolize
primary bile acids, synthesized in the liver to form secondary bile acids, demonstrating a
protective role in gastrointestinal physiology [34].
2.1. Gut-Blood Barrier (GBB) and Microbiota
The intestinal lumen forms a specific environment for symbiotic microbiota, enabling
its growth and physiological function. Certain factors, including oxygen concentration
and composition of nutrients, form specific conditions of this microbial environment. It
has been observed that composition and richness of microbiota differ significantly be-
tween the small and large intestine [35]. Even within the large intestine some researchers
have provided evidence that caecal and colon contents should be analysed separately, due
to the significant differences in conditions for growth of symbiotic bacteria [36,37]. In ro-
dents, cecum is proposed to have critical role in bacterial fermentation, however; its local-
ization and distance from the anal margin disturb its evaluation in live subjects [38]. In-
tercaecal administration of investigated compounds and the collection of samples requires
surgical preparation [39,40] and potential use of antibiotics that might significantly affect
microbial data. Due to this fact, the colon is more frequently used for the evaluation of
microbial communities and their impact on health in mammals [41,42]. The gut lumen is
separated from the circulation by layers of tissues, which altogether form the gut-blood
barrier (GBB). This barrier is not limited to the epithelium and mucous layers. Gut-asso-
ciated lymphoid tissue (GALT), symbiotic bacteria and secretory proteins, including lac-
toferrin, prevent the transmission of pathogenic bacteria and their toxins into circulation
[43]. Disruption of this protective action of GBB has been observed in several diseases,
including diabetes, hypertension, and inflammatory bowel diseases [44,45], leading to in-
creased permeability to gut bacteria-derived metabolites, including trimethylamine
(TMA) [45]. Jaworska et al. observed increased permeability of GBB to SCFAs in an acetic
acid-induced rat model of colitis, and paediatric patients with inflammatory bowel dis-
ease [44].
Int. J. Mol. Sci. 2022, 23, 1222 3 of 21
2.2. Gut Microbiota-Derived Metabolites
Several dietary nutrients were proven to undergo both endogenous and bacterial me-
tabolism. For example, dietary choline can be absorbed in the intestines and used for the
synthesis of phospholipids, vital components of cells’ membranes and lipoproteins, taking
part in the transport of triglycerides and cholesterol between liver and peripheral organs
[46]. Additionally, choline is used for the synthesis of acetylcholine, an important neuro-
transmitter of the parasympathetic nervous system regulating vital physiological func-
tions at a resting state [47]. Furthermore, choline can also be transformed by gut microbi-
ota, leading to the synthesis of TMA [48], which has been revealed to have a negative
impact on the cardiovascular and nervous system in mammals by increasing blood pres-
sure [49], promoting formation of atherosclerotic plaques [50] and taking part in the path-
ophysiology of epilepsy and behavioural disorders [51]. TMA can be then further oxidized
to trimethylamine N-oxide (TMAO) by hepatic flavin monooxygenases [52]. TMAO syn-
thesis increases after phosphatidylcholine- and L-carnitine-rich meals [53], and depends
on the metabolism by gut microbiota, which was demonstrated in humans [54]. TMAO
has multiple known effects on the host, from lowering blood pressure and increasing di-
uresis [55], to acting as an osmolyte in order to protect mammalian cells from high hydro-
static and osmotic stress [56].
Dietary substrates, e.g., sulfates, sulfites and cysteine are also transformed into hy-
drogen sulfide (H2S) by microbes such as E. coli and Desulfovibrio or Enterobacter species
[57]. The vasodilatory and hypotensive properties of this gaseous transmitter have been
known for decades [58–60]. Recently, many studies have supported the hypothesis that
high and low concentrations of H2S have different biological effects on mammalian
health. Namely, low levels of hydrogen sulfide seem to protect the cellular bioenergetics
as well as intestinal epithelium integrity, while its high concentrations exert toxic effects
[61,62].
Diet rich in fibre is associated with the growth of specific bacteria producing SCFAs,
including acetic, propionic, butyric, and valeric acids [53,63]. SCFAs have a significant
impact on health in mammals by showing anti-inflammatory [64], hypotensive [5,65,66]
and hypolipidemic [67] effects, as well as by improving endothelial dysfunction induced
by angiotensin II [68]. Moreover, SCFAs have vasodilatory properties, which were inves-
tigated in coronary and colonic circulation, among others [69–72]. Additionally, microbi-
ota-derived indoles, metabolites of exogenous tryptophan, were proven to affect the nerv-
ous, immune, gastrointestinal, and cardiovascular systems in mammals [9,73], which will
be further discussed in this review.
