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Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease

Piotr Konopelski, Izabella Mogilnicka

International Journal of Molecular Sciences · 2022 · Review · CC BY

doi:10.3390/ijms23031222

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 bacterial 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 evidence that gut bacteria-derived metabolites of tryptophan share the biological effects of their precursor. 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 databases 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 concentration. IPA seems to be a promising new target, linking gut health with the cardiovascular system.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

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, diabetes and hypertension. Initially, research focused mainly on the role of short-chain fatty acids (SCFAs) and carnitine-derived metabolites. 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. So far, research projects on bacterial metabolism of tryptophan focused mainly on actions of indole, and its liver metabolite, indoxyl sulfate (IS). Indole decreases intestinal inflammation and has positive impact on gastrointestinal and liver homeostasis. On the other hand, IS can be classified as uremic toxin, as its concentration increases significantly in chronic kidney disease. IS is proposed to be one of the factors linking kidney dysfunction with an increased risk of developing cardiovascular disease.

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 literature. A review of articles summarizing the impact of tryptophan metabolism on cardiovascular system homeostasis has recently been published, however; the main focus of that paper was kynurenine- and the serotonin pathway. 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. IPA has a protective role on a cellular and tissue level, by limiting inflammation, lipid peroxidation, and the formation of free radicals. Additionally, IPA affects the function of the immune, nervous, gastrointestinal and cardiovascular system, and its synthesis decreases significantly in several pathogenic states and diseases, including colitis, diabetes, and obesity. The novelty of this review is that we assess the available evidence on biological effects of IPA and emphasize its potential therapeutic applications.

2. Gut Microbiota

The close relationship between host and symbiotic gut microbiota has gained scientific interest over the past few decades. It has been observed that this relationship is bidirectional and symbiotic, with both participants benefiting from this union. The host provides 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 and is associated with many biochemical pathways and the synthesis of specific metabolites that can be absorbed into the circulation. Gut bacteria participate in the breakdown of haemoglobin through their ability to transform bilirubin into stercobilinogen, enabling elimination of the latter in faeces. Additionally, gut bacteria metabolize primary bile acids, synthesized in the liver to form secondary bile acids, demonstrating a protective role in gastrointestinal physiology.

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 between the small and large intestine. 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. In rodents, cecum is proposed to have critical role in bacterial fermentation, however; its localization and distance from the anal margin disturb its evaluation in live subjects. Intercaecal administration of investigated compounds and the collection of samples requires surgical preparation 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. 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-associated lymphoid tissue (GALT), symbiotic bacteria and secretory proteins, including lactoferrin, prevent the transmission of pathogenic bacteria and their toxins into circulation. Disruption of this protective action of GBB has been observed in several diseases, including diabetes, hypertension, and inflammatory bowel diseases, leading to increased permeability to gut bacteria-derived metabolites, including trimethylamine (TMA). 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 disease.

2.2. Gut Microbiota-Derived Metabolites

Several dietary nutrients were proven to undergo both endogenous and bacterial metabolism. 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. Additionally, choline is used for the synthesis of acetylcholine, an important neurotransmitter of the parasympathetic nervous system regulating vital physiological functions at a resting state. Furthermore, choline can also be transformed by gut microbiota, leading to the synthesis of TMA, which has been revealed to have a negative impact on the cardiovascular and nervous system in mammals by increasing blood pressure, promoting formation of atherosclerotic plaques and taking part in the pathophysiology of epilepsy and behavioural disorders. TMA can be then further oxidized to trimethylamine N-oxide (TMAO) by hepatic flavin monooxygenases. TMAO synthesis increases after phosphatidylcholine- and L-carnitine-rich meals, and depends on the metabolism by gut microbiota, which was demonstrated in humans. TMAO has multiple known effects on the host, from lowering blood pressure and increasing diuresis, to acting as an osmolyte in order to protect mammalian cells from high hydrostatic and osmotic stress.

Dietary substrates, e.g., sulfates, sulfites and cysteine are also transformed into hydrogen sulfide (H2S) by microbes such as E. coli and Desulfovibrio or Enterobacter species. The vasodilatory and hypotensive properties of this gaseous transmitter have been known for decades. 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.

Diet rich in fibre is associated with the growth of specific bacteria producing SCFAs, including acetic, propionic, butyric, and valeric acids. SCFAs have a significant impact on health in mammals by showing anti-inflammatory, hypotensive and hypolipidemic effects, as well as by improving endothelial dysfunction induced by angiotensin II. Moreover, SCFAs have vasodilatory properties, which were investigated in coronary and colonic circulation, among others. Additionally, microbiota-derived indoles, metabolites of exogenous tryptophan, were proven to affect the nervous, immune, gastrointestinal, and cardiovascular systems in mammals, 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.

3.1. Kynurenine Pathway of Tryptophan Metabolism

In the kynurenine pathway (KP), which accounts for around 95% of tryptophan catabolism, tryptophan is oxidized to N-formylkynurenine (NFK) mainly by tryptophan 2,3-dioxygenase (TDO) located in the liver. 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. TDO is highly selective when it comes to substrates and works specifically with tryptophan. 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. Furthermore, formidase transforms NFK to Kyn. It is further metabolized by numerous enzymes into its derivatives such as anthranilic acid, kynurenic acid and quinolinic acid. The latter is converted into nicotinamide adenine dinucleotide (NAD) in a final step of KP.

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), which is further transformed into melatonin. Serotonin not only works as a neurotransmitter in the central nervous system, but also controls several physiological functions from the motility of the gastrointestinal tract to glucose homeostasis. Serotonin produced in the gut is released into the blood stream, where platelets use it as a signalling molecule in clot formation. Its metabolites also play important physiological roles and can be used for diagnostic purposes. One of them, melatonin, regulates circadian rhythm and has anti-inflammatory properties. 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 patients with serotonin-secreting neuroendocrine tumours.

3.3. Bacterial Metabolism of Tryptophan

Ingested tryptophan is, in large part, absorbed in the intestines to be further metabolized 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 metabolites that can influence the host’s homeostasis. Symbiotic microorganisms directly convert tryptophan to indole, skatole, indole-3-acetic acid (IAA), IPA, and indole-3-aldehyde (IAld).

3.3.1. Formation of IPA by Gut Microbiota

Bacteria taking part in the gut formation of IPA include Lactobacillus reuteri, Akkermansia and Clostiridum genus, including species Clostridium sporogenes and Clostridium caloritolerans, as well as some Peptostreptococci. Microbial pathway of IPA production is primarily controlled by tryptophan aminotransferase (TAA, aromatic amino acid aminotransferase, ArAT). Additionally, it has been also established that bacterial tryptophanase enables synthesis of IPA in the gut.

3.3.2. Formation of Other Indoles by Gut Microbiota

Multiple genera and species participate in the synthesis of specific indoles from tryptophan. According to Roager et al. Escherichia coli, Clostridium spp. and Bacteroides spp. catabolize tryptophan to indole using the enzyme tryptophanase. Furthermore, main bacteria producing IAA are Bacteroides such as Bacteroides ovatus, B. eggerthii, B. thetaiotaomicron, and B. fragilis, as well as some representants of the Clostridium, Bifidobacterium and Eubacterium genus. Decarboxylase and tryptophanase take part in IAA formation. Finally, several Lactobacilli can also synthesize IAld using aromatic amino acid aminotransferase.

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 interleukins. 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. 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. These effects justify increased IDO expression in pregnancy, as a factor enabling pregnancy tolerance in mammals. Furthermore, IDO expression increases in viral, bacterial, and parasitic infections and states associated with increased expression of tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ). Additionally, the expression of this enzyme is also increased in autoimmune and neurodegenerative diseases, including rheumatoid arthritis, multiple sclerosis, and Alzheimer’s disease. Moreover, IDO expression increases in carcinogenesis and enhanced tryptophan breakdown via KP is associated with poorer outcome and development of complications, including anaemia and fatigue, in cancer patients. IDO, as a first enzyme of the KP, promotes formations of Kyn and its further metabolites, simultaneously decreasing concentration of their precursor, tryptophan. Hence, Kyn/Trp (kynurenine/tryptophan) ratio was proposed as one of the markers of increased inflammatory response. Interestingly, tryptophan itself reveals strong antioxidative activity, and reduces LPS-induced lipoperoxidation. Endogenous metabolites of tryptophan, including melatonin, can also act as free radicals’ scavengers. Finally, decreased consumption of tryptophan in diet is associated with increased serum levels of pro-inflammatory cytokines, including IL-1alpha.

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 homeostasis. Research shows that excessive tryptophan consumption and tryptophan deficiency in the diet can affect body mass regulation in mammals. Rats consuming both tryptophan-low and tryptophan-free chow experienced a significant reduction in body weight gain. Interestingly, supplementing tryptophan in the diet reduces food intake and weight gain in rats. Similar effects were observed by intragastric administration of this amino acid in mice.

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 parameters. Small molecules, such as noradrenaline and adrenaline, which are metabolites of amino acid tyrosine, are well-known regulators of cardiovascular system function. Tryptophan also affects hemodynamic parameters. With tyrosine and histidine, tryptophan belongs to a group of sensitizers of β-adrenergic receptors (ESBAR). Additionally, tryptophan increases the contractility of human myocardial cells, demonstrating an inotropic property. Oral administration of this amino acid increases portal blood pressure and produces a trend towards higher mean arterial blood pressure in rats. Parenteral tryptophan infusion increases blood pressure in normotensive rats. Additionally, tryptophan given orally and parenterally reduces sodium excretion in the kidneys revealing an antidiuretic effect. On the other hand, parenteral infusion of tryptophan decreases blood pressure in spontaneously hypertensive rats. The hypotensive effect was also observed after oral administration to patients with essential hypertension. Moreover, IDO activity is also associated with blood pressure regulation. Increased IDO activity in mice infected with malarial parasite was associated with a decrease in systolic blood pressure. Interestingly, inhibition of IDO significantly increased blood pressure in infected mice, a pattern similar to effects of tryptophan administration in normotensive rats. 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).

5.1. IPA Improves Gut-Blood Barrier Function

Studies on the GBB demonstrate that indole and IPA, two tryptophan 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 and increases the number of goblet cells and mucosa thickness in rats. Moreover, IPA acts as a ligand of the aryl hydrocarbon receptor (AhR) present in colonic epithelial cells, activation of which is associated with anti-inflammatory and anticancer effects Interestingly, it has been observed that in patients suffering from colitis serum, IPA concentration decreases significantly. Apart from being an AhR ligand, IPA can also produce its biological action by activating the pregnane X receptor (PXR) present in colonic, liver endothelial and muscle cells. Complex laboratory 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. Venkatesh et al. proved that IPA decreases gut permeability by interacting with PXR.

5.2. IPA Protects against Oxidative Stress and Attenuates Inflammation

Physiological activity of the immune system is important in the regulation of mammalian 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, regulatory mechanisms moderating the immune response must be preserved to prevent the excessive activation of immune cells associated with autoimmune diseases. Bacterial metabolites 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) and induces expression of proinflammatory cytokines, including IL-1β, TNF-α and MCP-1. Interestingly, IPA protects cells from ROS, oxidative damage and lipid peroxidation caused by potassium bromate, potassium iodate, iron (II) sulphate, iron (III) chloride, chromium (III) chloride, and 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS). Additionally, IPA decreases the expression of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-12, IL-13 and MCP-1. Interestingly, IPA also shows antimicrobial activity by inhibiting the growth of Legionella pneumophila, and Salmonella typhimurium. Apart from that, in patients with type II diabetes, serum concentration of IPA is negatively correlated with high-sensitivity C-reactive protein (hsCRP). Moreover, Nyström et al. observed that in immunodeficient patients with HIV infection synthesis of IPA is significantly diminished.

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 enhancing 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. 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. Both melatonin and IPA can be classified as free radical’s scavengers, and their antitumor potential have been investigated in the scientific literature. IPA prevents DNA damage in hamsters’ kidneys exposed to oestradiol, rats’ brains exposed to chlorpyrifos, and calf thymus samples exposed to chromium (III) chloride. Additionally, IPA decreases fluidity of rats’ liver microsomal membranes incubated with chromium (III) chloride. Due to its positive cellular effects, IPA has become a promising particle used for the chemical modification of well-known antineoplastic drugs and compounds. Addition of an IPA particle as a ligand to a cisplatin structure caused significant cytotoxic effect, associated with increased ROS formation. Cadmium-IPA complexes possess antiproliferative and proteasome-inhibitory activity in in vitro breast cancer cells. Interestingly, IPA alleviates hematopoietic and gastrointestinal side effects of radiotherapy in the mice model. 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 development of Alzheimer’s, Parkinson’s and Huntington’s diseases is associated with pathological accumulation of specific proteins in vital brain centres responsible for cognition, memory, motor activity and other essential neurological processes.

5.4.1. IPA in Alzheimer’s Disease

Abnormal folding of amyloid β-proteins and their deposition in amyloid plaques reveals neurodegenerative properties due to the activation of ROS.

Melatonin has antioxidative action, and also increases clearance of amyloid β-protein in the mice model of Alzheimer’s disease amyloidosis. IPA shares protective biological effects against oxidative stress with melatonin and decreases aggregation of amyloid β-protein in in vitro experiments. The addition of IPA to media of the primary neurons and neuroblastoma cells exposed to amyloid β-protein significantly reduced toxicity and prevented cell death. Dragicevic et al. observed that both IPA and melatonin restore mitochondrial function in the in vitro model of Alzheimer’s disease. Interestingly, IPA also protects brain tissue from oxidative stress, lipid peroxidation and oxidative DNA damage in hippocampal region after acute brain ischemia. Additionally, IPA acts synergistically with glutathione to prevent ABTS-related formation of free radicals in the rat brain and reduces associated lipid peroxidation. Surprisingly, Huangs et al. observed a trend towards higher plasma IPA levels in patients with progressive mild cognitive impairment (MCI) and Alzheimer’s disease, compared to patients with stable MCI. However, these changes were not statistically significant. Additional 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 and denatured proteins. In two cell culture models of Parkinson’s disease associated with overexpression of Parkin-associated endothelin receptor-like receptor (Pael-R) and α-synuclein, IPA significantly reduced ROS-associated cell death 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 formation. On the contrary, increased IPA formation was observed in mice with experimental autoimmune encephalitis (EAE), animal model of multiple sclerosis (MS), and patients with relapsing-remitting MS.