3. Tryptophan Metabolism
Tryptophan is an essential amino acid vital for maintaining health and homeostasis
afforded by its complex metabolism (Figure 1) and biological actions.
Int. J. Mol. Sci. 2022, 23, 1222 4 of 21
Figure 1. Simplified representation of metabolic pathways of tryptophan in mammals. Tryptophan
can be metabolized by host’s own cells (endogenous pathways, grey arrows) and by symbiotic gut
microbiota (bacterial pathways, black arrow). TpH–tryptophan hydroxylase; TDO–tryptophan 2,3-
dioxygenase; IDO–indoleamine 2,3-dioxygenase; TAA–tryptophan aminotransferase; ArAT–aro-
matic amino acid aminotransferase.
3.1. Kynurenine Pathway of Tryptophan Metabolism
In the kynurenine pathway (KP), which accounts for around 95% of tryptophan ca-
tabolism, tryptophan is oxidized to N-formylkynurenine (NFK) mainly by tryptophan 2,3-
dioxygenase (TDO) located in the liver [18,74]. It is the first and rate-limiting step in this
pathway and its activity is regulated by steroids, including cortisol, and systemic levels of
tryptophan [75]. TDO is highly selective when it comes to substrates and works specifi-
cally with tryptophan [76]. Other enzymes, including indoleamine 2, 3-dioxygenase 1
(IDO) and indoleamine 2, 3-dioxygenase 2 (IDO2) contribute to tryptophan breakdown in
extrahepatic tissues and accept other substrates as well. Under normal circumstances,
those enzymes are significantly less active than TDO and thus, a great part of KP takes
place in the liver. However, it has been reported that inflammation might increase the
significance of extrahepatic kynurenine (Kyn) formation [75]. Furthermore, formidase
transforms NFK to Kyn. It is further metabolized by numerous enzymes into its deriva-
tives such as anthranilic acid, kynurenic acid and quinolinic acid. The latter is converted
into nicotinamide adenine dinucleotide (NAD) in a final step of KP [18,74].
3.2. Serotonergic Pathway of Tryptophan Metabolism
Serotonergic pathway degrades only a small fraction (1–2%) of ingested tryptophan.
Two essential enzymes involved in these processes are tryptophan hydroxylase 1 and 2
(TPH1 and TPH2). They produce an active metabolic intermediate, 5-hydroxytryptamine
(serotonin, 5-HT), in the gut (TPH1) and in the brain (TPH2) [74], which is further trans-
formed into melatonin. Serotonin not only works as a neurotransmitter in the central nerv-
ous system, but also controls several physiological functions from the motility of the gas-
trointestinal tract to glucose homeostasis [77]. Serotonin produced in the gut is released
into the blood stream, where platelets use it as a signalling molecule in clot formation [78].
Int. J. Mol. Sci. 2022, 23, 1222 5 of 21
Its metabolites also play important physiological roles and can be used for diagnostic pur-
poses. One of them, melatonin, regulates circadian rhythm and has anti-inflammatory
properties [79]. Finally, measurement of urine levels of 5-HIAA (5-hydroxy indoleacetic
acid, a waste product of serotonin breakdown), is used to estimate serotonin levels in pa-
tients with serotonin-secreting neuroendocrine tumours [80,81].
3.3. Bacterial Metabolism of Tryptophan
Ingested tryptophan is, in large part, absorbed in the intestines to be further metab-
olized by host’s cells. Fractions of this metabolite remaining in intestinal lumen can be
absorbed by symbiotic microbiota, enabling bacterial growth and function. Gut bacteria
use this amino acid for their own needs, simultaneously producing biologically active me-
tabolites that can influence the host’s homeostasis. Symbiotic microorganisms directly
convert tryptophan to indole, skatole, indole-3-acetic acid (IAA), IPA, and indole-3-alde-
hyde (IAld) [9,18,73].