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. Recently, it has been established that IPA itself can also affect cardiovascular system. Additionally, its synthesis can change in presence of cardiovascular-related diseases (Table 1).

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. Additionally, diets with a high content of red meat increase the synthesis of TMA, a bacterial metabolite formed mainly from carnitine. 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. Moreover, diets rich in fibre and inulin 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. Interestingly, the addition of IPA to a high-fat diet in mice restores bone mineralization and osteoblasts’ function diminished in mice ingesting a high-fat diet alone.

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. Association of high concentration of triglycerides and low HDL cholesterol level is classified as atherogenic dyslipidaemia and is linked to the progression of atherosclerosis. Long-lasting disturbances in lipid metabolism lead to obesity, metabolic syndrome and non-alcoholic fatty liver disease. Plasma concentration of IPA is significantly reduced in patients with dyslipidaemia. Hypolipidemic interventions, including the administration of mulberry leaf extract and 1-deoxynojirimycin, are associated with increased IPA concentration in stools. Additionally, IPA plasma concentration correlates negatively with lipid parameters, including triglycerides and LDL-C plasma levels. Moreover, IPA reduces hepatic steatosis and hepatocyte dysfunction in a rat model of high-fat diet-induced steatohepatitis. In patients with hepatic lobular inflammation and liver fibrosis significant decrease in circulating IPA levels in serum can be observed. Surprisingly, IPA enhances liver damage in mice with carbon tetrachloride-induced liver fibrosis, without affecting the liver functions of healthy controls. Previous observations 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. Taken together, more research data is needed to fully understand 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 experiments.

5.5.3. Obesity

The number of patients with excess body fat increases drastically each year, and data extrapolations suggest this trend will continue. Increased body weight and obesity are associated with a broad group of metabolic disturbances due to excessive adipose tissue accumulation and increased cytokine synthesis. Previously, we discussed the positive role of tryptophan in the reduction in body mass. Recent results from our laboratory showed that parenteral administration of IPA significantly recuses weight gain in rats. 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 compared to women with normal weight. Apart from that, in an animal model of glucocorticoid withdrawal syndrome, IPA formation is significantly diminished, showing that its synthesis might also by affected by changes in the function of the adrenal glands.

5.5.4. Hyperglycaemia

Increased plasma glucose concentration is associated with severe complications, including endothelial dysfunction, atherosclerosis progression, and lipid homeostasis changes. Diabetes and prediabetic states are considered significant risk factors for cardiovascular disease, the prime cause of death in this patient population. Despite multiple therapeutic options and new innovative treatments, many patients struggle to control their glycaemia adequately. New research findings suggest that carbohydrate homeostasis might be affected by metabolites produced by gut bacteria, including indoles. 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. Furthermore, in a human study of the Finnish population, patients who developed type II diabetes had significantly lower serum concentration of IPA. 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.

5.5.5. Hypertension

Blood pressure control depends on two main components: mechanical action of the myocardium and peripheral vasculature. Elevated blood pressure is an important cardiovascular risk factor, as it takes part in the pathophysiology of atherosclerosis and causes microcirculatory dysfunction and progressive tissue damage. Bacterial metabolites 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. The scientific literature indicates that IPA is also involved in blood pressure regulation in mammals. Using the Langendorff heart model in mice, an IPA-dependent increase in myocardial contractility was demonstrated. Additionally, this metabolite causes vasoconstriction of the endothelium-denuded mesenteric resistance arteries and diminishes vasodilatation associated with pre-treatment with sodium nitroprusside and acetylcholine. The vascular effect of IPA might be mediated by the activation of PXR. So far, it has not been elucidated whether long-term administration of IPA takes part in the pathophysiology of hypertension and hypertension-related cardiovascular diseases. Human studies revealed that patients with advanced atherosclerosis had significantly reduced plasma IPA concentrations. Additionally, in this group, IPA levels correlated strongly with higher ankle-brachial index (ABI) and less severe peripheral arterial disease (PAD).

6.1. Antibiotics

Knowledge of antibiotics and their potential in treating infections dates back to the discovery of penicillin by Alexander Flemming in 1928. Nowadays, antibiotics are some of the most frequently prescribed medications in everyday medical practice. Growing 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. Antibiotic groups differ 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. Behr et al. tested how oral administration of specific 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. 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. Other antibiotics, including ampicillin, might also affect the bacterial metabolism of tryptophan.

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 introduction of a tryptophan-rich diet for 2 weeks significantly increases the concentration of IPA in colon contents, portal, and peripheral blood. On the other hand, a tryptophan-free diet, administered for the same period, significantly reduces the synthesis of this metabolite. Tryptophan concentration in the diet is not the only nutritional factor affecting the synthesis of IPA.

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. Probiotics co-administered with antibiotics seem to decrease the risk of developing severe adverse effects, including Clostridioides difficile infection. Probiotics restore healthy gut microbiota composition and its functions, including synthesis of specific metabolites. Lactobacillus reuteri can be administered as a probiotic, revealing a positive impact, by improving infantile colic symptoms. Simultaneously it has been observed that this bacterial species is able to synthetize IPA. It still needs to be elucidated whether the positive impact of L. reuteri might be due to the synthesis of specific metabolites, 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 microbiota, tryptophan, indoles, indole-3-propionic acid. The search was confined to manuscripts that were published from 1961 to December 2021. Specific steps of the review process 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 excluded from further analysis. Exclusion criteria were language other than English (2 records), 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.

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 diseases, making it a promising new pharmacotherapeutic target.

References 200

  1. 1.

    Davis C.D. The gut microbiome and its role in obesity. Nutr Today. 2016;51:167-174.

    Not in our library10.1097/nt.0000000000000167

  2. 2.

    Gurung M., Li Z., You H., Rodrigues R., Jump D.B., Morgun A., Shulzhenko N. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine. 2020;51:102590.

    Not in our library10.1016/j.ebiom.2019.11.051

  3. 3.

    Durgan D.J., Ganesh B.P., Cope J.L., Ajami N.J., Phillips S.C., Petrosino J.F., Hollister E.B., Bryan R.M. Role of the gut microbiome in obstructive sleep apnea-induced hypertension. Hypertension. 2016;67:469-474.

    Not in our library10.1161/hypertensionaha.115.06672

  4. 4.

    Yang T., Santisteban M.M., Rodriguez V., Li E., Ahmari N., Carvajal J.M., Zadeh M., Gong M., Qi Y., Zubcevic J., et al. Gut dysbiosis is linked to hypertension. Hypertension. 2015;65:1331-1340.

    Not in our library10.1161/hypertensionaha.115.05315

  5. 5.
    Butyric acid, a gut bacteria metabolite, lowers arterial blood pressure via colon-vagus nerve signaling and GPR41/43 receptors · 2019
    No notice
  6. 6.

    Koeth R.A., Wang Z., Levison B.S., Buffa J.A., Org E., Sheehy B.T., Britt E.B., Fu X., Wu Y., Li L., et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 2013;19:576-585.

    Not in our library10.1038/nm.3145

  7. 7.

    Ussher J.R., Lopaschuk G.D., Arduini A. Gut microbiota metabolism of L-carnitine and cardiovascular risk. Atherosclerosis. 2013;231:456-461.

    Not in our library10.1016/j.atherosclerosis.2013.10.013

  8. 8.

    Li D.Y., Tang W.H.W. Gut microbiota and atherosclerosis. Curr. Atheroscler. Rep. 2017;19:39.

    Not in our library10.1007/s11883-017-0675-9

  9. 9.

    Konopelski P., Ufnal M. Indoles—Gut bacteria metabolites of tryptophan with pharmacotherapeutic potential. Curr. Drug Metab. 2018;19:883-890.

    Not in our library10.2174/1389200219666180427164731

  10. 10.

    Bansal T., Alaniz R.C., Wood T.K., Jayaraman A. The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc. Natl. Acad. Sci. USA. 2010;107:228-233.

    Not in our library10.1073/pnas.0906112107

  11. 11.

    Huc T., Konop M., Onyszkiewicz M., Podsadni P., Szczepanska A., Turlo J., Ufnal M. Colonic indole, gut bacteria metabolite of tryptophan, increases portal blood pressure in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2018;315:R646-R655.

    Not in our library10.1152/ajpregu.00111.2018

  12. 12.

    Lekawanvijit S. Role of gut-derived protein-bound uremic toxins in cardiorenal syndrome and potential treatment modalities. Circ. J. 2015;79:2088-2097.

    Not in our library10.1253/circj.cj-15-0749

  13. 13.

    Huc T., Nowinski A., Drapala A., Konopelski P., Ufnal M. Indole and indoxyl sulfate, gut bacteria metabolites of tryptophan, change arterial blood pressure via peripheral and central mechanisms in rats. Pharmacol. Res. 2018;130:172-179.

    Not in our library10.1016/j.phrs.2017.12.025

  14. 14.

    Knudsen C., Neyrinck A.M., Leyrolle Q., Baldin P., Leclercq S., Rodriguez J., Beaumont M., Cani P.D., Bindels L.B., Lanthier N., et al. Hepatoprotective effects of indole, a gut microbial metabolite, in leptin-deficient obese mice. J. Nutr. 2021;151:1507-1516.

    Not in our library10.1093/jn/nxab032

  15. 15.

    Hobby G.P., Karaduta O., Dusio G.F., Singh M., Zybailov B.L., Arthur J.M. Chronic kidney disease and the gut microbiome. Am. J. Physiol. Renal. Physiol. 2019;316:F1211-F1217.

    Not in our library10.1152/ajprenal.00298.2018

  16. 16.
    Chronic Kidney Disease-Induced Cardiac Fibrosis Is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uremic Toxin, Indoxyl Sulfate · 2012
    No notice
  17. 17.

    Gao H., Liu S. Role of uremic toxin indoxyl sulfate in the progression of cardiovascular disease. Life Sci. 2017;185:23-29.

    Not in our library10.1016/j.lfs.2017.07.027

  18. 18.

    Melhem N.J., Taleb S. Tryptophan: From diet to cardiovascular diseases. Int. J. Mol. Sci. 2021;22:9904.

    Not in our library10.3390/ijms22189904

  19. 19.

    Konopelski P., Chabowski D., Aleksandrowicz M., Kozniewska E., Podsadni P., Szczepanska A., Ufnal M. Indole-3-propionic acid, a tryptophan-derived bacterial metabolite, increases blood pressure via cardiac and vascular mechanisms in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2021;321:R969-R981.

    Not in our library10.1152/ajpregu.00142.2021

  20. 20.

    Li J., Zhang L., Wu T., Li Y., Zhou X., Ruan Z. Indole-3-propionic acid improved the intestinal barrier by enhancing epithelial barrier and mucus barrier. J. Agric. Food. Chem. 2021;69:1487-1495.

    Not in our library10.1021/acs.jafc.0c05205

  21. 21.

    Pappolla M.A., Perry G., Fang X., Zagorski M., Sambamurti K., Poeggeler B. Indoles as essential mediators in the gut-brain axis. Their role in Alzheimer’s disease. Neurobiol. Dis. 2021;156:105403.

    Not in our library10.1016/j.nbd.2021.105403

  22. 22.

    Garcez M.L., Tan V.X., Heng B., Guillemin G.J. Sodium Butyrate and Indole-3-propionic acid prevent the increase of cytokines and kynurenine levels in LPS-induced human primary astrocytes. Int. J. Tryptophan. Res. 2020;13:1178646920978404.

    Not in our library10.1177/1178646920978404

  23. 23.

    Du L., Qi R., Wang J., Liu Z., Wu Z. Indole-3-Propionic acid, a functional metabolite of clostridium sporogenes, promotes muscle tissue development and reduces muscle cell inflammation. Int. J. Mol. Sci. 2021;22:12435.

    Not in our library10.3390/ijms222212435

  24. 24.

    Iwan P., Stepniak J., Karbownik-Lewinska M. Cumulative protective effect of melatonin and indole-3-propionic acid against KIO3-induced lipid peroxidation in porcine thyroid. Toxics. 2021;9:89.

    Not in our library10.3390/toxics9050089

  25. 25.
    Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions · 2016
    No notice
  26. 26.

    Hwang I.K., Yoo K.Y., Li H., Park O.K., Lee C.H., Choi J.H., Jeong Y.G., Lee Y.L., Kim Y.M., Kwon Y.G., et al. Indole-3-propionic acid attenuates neuronal damage and oxidative stress in the ischemic hippocampus. J. Neurosci. Res. 2009;87:2126-2137.

    Not in our library10.1002/jnr.22030

  27. 27.
    Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats · 2019
    No notice
  28. 28.

    Alexeev E.E., Lanis J.M., Kao D.J., Campbell E.L., Kelly C.J., Battista K.D., Gerich M.E., Jenkins B.R., Walk S.T., Kominsky D.J., et al. Microbiota-derived indole metabolites promote human and murine intestinal homeostasis through regulation of interleukin-10 receptor. Am. J. Pathol. 2018;188:1183-1194.

    Not in our library10.1016/j.ajpath.2018.01.011

  29. 29.
    Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study · 2017
    No notice
  30. 30.

    Ruebel M.L., Piccolo B.D., Mercer K.E., Pack L., Moutos D., Shankar K., Andres A. Obesity leads to distinct metabolomic signatures in follicular fluid of women undergoing in vitro fertilization. Am. J. Physiol. Endocrinol. Metab. 2019;316:E383-E396.

    Not in our library10.1152/ajpendo.00401.2018

  31. 31.
    Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes · 2015
    No notice
  32. 32.
    Gut microbiota derived metabolites in cardiovascular health and disease · 2018
    No notice
  33. 33.

    Vitek L., Majer F., Muchova L., Zelenka J., Jiraskova A., Branny P., Malina J., Ubik K. Identification of bilirubin reduction products formed by Clostridium perfringens isolated from human neonatal fecal flora. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2006;833:149-157.

    Not in our library10.1016/j.jchromb.2006.01.032

  34. 34.

    Ramirez-Perez O., Cruz-Ramon V., Chinchilla-Lopez P., Mendez-Sanchez N. The Role of the Gut Microbiota in Bile Acid Metabolism. Ann. Hepatol. 2017;16:s15-s20.

    Not in our library10.5604/01.3001.0010.5672

  35. 35.