3.3.1. Formation of IPA by Gut Microbiota
Bacteria taking part in the gut formation of IPA include Lactobacillus reuteri [82], Ak-
kermansia and Clostiridum genus [83,84], including species Clostridium sporogenes [85–88]
and Clostridium caloritolerans [88], as well as some Peptostreptococci [89]. Microbial path-
way of IPA production is primarily controlled by tryptophan aminotransferase (TAA, ar-
omatic amino acid aminotransferase, ArAT) [73,89]. Additionally, it has been also estab-
lished that bacterial tryptophanase enables synthesis of IPA in the gut [18].
3.3.2. Formation of Other Indoles by Gut Microbiota
Multiple genera and species participate in the synthesis of specific indoles from tryp-
tophan [89]. According to Roager et al. Escherichia coli, Clostridium spp. and Bacteroides spp.
catabolize tryptophan to indole using the enzyme tryptophanase [89]. Furthermore, main
bacteria producing IAA are Bacteroides such as Bacteroides ovatus, B. eggerthii, B. thetaiota-
omicron, and B. fragilis, as well as some representants of the Clostridium, Bifidobacterium
and Eubacterium genus [21,90]. Decarboxylase and tryptophanase take part in IAA for-
mation [18]. Finally, several Lactobacilli can also synthesize IAld using aromatic amino
acid aminotransferase [21,90].
4. Biological Effects of Tryptophan and IPA
4.1. Tryptophan and Immune System
The relationship between tryptophan and the immune system is bidirectional. On
one hand, tryptophan and its metabolites have an impact on the expression of interleu-
kins. On the other hand, it has been observed that, in the presence of inflammatory and
autoimmune diseases, tryptophan metabolism shifts, leading to increased synthesis of
kynurenines [91,92]. Tryptophan breakdown by IDO is associated with immune system
function, since metabolites of the KP reveal immunomodulatory activity, by reducing Th-
17 cells formation and promoting formation of regulatory T cells [93]. These effects justify
increased IDO expression in pregnancy, as a factor enabling pregnancy tolerance in mam-
mals [94]. Furthermore, IDO expression increases in viral [93], bacterial [95], and parasitic
[96] infections and states associated with increased expression of tumor necrosis factor α
(TNF-α) and interferon-γ (IFN-γ) [97]. Additionally, the expression of this enzyme is also
increased in autoimmune and neurodegenerative diseases, including rheumatoid arthri-
tis, multiple sclerosis, and Alzheimer’s disease [91]. Moreover, IDO expression increases
in carcinogenesis [98] and enhanced tryptophan breakdown via KP is associated with
poorer outcome and development of complications, including anaemia and fatigue, in
cancer patients [99]. IDO, as a first enzyme of the KP, promotes formations of Kyn and its
further metabolites, simultaneously decreasing concentration of their precursor, trypto-
phan. Hence, Kyn/Trp (kynurenine/tryptophan) ratio was proposed as one of the markers
Int. J. Mol. Sci. 2022, 23, 1222 6 of 21
of increased inflammatory response [74,93]. Interestingly, tryptophan itself reveals strong
antioxidative activity [100], and reduces LPS-induced lipoperoxidation [101]. Endogenous
metabolites of tryptophan, including melatonin, can also act as free radicals’ scavengers
[102]. Finally, decreased consumption of tryptophan in diet is associated with increased
serum levels of pro-inflammatory cytokines, including IL-1alpha [103].
4.2. Tryptophan and Body Mass Regulation
Tryptophan is an essential amino acid and component of a balanced diet. Its presence
in the diet is vital for protein synthesis, metabolism and other functions maintaining ho-
meostasis. Research shows that excessive tryptophan consumption and tryptophan defi-
ciency in the diet can affect body mass regulation in mammals. Rats consuming both tryp-
tophan-low and tryptophan-free chow experienced a significant reduction in body weight
gain [104–106]. Interestingly, supplementing tryptophan in the diet reduces food intake
and weight gain in rats [105,107]. Similar effects were observed by intragastric administra-
tion of this amino acid in mice [108].
4.3. Tryptophan and Cardiovascular System Regulation
Regulation of the cardiovascular system involves action of many specific tissues and
hormones to adapt to rapid changes in blood pressure and other hemodynamic parame-
ters. Small molecules, such as noradrenaline and adrenaline, which are metabolites of
amino acid tyrosine, are well-known regulators of cardiovascular system function [109].