    Adak A., Khan M.R. An insight into gut microbiota and its functionalities. Cell. Mol. Life. Sci. 2019;76:473-493.

    Not in our library10.1007/s00018-018-2943-4

  36. 36.
    A High-Fat Diet Increases Gut Microbiota Biodiversity and Energy Expenditure Due to Nutrient Difference · 2020
    No notice
  37. 37.

    James K.R., Gomes T., Elmentaite R., Kumar N., Gulliver E.L., King H.W., Stares M.D., Bareham B.R., Ferdinand J.R., Petrova V.N., et al. Distinct microbial and immune niches of the human colon. Nat. Immunol. 2020;21:343-353.

    Not in our library10.1038/s41590-020-0602-z

  38. 38.

    Bartoli R., Boix J., Odena G., De la Ossa N.D., de Vega V.M., Lorenzo-Zuniga V. Colonoscopy in rats: An endoscopic, histological and tomographic study. World J. Gastrointest. Endosc. 2013;5:226-230.

    Not in our library10.4253/wjge.v5.i5.226

  39. 39.

    Koruda M.J., Rolandelli R.H., Bliss D.Z., Hastings J., Rombeau J.L., Settle R.G. Parenteral nutrition supplemented with short-chain fatty acids: Effect on the small-bowel mucosa in normal rats. Am. J. Clin. Nutr. 1990;51:685-689.

    Not in our library10.1093/ajcn/51.4.685

  40. 40.

    Medina V., Afonso J.J., Alvarez-Arguelles H., Hernandez C., Gonzalez F. Sodium butyrate inhibits carcinoma development in a 1,2-dimethylhydrazine-induced rat colon cancer. JPEN J. Parenter Enteral. Nutr. 1998;22:14-17.

    Not in our library10.1177/014860719802200114

  41. 41.

    Konopelski P., Konop M., Perlejewski K., Bukowska-Osko I., Radkowski M., Onyszkiewicz M., Jaworska K., Mogilnicka I., Samborowska E., Ufnal M. Genetically determined hypertensive phenotype affects gut microbiota composition, but not vice versa. J. Hypertens. 2021;39:1790-1799.

    Not in our library10.1097/hjh.0000000000002864

  42. 42.

    Morris G.P., Beck P.L., Herridge M.S., Depew W.T., Szewczuk M.R., Wallace J.L. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology. 1989;96:795-803.

    Not in our library10.1016/0016-5085(89)90904-9

  43. 43.

    Vega-Bautista A., de la Garza M., Carrero J.C., Campos-Rodriguez R., Godinez-Victoria M., Drago-Serrano M.E. The Impact of Lactoferrin on the Growth of Intestinal Inhabitant Bacteria. Int. J. Mol. Sci. 2019;20:4707.

    Not in our library10.3390/ijms20194707

  44. 44.

    Jaworska K., Konop M., Bielinska K., Hutsch T., Dziekiewicz M., Banaszkiewicz A., Ufnal M. Inflammatory bowel disease is associated with increased gut-to-blood penetration of short-chain fatty acids: A new, non-invasive marker of a functional intestinal lesion. Exp. Physiol. 2019;104:1226-1236.

    Not in our library10.1113/ep087773

  45. 45.
    Hypertension in rats is associated with an increased permeability of the colon to TMA, a gut bacteria metabolite · 2017
    No notice
  46. 46.

    Ueland P.M. Choline and betaine in health and disease. J. Inherit. Metab. Dis. 2011;34:3-15.

    Not in our library10.1007/s10545-010-9088-4

  47. 47.
    Dietary Choline Intake: Current State of Knowledge Across the Life Cycle · 2018
    No notice
  48. 48.

    Zeisel S.H., Warrier M. Trimethylamine N-Oxide, the microbiome, and heart and kidney disease. Annu. Rev. Nutr. 2017;37:157-181.

    Not in our library10.1146/annurev-nutr-071816-064732

  49. 49.

    Jaworska K., Bielinska K., Gawrys-Kopczynska M., Ufnal M. TMA (trimethylamine), but not its oxide TMAO (trimethylamine-oxide), exerts haemodynamic effects: Implications for interpretation of cardiovascular actions of gut microbiome. Cardiovasc. Res. 2019;115:1948-1949.

    Not in our library10.1093/cvr/cvz231

  50. 50.

    Srinivasa S., Fitch K.V., Lo J., Kadar H., Knight R., Wong K., Abbara S., Gauguier D., Capeau J., Boccara F., et al. Plaque burden in HIV-infected patients is associated with serum intestinal microbiota-generated trimethylamine. AIDS. 2015;29:443-452.

    Not in our library10.1097/qad.0000000000000565

  51. 51.

    McConnell H.W., Mitchell S.C., Smith R.L., Brewster M. Trimethylaminuria associated with seizures and behavioural disturbance: A case report. Seizure. 1997;6:317-321.

    Not in our library10.1016/s1059-1311(97)80080-5

  52. 52.

    Agus A., Clement K., Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut. 2021;70:1174-1182.

    Not in our library10.1136/gutjnl-2020-323071

  53. 53.

    Nowinski A., Ufnal M. Gut bacteria-derived molecules as mediators and markers in cardiovascular diseases. The role of the gut-blood barrier. Kardiol. Pol. 2018;76:320-327.

    Not in our library10.5603/kp.a2017.0204

  54. 54.

    Tang W.H., Wang Z., Levison B.S., Koeth R.A., Britt E.B., Fu X., Wu Y., Hazen S.L. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 2013;368:1575-1584.

    Not in our library10.1056/nejmoa1109400

  55. 55.

    Gawrys-Kopczynska M., Konop M., Maksymiuk K., Kraszewska K., Derzsi L., Sozanski K., Holyst R., Pilz M., Samborowska E., Dobrowolski L., et al. TMAO, a seafood-derived molecule, produces diuresis and reduces mortality in heart failure rats. Elife. 2020;9:57028.

    Not in our library10.7554/elife.57028

  56. 56.

    Yancey P.H., Siebenaller J.F. Co-evolution of proteins and solutions: Protein adaptation versus cytoprotective micromolecules and their roles in marine organisms. J. Exp. Biol. 2015;218:1880-1896.

    Not in our library10.1242/jeb.114355

  57. 57.

    Tomasova L., Grman M., Ondrias K., Ufnal M. The impact of gut microbiota metabolites on cellular bioenergetics and cardiometabolic health. Nutr. Metab. 2021;18:72.

    Not in our library10.1186/s12986-021-00598-5

  58. 58.

    Tomasova L., Dobrowolski L., Jurkowska H., Wrobel M., Huc T., Ondrias K., Ostaszewski R., Ufnal M. Intracolonic hydrogen sulfide lowers blood pressure in rats. Nitric Oxide. 2016;60:50-58.

    Not in our library10.1016/j.niox.2016.09.007

  59. 59.

    Al-Magableh M.R., Kemp-Harper B.K., Hart J.L. Hydrogen sulfide treatment reduces blood pressure and oxidative stress in angiotensin II-induced hypertensive mice. Hypertens. Res. 2015;38:13-20.

    Not in our library10.1038/hr.2014.125

  60. 60.

    Zoccali C., Catalano C., Rastelli S. Blood pressure control: Hydrogen sulfide, a new gasotransmitter, takes stage. Nephrol. Dial. Transplant. 2009;24:1394-1396.

    Not in our library10.1093/ndt/gfp053

  61. 61.

    Blachier F., Beaumont M., Kim E. Cysteine-derived hydrogen sulfide and gut health: A matter of endogenous or bacterial origin. Curr. Opin. Clin. Nutr. Metab. Care. 2019;22:68-75.

    Not in our library10.1097/mco.0000000000000526

  62. 62.

    Modis K., Wolanska K., Vozdek R. Hydrogen sulfide in cell signaling, signal transduction, cellular bioenergetics and physiology in C. elegans. Gen. Physiol. Biophys. 2013;32:1-22.

    Not in our library10.4149/gpb_2013001

  63. 63.

    Koh A., De Vadder F., Kovatcheva-Datchary P., Backhed F. From dietary fiber to host physiology: Short-chain fatty acids as key bacterial metabolites. Cell. 2016;165:1332-1345.

    Not in our library10.1016/j.cell.2016.05.041

  64. 64.

    Al-Lahham S., Rezaee F. Propionic acid counteracts the inflammation of human subcutaneous adipose tissue: A new avenue for drug development. Daru. 2019;27:645-652.

    Not in our library10.1007/s40199-019-00294-z

  65. 65.

    Kondo S., Tayama K., Tsukamoto Y., Ikeda K., Yamori Y. Antihypertensive effects of acetic acid and vinegar on spontaneously hypertensive rats. Biosci. Biotechnol. Biochem. 2001;65:2690-2694.

    Not in our library10.1271/bbb.65.2690

  66. 66.

    Natarajan N., Hori D., Flavahan S., Steppan J., Flavahan N.A., Berkowitz D.E., Pluznick J.L. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41. Physiol. Genom. 2016;48:826-834.

    Not in our library10.1152/physiolgenomics.00089.2016

  67. 67.

    Demigne C., Morand C., Levrat M.A., Besson C., Moundras C., Remesy C. Effect of propionate on fatty acid and cholesterol synthesis and on acetate metabolism in isolated rat hepatocytes. Br. J. Nutr. 1995;74:209-219.

    Not in our library10.1079/bjn19950124

  68. 68.

    Robles-Vera I., Toral M., de la Visitacion N., Aguilera-Sanchez N., Redondo J.M., Duarte J. Protective effects of short-chain fatty acids on endothelial dysfunction induced by angiotensin II. Front. Physiol. 2020;11:277.

    Not in our library10.3389/fphys.2020.00277

  69. 69.

    Knock G., Psaroudakis D., Abbot S., Aaronson P.I. Propionate-induced relaxation in rat mesenteric arteries: A role for endothelium-derived hyperpolarising factor. J. Physiol. 2002;538:879-890.

    Not in our library10.1113/jphysiol.2001.013105

  70. 70.

    Mortensen F.V., Nielsen H., Mulvany M.J., Hessov I. Short chain fatty acids dilate isolated human colonic resistance arteries. Gut. 1990;31:1391-1394.

    Not in our library10.1136/gut.31.12.1391

  71. 71.

    Hulsmann W.C. Coronary vasodilation by fatty acids. Basic Res. Cardiol. 1976;71:179-191.

    Not in our library10.1007/bf01927870

  72. 72.

    Nutting C.W., Islam S., Daugirdas J.T. Vasorelaxant effects of short chain fatty acid salts in rat caudal artery. Am. J. Physiol. 1991;261:H561-H567.

    Not in our library10.1152/ajpheart.1991.261.2.h561

  73. 73.

    Agus A., Planchais J., Sokol H. Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host Microbe. 2018;23:716-724.

    Not in our library10.1016/j.chom.2018.05.003

  74. 74.

    Kanova M., Kohout P. Tryptophan: A Unique Role in the Critically Ill. Int. J. Mol. Sci. 2021;22:11714.

    Not in our library10.3390/ijms222111714

  75. 75.

    Badawy A.A. Kynurenine pathway of tryptophan metabolism: Regulatory and functional aspects. Int. J. Tryptophan Res. 2017;10:1178646917691938.

    Not in our library10.1177/1178646917691938

  76. 76.
    Tryptophan-Catabolizing Enzymes – Party of Three · 2014
    No notice
  77. 77.

    Jones L.A., Sun E.W., Martin A.M., Keating D.J. The ever-changing roles of serotonin. Int. J. Biochem. Cell Biol. 2020;125:105776.

    Not in our library10.1016/j.biocel.2020.105776

  78. 78.

    Fernstrom J.D. A Perspective on the safety of supplemental tryptophan based on its metabolic fates. J. Nutr. 2016;146:2601S-2608S.

    Not in our library10.3945/jn.115.228643

  79. 79.
    Melatonin Synthesis and Function: Evolutionary History in Animals and Plants · 2019
    No notice
  80. 80.

    Deacon A.C. The measurement of 5-hydroxyindoleacetic acid in urine. Ann. Clin. Biochem. 1994;31:215-232.

    Not in our library10.1177/000456329403100302

  81. 81.

    Wedin M., Mehta S., Angeras-Kraftling J., Wallin G., Daskalakis K. The Role of Serum 5-HIAA as a Predictor of progression and an alternative to 24-h urine 5-HIAA in well-differentiated neuroendocrine neoplasms. Biology. 2021;10:76.

    Not in our library10.3390/biology10020076

  82. 82.

    Rothhammer V., Mascanfroni I.D., Bunse L., Takenaka M.C., Kenison J.E., Mayo L., Chao C.C., Patel B., Yan R., Blain M., et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 2016;22:586-597.

    Not in our library10.1038/nm.4106

  83. 83.

    Li Y., Xu W., Zhang F., Zhong S., Sun Y., Huo J., Zhu J., Wu C. The Gut Microbiota-Produced Indole-3-Propionic Acid Confers the antihyperlipidemic effect of mulberry-derived 1-Deoxynojirimycin. mSystems. 2020;5:e00313-20.

    Not in our library10.1128/msystems.00313-20

  84. 84.

    Mercer K.E., Yeruva L., Pack L., Graham J.L., Stanhope K.L., Chintapalli S.V., Wankhade U.D., Shankar K., Havel P.J., Adams S.H., et al. Xenometabolite signatures in the UC Davis type 2 diabetes mellitus rat model revealed using a metabolomics platform enriched with microbe-derived metabolites. Am. J. Physiol. Gastrointest. Liver. Physiol. 2020;319:G157-G169.

    Not in our library10.1152/ajpgi.00105.2020

  85. 85.

    Wikoff W.R., Anfora A.T., Liu J., Schultz P.G., Lesley S.A., Peters E.C., Siuzdak G. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. USA. 2009;106:3698-3703.

    Not in our library10.1073/pnas.0812874106

  86. 86.

    Dodd D., Spitzer M.H., Van Treuren W., Merrill B.D., Hryckowian A.J., Higginbottom S.K., Le A., Cowan T.M., Nolan G.P., Fischbach M.A., et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature. 2017;551:648-652.

    Not in our library10.1038/nature24661

  87. 87.