Tryptophan also affects hemodynamic parameters. With tyrosine and histidine, trypto-
phan belongs to a group of sensitizers of β-adrenergic receptors (ESBAR) [110]. Addition-
ally, tryptophan increases the contractility of human myocardial cells, demonstrating an
inotropic property [111]. Oral administration of this amino acid increases portal blood
pressure and produces a trend towards higher mean arterial blood pressure in rats [11].
Parenteral tryptophan infusion increases blood pressure in normotensive rats [112]. Ad-
ditionally, tryptophan given orally and parenterally reduces sodium excretion in the kid-
neys revealing an antidiuretic effect [113,114]. On the other hand, parenteral infusion of
tryptophan decreases blood pressure in spontaneously hypertensive rats [112]. The hypo-
tensive effect was also observed after oral administration to patients with essential hyper-
tension [115]. Moreover, IDO activity is also associated with blood pressure regulation.
Increased IDO activity in mice infected with malarial parasite was associated with a de-
crease in systolic blood pressure. Interestingly, inhibition of IDO significantly increased
blood pressure in infected mice [96], a pattern similar to effects of tryptophan administra-
tion in normotensive rats [112]. These observations show complex biological effects of
tryptophan that might be explained, at least partially, by the action of its endogenous and
microbiota-derived metabolites, including IPA.
5. Biological Effects of IPA and Its Impact on Health in Mammals
Knowledge on the biological action of IPA has increased significantly over the past
several years, giving new evidence on the positive and protective effects of this metabolite
(Figure 2).
Int. J. Mol. Sci. 2022, 23, 1222 7 of 21
Figure 2. Protective effects of indole-3-propionic acid (IPA) on cellular and tissue level. GBB- gut-
blood barrier; ROS–reactive oxygen species.
5.1. IPA Improves Gut-Blood Barrier Function
Studies on the GBB demonstrate that indole [10] and IPA [20,116,117], two trypto-
phan metabolites, improve barrier properties by increasing the expression of claudins and
other tight junction proteins. Additionally, IPA increases secretion of mucins in in vitro
human colonic culture [20] and increases the number of goblet cells and mucosa thickness
in rats [118]. Moreover, IPA acts as a ligand of the aryl hydrocarbon receptor (AhR) pre-
sent in colonic epithelial cells, activation of which is associated with anti-inflammatory
and anticancer effects [119] Interestingly, it has been observed that in patients suffering
from colitis serum, IPA concentration decreases significantly [28]. Apart from being an
AhR ligand, IPA can also produce its biological action by activating the pregnane X recep-
tor (PXR) present in colonic, liver endothelial and muscle cells [23,119,120]. Complex la-
boratory techniques allow testing the function of GBB by measuring its permeability to
specific substances, including Fluorescein Isothiocyanate-Dextran (FITC-Dextran). Three
independent research projects revealed that IPA decreases FITC-dextran-dependent gut
permeability in mice [121–123]. Venkatesh et al. proved that IPA decreases gut permea-
bility by interacting with PXR [121].
5.2. IPA Protects against Oxidative Stress and Attenuates Inflammation
Physiological activity of the immune system is important in the regulation of mam-
malian health and represents a dualistic approach. Its activation limits the invasion of
pathogens and is a key mechanism protecting from infections. On the other hand, regula-
tory mechanisms moderating the immune response must be preserved to prevent the ex-
cessive activation of immune cells associated with autoimmune diseases. Bacterial metab-
olites of tryptophan have a complex impact on the immune system, revealing both pro-
and anti-inflammatory properties. IS, the liver metabolite of microbiota-derived indole,
promotes the production of reactive oxygen species (ROS) [124] and induces expression
of proinflammatory cytokines, including IL-1β [125], TNF-α [125] and MCP-1 [125–127].