    Rosas H.D., Doros G., Bhasin S., Thomas B., Gevorkian S., Malarick K., Matson W., Hersch S.M. A systems-level ‘’misunderstanding’’: The plasma metabolome in Huntington’s disease. Ann. Clin. Transl. Neurol. 2015;2:756-768.

    Not in our library10.1002/acn3.214

  88. 88.

    Elsden S.R., Hilton M.G., Waller J.M. The end products of the metabolism of aromatic amino acids by Clostridia. Arch. Microbiol. 1976;107:283-288.

    Not in our library10.1007/bf00425340

  89. 89.
    Microbial tryptophan catabolites in health and disease · 2018
    No notice
  90. 90.
    A Three-Ring Circus: Metabolism of the Three Proteogenic Aromatic Amino Acids and Their Role in the Health of Plants and Animals · 2018
    No notice
  91. 91.
    IDO and Kynurenine Metabolites in Peripheral and CNS Disorders · 2020
    No notice
  92. 92.

    Biernacki T., Sandi D., Bencsik K., Vecsei L. Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives. Cells. 2020;9:1564.

    Not in our library10.3390/cells9061564

  93. 93.

    Barth H., Raghuraman S. Persistent infectious diseases say-IDO. Role of indoleamine-2,3-dioxygenase in disease pathogenesis and implications for therapy. Crit. Rev. Microbiol. 2014;40:360-368.

    Not in our library10.3109/1040841x.2012.742037

  94. 94.

    Li X., Zhou J., Fang M., Yu B. Pregnancy immune tolerance at the maternal-fetal interface. Int. Rev. Immunol. 2020;39:247-263.

    Not in our library10.1080/08830185.2020.1777292

  95. 95.

    Suzuki Y., Suda T., Asada K., Miwa S., Suzuki M., Fujie M., Furuhashi K., Nakamura Y., Inui N., Shirai T., et al. Serum indoleamine 2,3-dioxygenase activity predicts prognosis of pulmonary tuberculosis. Clin. Vaccine Immunol. 2012;19:436-442.

    Not in our library10.1128/cvi.05402-11

  96. 96.

    Wang Y., Liu H., McKenzie G., Witting P.K., Stasch J.P., Hahn M., Changsirivathanathamrong D., Wu B.J., Ball H.J., Thomas S.R., et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat. Med. 2010;16:279-285.

    Not in our library10.1038/nm.2092

  97. 97.

    Cervenka I., Agudelo L.Z., Ruas J.L. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science. 2017;357:eaaf9749.

    Not in our library10.1126/science.aaf9794

  98. 98.

    Munn D.H., Mellor A.L. IDO in the tumor microenvironment: Inflammation, counter-regulation, and tolerance. Trends Immunol. 2016;37:193-207.

    Not in our library10.1016/j.it.2016.01.002

  99. 99.
    Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer · 2020
    No notice
  100. 100.

    Tsopmo A., Diehl-Jones B.W., Aluko R.E., Kitts D.D., Elisia I., Friel J.K. Tryptophan released from mother’s milk has antioxidant properties. Pediatr. Res. 2009;66:614-618.

    Not in our library10.1203/pdr.0b013e3181be9e7e

  101. 101.

    Bitzer-Quintero O.K., Davalos-Marin A.J., Ortiz G.G., Meza A.R., Torres-Mendoza B.M., Robles R.G., Huerta V.C., Beas-Zarate C. Antioxidant activity of tryptophan in rats under experimental endotoxic shock. Biomed. Pharmacother. 2010;64:77-81.

    Not in our library10.1016/j.biopha.2009.07.002

  102. 102.

    Sanchez A., Calpena A.C., Clares B. Evaluating the Oxidative Stress in Inflammation: Role of Melatonin. Int. J. Mol. Sci. 2015;16:16981-17004.

    Not in our library10.3390/ijms160816981

  103. 103.

    Yusufu I., Ding K., Smith K., Wankhade U.D., Sahay B., Patterson G.T., Pacholczyk R., Adusumilli S., Hamrick M.W., Hill W.D., et al. A Tryptophan-Deficient Diet Induces Gut Microbiota Dysbiosis and Increases Systemic Inflammation in Aged Mice. Int. J. Mol. Sci. 2021;22:5005.

    Not in our library10.3390/ijms22095005

  104. 104.

    Bortolato M., Frau R., Orru M., Collu M., Mereu G., Carta M., Fadda F., Stancampiano R. Effects of tryptophan deficiency on prepulse inhibition of the acoustic startle in rats. Psychopharmacology. 2008;198:191-200.

    Not in our library10.1007/s00213-008-1116-9

  105. 105.

    Konopelski P., Konop M., Gawrys-Kopczynska M., Podsadni P., Szczepanska A., Ufnal M. Indole-3-propionic acid, a tryptophan-derived bacterial metabolite, reduces weight gain in rats. Nutrients. 2019;11:591.

    Not in our library10.3390/nu11030591

  106. 106.

    Franklin M., Bermudez I., Murck H., Singewald N., Gaburro S. Sub-chronic dietary tryptophan depletion—An animal model of depression with improved face and good construct validity. J. Psychiatr. Res. 2012;46:239-247.

    Not in our library10.1016/j.jpsychires.2011.10.003

  107. 107.

    Ayaso R., Ghattas H., Abiad M., Obeid O. Meal pattern of male rats maintained on amino acid supplemented diets: The effect of tryptophan, lysine, arginine, proline and threonine. Nutrients. 2014;6:2509-2522.

    Not in our library10.3390/nu6072509

  108. 108.

    Gartner S.N., Aidney F., Klockars A., Prosser C., Carpenter E.A., Isgrove K., Levine A.S., Olszewski P.K. Intragastric preloads of l-tryptophan reduce ingestive behavior via oxytocinergic neural mechanisms in male mice. Appetite. 2018;125:278-286.

    Not in our library10.1016/j.appet.2018.02.015

  109. 109.

    Ufnal M., Skrzypecki J. Blood borne hormones in a cross-talk between peripheral and brain mechanisms regulating blood pressure, the role of circumventricular organs. Neuropeptides. 2014;48:65-73.

    Not in our library10.1016/j.npep.2014.01.003

  110. 110.

    Toropov A.L., Tsirkin V.I., Kostyaev A.A. Combined effects of blood serum as a source of endogenous beta-adrenoceptor-sensitizing agent and its analogues histidine, tryptophan, tyrosine, mildronat, and preductal. Bull. Exp. Biol. Med. 2011;151:84-87.

    Not in our library10.1007/s10517-011-1265-4

  111. 111.

    Korotaeva K.N., Tsirkin V.I., Vyaznikov V.A. Positive inotropic effect of tyrosine, histidine, and tryptophan in experiments on isolated human myocardium. Bull. Exp. Biol. Med. 2012;153:51-53.

    Not in our library10.1007/s10517-012-1640-9

  112. 112.

    Wolf W.A., Kuhn D.M. Effects of L-tryptophan on blood pressure in normotensive and hypertensive rats. J. Pharmacol. Exp. Ther. 1984;230:324-329.

    Not in our library

  113. 113.

    Bertaccini G., Nobili M.B. Effect of L-tryptophan on diuresis and 5-hydroxyindoleacetic acid excretion in the rat. Br. J. Pharmacol. Chemother. 1961;17:519-525.