Interestingly, IPA protects cells from ROS [25,128,129], oxidative damage and lipid perox-
idation caused by potassium bromate [130–132], potassium iodate [24], iron (II) sulphate
[133,134], iron (III) chloride [135], chromium (III) chloride [136], and 2,2′-Azino-bis(3-
ethylbenzothiazoline-6-sulfonic acid (ABTS) [137]. Additionally, IPA decreases the ex-
pression of proinflammatory cytokines, including TNF-α [22,27,121], IL-1β [23,27], IL-6
[27], IL-12 [22], IL-13 [22] and MCP-1 [22,82]. Interestingly, IPA also shows antimicrobial
activity by inhibiting the growth of Legionella pneumophila [138,139], and Salmonella typhi-
murium [140]. Apart from that, in patients with type II diabetes, serum concentration of
Int. J. Mol. Sci. 2022, 23, 1222 8 of 21
IPA is negatively correlated with high-sensitivity C-reactive protein (hsCRP) [141]. More-
over, Nyström et al. observed that in immunodeficient patients with HIV infection syn-
thesis of IPA is significantly diminished [142].
5.3. IPA Protects against Carcinogens and Has an Antitumor Potential
Carcinogenesis is a complex and complicated process of modification of healthy cells
into autonomous and self-sufficient pathogenic conglomerate of cells. Many factors en-
hancing carcinogenesis have been established, including ionizing radiation, ultraviolet
(UV) radiation, oxidative stress, DNA damage, viral infections, and lifestyle factors, such
as tobacco smoke, ethanol consumption, and ingestion of nutritional carcinogens
[143,144]. Increased formation of ROS has a negative impact on lipid barriers, affects DNA
structure, and takes part in carcinogenesis; therefore antioxidants, both nutritional and
pharmacological, have been targets of great research interest over the past years [145,146].
Both melatonin and IPA can be classified as free radical’s scavengers, and their antitumor
potential have been investigated in the scientific literature [136,147]. IPA prevents DNA
damage in hamsters’ kidneys exposed to oestradiol [147], rats’ brains exposed to chlorpyr-
ifos [148], and calf thymus samples exposed to chromium (III) chloride [136]. Addition-
ally, IPA decreases fluidity of rats’ liver microsomal membranes incubated with chro-
mium (III) chloride [149]. Due to its positive cellular effects, IPA has become a promising
particle used for the chemical modification of well-known antineoplastic drugs [150] and
compounds [151,152]. Addition of an IPA particle as a ligand to a cisplatin structure
caused significant cytotoxic effect, associated with increased ROS formation [150]. Cad-
mium-IPA complexes possess antiproliferative and proteasome-inhibitory activity in in
vitro breast cancer cells [151]. Interestingly, IPA alleviates hematopoietic and gastrointes-
tinal side effects of radiotherapy in the mice model [153]. Further research projects should
focus on testing the impact of IPA on neoplastic cells’ survival and evaluate its role in both
cancer prevention and therapy.
5.4. IPA has a protective role in neurodegenerative disease models
The pathophysiology of neurodegenerative diseases is complex, and many possible
pathways have been proposed as therapeutic targets to slow down disease progression
and preserve neurological functions of the affected individuals. In general, the develop-
ment of Alzheimer’s, Parkinson’s and Huntington’s diseases is associated with patholog-
ical accumulation of specific proteins in vital brain centres responsible for cognition,
memory, motor activity and other essential neurological processes [154,155].
5.4.1. IPA in Alzheimer’s Disease
Abnormal folding of amyloid β-proteins and their deposition in amyloid plaques re-
veals neurodegenerative properties due to the activation of ROS[156].
Melatonin has antioxidative action, and also increases clearance of amyloid β-protein
in the mice model of Alzheimer’s disease amyloidosis [157]. IPA shares protective biolog-
ical effects against oxidative stress with melatonin [24,133] and decreases aggregation of
amyloid β-protein in in vitro experiments [158]. The addition of IPA to media of the pri-
mary neurons and neuroblastoma cells exposed to amyloid β-protein significantly re-
duced toxicity and prevented cell death [159]. Dragicevic et al. observed that both IPA and
melatonin restore mitochondrial function in the in vitro model of Alzheimer’s disease
[160]. Interestingly, IPA also protects brain tissue from oxidative stress, lipid peroxidation
and oxidative DNA damage in hippocampal region after acute brain ischemia [26]. Addi-
tionally, IPA acts synergistically with glutathione to prevent ABTS-related formation of
free radicals in the rat brain and reduces associated lipid peroxidation [128]. Surprisingly,
Huangs et al. observed a trend towards higher plasma IPA levels in patients with pro-
gressive mild cognitive impairment (MCI) and Alzheimer’s disease, compared to patients
Int. J. Mol. Sci. 2022, 23, 1222 9 of 21
with stable MCI. However, these changes were not statistically significant [161]. Addi-
tional research data are needed to fully evaluate role of IPA as a protective or predictive
factor in Alzheimer’s disease.
5.4.2. IPA and other Neurodegenerative Diseases
IPA exerts a chemical chaperone-like activity and inhibits abnormal aggregation of
the regular [162] and denatured [163] proteins. In two cell culture models of Parkinson’s
disease associated with overexpression of Parkin-associated endothelin receptor-like re-
ceptor (Pael-R) and α-synuclein, IPA significantly reduced ROS-associated cell death [163]
Additionally, patients with Huntington’s disease have lower plasma concentration of IPA,
which might be associated with system-wide decreased ability to protect against ROS for-
mation [87]. On the contrary, increased IPA formation was observed in mice with experi-
mental autoimmune encephalitis (EAE) [164], animal model of multiple sclerosis (MS),
and patients with relapsing-remitting MS [165].
5.5. IPA has a Positive Impact on Cardiovascular Disease Risk Factors
Initially endogenous metabolites of tryptophan were suspected to be accountable for
tryptophan’s cardiovascular actions [166]. Recently, it has been established that IPA itself
can also affect cardiovascular system [19,167]. Additionally, its synthesis can change in
presence of cardiovascular-related diseases (Table 1).
Table 1. Comparison of tendencies in the synthesis of indole-3-propionic acid (IPA) associated with
protective and harmful factors of cardiovascular diseases.
Impact of a Factor on
Cardiovascular Health
Factor Affecting
Cardiovascular Health
Change in the
Synthesis of IPA References
Positive
Mediterranean diet Increase [168]
Increased composition of fibre
in the diet Increase [29,141]
Increased mulberry consumption Increase [83]
Negative
Diabetes Decrease [29]
Dyslipidaemia Decrease [169]
Obesity Decrease [30]
Atherosclerosis Decrease [170]
5.5.1. Diet
The composition of specific nutrients in diet can affect mammalian health and disrupt
lipid and carbohydrate homeostasis. Diets rich in red meat and saturated fatty acids are
long-established cardiovascular disease risk factors [171]. Additionally, diets with a high
content of red meat increase the synthesis of TMA, a bacterial metabolite formed mainly
from carnitine [6,172]. Complex nutritional interventions stimulate the formation of other
microbiota-derived metabolites, including IPA. The Mediterranean diet, known for its
beneficial and cardio-protective role, significantly increases the plasma concentration of
IPA in humans [168]. Moreover, diets rich in fibre [29,141] and inulin [173] also promote
the synthesis of this metabolite. On the contrary, a fast-food diet, a known risk factor for
cardiovascular diseases, significantly reduces the plasma concentration of IPA in humans
[168]. Interestingly, the addition of IPA to a high-fat diet in mice restores bone minerali-
zation and osteoblasts’ function diminished in mice ingesting a high-fat diet alone [174].
5.5.2. Dyslipidaemia
Disturbances in lipid metabolism, including the rise in total cholesterol levels, have
been linked to an increased risk of cardiovascular disease-related mortality [175]. Associ-
ation of high concentration of triglycerides and low HDL cholesterol level is classified as
atherogenic dyslipidaemia and is linked to the progression of atherosclerosis [176]. Long-
Int. J. Mol. Sci. 2022, 23, 1222 10 of 21
lasting disturbances in lipid metabolism lead to obesity, metabolic syndrome and non-
alcoholic fatty liver disease [177]. Plasma concentration of IPA is significantly reduced in
patients with dyslipidaemia [169]. Hypolipidemic interventions, including the admin-
istration of mulberry leaf extract and 1-deoxynojirimycin, are associated with increased
IPA concentration in stools [83]. Additionally, IPA plasma concentration correlates nega-
tively with lipid parameters, including triglycerides and LDL-C plasma levels [173]. More-
over, IPA reduces hepatic steatosis and hepatocyte dysfunction in a rat model of high-fat
diet-induced steatohepatitis [27]. In patients with hepatic lobular inflammation and liver
fibrosis significant decrease in circulating IPA levels in serum can be observed [178]. Sur-
prisingly, IPA enhances liver damage in mice with carbon tetrachloride-induced liver fi-
brosis, without affecting the liver functions of healthy controls [179]. Previous observa-
tions need to be further investigated to establish whether IPA has a positive or negative
effect on liver function. There is only one research paper, in which IPA failed to reveal
protective metabolic effects in mice fed Western diet, while simultaneously improving
intestinal functions [122]. Taken together, more research data is needed to fully under-
stand regulatory role of IPA in lipid, metabolic, and liver homeostasis. It is possible that
specific metabolic changes occur when the concentration of this metabolite in peripheral
blood increases above a certain threshold that needs to be established in further experi-
ments.
5.5.3. Obesity
The number of patients with excess body fat increases drastically each year, and data
extrapolations suggest this trend will continue [180]. Increased body weight and obesity
are associated with a broad group of metabolic disturbances due to excessive adipose tis-
sue accumulation and increased cytokine synthesis [181]. Previously, we discussed the
positive role of tryptophan in the reduction in body mass. Recent results from our labor-
atory showed that parenteral administration of IPA significantly recuses weight gain in
rats [105]. Additionally, human studies showed that in obese female patients, a significant
decrease in the concentration of IPA in serum and follicular fluid could be observed com-
pared to women with normal weight [30]. Apart from that, in an animal model of gluco-
corticoid withdrawal syndrome, IPA formation is significantly diminished, showing that
its synthesis might also by affected by changes in the function of the adrenal glands [182].
5.5.4. Hyperglycaemia
Increased plasma glucose concentration is associated with severe complications, in-
cluding endothelial dysfunction, atherosclerosis progression, and lipid homeostasis
changes [183]. Diabetes and prediabetic states are considered significant risk factors for
cardiovascular disease, the prime cause of death in this patient population [184]. Despite
multiple therapeutic options and new innovative treatments, many patients struggle to
control their glycaemia adequately. New research findings suggest that carbohydrate ho-
meostasis might be affected by metabolites produced by gut bacteria, including indoles
[29,185]. Abildgaard et al. observed that introducing an IPA-enriched diet for 6 weeks
significantly reduces fasting blood glucose concentration and plasma insulin level in rats
[186]. Furthermore, in a human study of the Finnish population, patients who developed
type II diabetes had significantly lower serum concentration of IPA [29]. Additionally, the
concentration of this metabolite has been inversely correlated with the incidence of type
II diabetes and tended to be positively correlated with insulin secretion [141].
5.5.5. Hypertension
Blood pressure control depends on two main components: mechanical action of the
myocardium and peripheral vasculature [187]. Elevated blood pressure is an important
cardiovascular risk factor, as it takes part in the pathophysiology of atherosclerosis and
Int. J. Mol. Sci. 2022, 23, 1222 11 of 21
causes microcirculatory dysfunction and progressive tissue damage [188]. Bacterial me-
tabolites of tryptophan reveal similar hemodynamic patterns as their precursor. Results
from our laboratory show that both IS and indole increase blood pressure in normotensive
rats, with and without a concomitant increase in heart rate [13]. The scientific literature
indicates that IPA is also involved in blood pressure regulation in mammals [19]. Using
the Langendorff heart model in mice, an IPA-dependent increase in myocardial contrac-
tility was demonstrated [167]. Additionally, this metabolite causes vasoconstriction of the
endothelium-denuded mesenteric resistance arteries [19] and diminishes vasodilatation
associated with pre-treatment with sodium nitroprusside [189] and acetylcholine [19]. The
vascular effect of IPA might be mediated by the activation of PXR [189]. So far, it has not
been elucidated whether long-term administration of IPA takes part in the pathophysiol-
ogy of hypertension and hypertension-related cardiovascular diseases. Human studies
revealed that patients with advanced atherosclerosis had significantly reduced plasma
IPA concentrations [170]. Additionally, in this group, IPA levels correlated strongly with
higher ankle-brachial index (ABI) and less severe peripheral arterial disease (PAD) [170].
6. Modulation of IPA Concentration as a Therapeutic Target
6.1. Antibiotics
Knowledge of antibiotics and their potential in treating infections dates back to the
discovery of penicillin by Alexander Flemming in 1928 [190]. Nowadays, antibiotics are
some of the most frequently prescribed medications in everyday medical practice. Grow-
ing evidence suggests that using antibiotics affects pathogenic bacteria and strikes back
against symbiotic microbiota, leading to the development of serious diseases, including
Clostridioides difficile infection and pseudomembranous colitis [191]. Antibiotic groups dif-
fer in their pharmacokinetic properties, which affects their distribution and action site in
the organism. For example, neomycin given orally acts predominantly in the gut due to
its low absorption in the intestines [192]. Behr et al. tested how oral administration of spe-
cific antibiotics affects the synthesis of certain bacterial metabolites, including IPA. A 4-
week treatment with fluoroquinolones, tetracyclines and aminoglycosides significantly
reduced IPA plasma concentration, with the greatest effect on the third group [193]. Data
from our laboratory confirmed the observation, as mentioned above. A 2-week-long oral
administration of neomycin significantly reduced the levels of IPA in the stool, portal, and
peripheral blood of Sprague Dawley rats [105]. Other antibiotics, including ampicillin,
might also affect the bacterial metabolism of tryptophan [82].
6.2. Tryptophan Concentration in Diet
Several factors affect IPA metabolism in mammals. Diet, medications, and intestinal
disturbances can influence the concentration of this metabolite in the gut. The introduc-
tion of a tryptophan-rich diet for 2 weeks significantly increases the concentration of IPA
in colon contents, portal, and peripheral blood [105]. On the other hand, a tryptophan-free
diet, administered for the same period, significantly reduces the synthesis of this metabo-
lite [105]. Tryptophan concentration in the diet is not the only nutritional factor affecting
the synthesis of IPA [83,168].
6.3. Probiotics
Administration of specific bacterial species as probiotics has increased its recognition
as a therapeutic option in gastrointestinal diseases over the past few years [194,195]. Pro-
biotics co-administered with antibiotics seem to decrease the risk of developing severe
adverse effects, including Clostridioides difficile infection [194]. Probiotics restore healthy
gut microbiota composition and its functions, including synthesis of specific metabolites
[174,196–198]. Lactobacillus reuteri can be administered as a probiotic, revealing a positive
impact, by improving infantile colic symptoms [199,200]. Simultaneously it has been ob-
served that this bacterial species is able to synthetize IPA [82]. It still needs to be elucidated
Int. J. Mol. Sci. 2022, 23, 1222 12 of 21
whether the positive impact of L. reuteri might be due to the synthesis of specific metabo-
lites, including IPA.
7. Materials and Methods
We searched PUBMED and Google Scholar databases to identify pre-clinical and
clinical studies on synthesis and biological effects of IPA. The key words included micro-
biota, tryptophan, indoles, indole-3-propionic acid. The search was confined to manu-
scripts that were published from 1961 to December 2021. Specific steps of the review pro-
cess and the evaluation of scientific papers are present in Figure 3. A total of 131 records
on IPA were obtained from databases, and an additional 10 papers were included from
other sources. A total of 141 papers were screened for relevance and 67 records were ex-
cluded from further analysis. Exclusion criteria were language other than English (2 rec-
ords), chemistry-focused papers (21 records), papers evaluating results from experiments
on subjects other than mammals and bacteria (24 records), and papers on indoles other
than IPA and not evaluating effects of IPA (20 records). Finally, 74 papers evaluating the
synthesis and biological effects of IPA were included in this review.
Figure 3. Schematic representation of study protocol of papers evaluating synthesis and biological
effects of IPA. Black arrows show steps of the review process. IPA–indole-3-propionic acid.
8. Conclusions
Symbiotic gut microbiota is able to produce biologically active metabolites that can
affect functions of the host. IPA belongs to the wide group of indoles, microbiota derived
metabolites of tryptophan. It has been observed that IPA has beneficial impact on host
health by possessing anti-inflammatory and ROS-scavenging activity. Further research
projects should evaluate its possible clinical applications in the treatment of autoimmune,
inflammatory and oncological diseases. Additionally, its synthesis decreases in many
pathological states associated with an increased risk of developing cardiovascular dis-
eases, making it a promising new pharmacotherapeutic target.
Funding: This research was funded by the PRELUDIUM grant of the Polish National Science Centre
(2019/35/N/NZ4/01111) to P.K.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All relevant data are presented in this paper.
Acknowledgments: No assistance in the preparation of this article is to be declared.
Conflicts of Interest: The authors declare no conflict of interest.
Int. J. Mol. Sci. 2022, 23, 1222 13 of 21
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