    Not in our library10.1111/j.1476-5381.1961.tb01138.x

  114. 114.

    Reuther E., Weber H.J., Herken H. Studies on sodium ion retention and antidiuretic effects after administration of L-tryptophan to rats. Naunyn. Schmiedebergs Arch. Pharmacol. 1977;297:213-217.

    Not in our library10.1007/bf00509263

  115. 115.

    Feltkamp H., Meurer K.A., Godehardt E. Tryptophan-induced lowering of blood pressure and changes of serotonin uptake by platelets in patients with essential hypertension. Klin. Wochenschr. 1984;62:1115-1119.

    Not in our library10.1007/bf01782468

  116. 116.
    Surface components and metabolites of probiotics for regulation of intestinal epithelial barrier · 2020
    No notice
  117. 117.

    Galligan J.J. Beneficial actions of microbiota-derived tryptophan metabolites. Neurogastroenterol. Motil. 2018;30:e13283.

    Not in our library10.1111/nmo.13283

  118. 118.

    Wu Y., Li J., Ding W., Ruan Z., Zhang L. Enhanced Intestinal Barriers by Puerarin in Combination with Tryptophan. J. Agric. Food Chem. 2021;69:15575-15584.

    Not in our library10.1021/acs.jafc.1c05830

  119. 119.

    Sivaprakasam S., Bhutia Y.D., Ramachandran S., Ganapathy V. Cell-Surface and Nuclear Receptors in the Colon as Targets for Bacterial Metabolites and Its Relevance to Colon Health. Nutrients. 2017;9:856.

    Not in our library10.3390/nu9080856

  120. 120.

    Dutta M., Lim J.J., Cui J.Y. PXR and the gut-liver axis: A recent update. Drug Metab. Dispos. 2021;50:000415.

    Not in our library10.1124/dmd.121.000415

  121. 121.

    Venkatesh M., Mukherjee S., Wang H., Li H., Sun K., Benechet A.P., Qiu Z., Maher L., Redinbo M.R., Phillips R.S., et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity. 2014;41:296-310.

    Not in our library10.1016/j.immuni.2014.06.014

  122. 122.

    Lee D.M., Ecton K.E., Trikha S.R.J., Wrigley S.D., Thomas K.N., Battson M.L., Wei Y., Johnson S.A., Weir T.L., Gentile C.L. Microbial metabolite indole-3-propionic acid supplementation does not protect mice from the cardiometabolic consequences of a Western diet. Am. J. Physiol. Gastrointest. Liver. Physiol. 2020;319:G51-G62.

    Not in our library10.1152/ajpgi.00375.2019

  123. 123.

    Jennis M., Cavanaugh C.R., Leo G.C., Mabus J.R., Lenhard J., Hornby P.J. Microbiota-derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo. Neurogastroenterol. Motil. 2018;30:e13178.

    Not in our library10.1111/nmo.13178

  124. 124.

    Niwa T. Indoxyl sulfate is a nephro-vascular toxin. J. Ren. Nutr. 2010;20:S2-S6.

    Not in our library10.1053/j.jrn.2010.05.002

  125. 125.

    Nakano T., Katsuki S., Chen M., Decano J.L., Halu A., Lee L.H., Pestana D.V.S., Kum A.S.T., Kuromoto R.K., Golden W.S., et al. Uremic toxin indoxyl sulfate promotes proinflammatory macrophage activation via the interplay of OATP2B1 and Dll4-notch signaling. Circulation. 2019;139:78-96.

    Not in our library10.1161/circulationaha.118.034588

  126. 126.

    Tanaka S., Watanabe H., Nakano T., Imafuku T., Kato H., Tokumaru K., Arimura N., Enoki Y., Maeda H., Tanaka M., et al. Indoxyl sulfate contributes to adipose tissue inflammation through the activation of NADPH oxidase. Toxins. 2020;12:502.

    Not in our library10.3390/toxins12080502

  127. 127.

    Yisireyili M., Takeshita K., Saito S., Murohara T., Niwa T. Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells. Nagoya J. Med. Sci. 2017;79:477-486.

    Not in our library10.18999/nagjms.79.4.477

  128. 128.

    Poeggeler B., Pappolla M.A., Hardeland R., Rassoulpour A., Hodgkins P.S., Guidetti P., Schwarcz R. Indole-3-propionate: A potent hydroxyl radical scavenger in rat brain. Brain Res. 1999;815:382-388.

    Not in our library10.1016/s0006-8993(98)01027-0

  129. 129.

    Hardeland R., Zsizsik B.K., Poeggeler B., Fuhrberg B., Holst S., Coto-Montes A. Indole-3-pyruvic and -propionic acids, kynurenic acid, and related metabolites as luminophores and free-radical scavengers. Adv. Exp. Med. Biol. 1999;467:389-395.

    Not in our library10.1007/978-1-4615-4709-9_49

  130. 130.

    Karbownik M., Stasiak M., Zasada K., Zygmunt A., Lewinski A. Comparison of potential protective effects of melatonin, indole-3-propionic acid, and propylthiouracil against lipid peroxidation caused by potassium bromate in the thyroid gland. J. Cell Biochem. 2005;95:131-138.

    Not in our library10.1002/jcb.20404

  131. 131.

    Karbownik M., Stasiak M., Zygmunt A., Zasada K., Lewinski A. Protective effects of melatonin and indole-3-propionic acid against lipid peroxidation, caused by potassium bromate in the rat kidney. Cell Biochem. Funct. 2006;24:483-489.

    Not in our library10.1002/cbf.1321

  132. 132.

    Stasiak M., Zasada K., Lewinski A., Karbownik-Lewinska M. Melatonin restores the basal level of lipid peroxidation in rat tissues exposed to potassium bromate in vitro. Neuro. Endocrinol. Lett. 2010;31:363-369.

    Not in our library

  133. 133.

    Rynkowska A., Stepniak J., Karbownik-Lewinska M. Melatonin and Indole-3-Propionic acid reduce oxidative damage to membrane lipids induced by high iron concentrations in porcine skin. Membranes. 2021;11:571.

    Not in our library10.3390/membranes11080571

  134. 134.

    Karbownik M., Gitto E., Lewinski A., Reiter R.J. Relative efficacies of indole antioxidants in reducing autoxidation and iron-induced lipid peroxidation in hamster testes. J. Cell. Biochem. 2001;81:693-699.

    Not in our library10.1002/jcb.1100

  135. 135.

    Karbownik M., Reiter R.J., Garcia J.J., Cabrera J., Burkhardt S., Osuna C., Lewinski A. Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: Relevance to cancer reduction. J. Cell Biochem. 2001;81:507-513.

    Not in our library10.1002/1097-4644(20010601)81:3<507::aid-jcb1064>3.0.co;2-m

  136. 136.

    Qi W., Reiter R.J., Tan D.X., Manchester L.C., Siu A.W., Garcia J.J. Increased levels of oxidatively damaged DNA induced by chromium(III) and H2O2: Protection by melatonin and related molecules. J. Pineal Res. 2000;29:54-61.

    Not in our library10.1034/j.1600-079x.2000.290108.x

  137. 137.

    Ortial S., Durand G., Poeggeler B., Polidori A., Pappolla M.A., Boker J., Hardeland R., Pucci B. Fluorinated amphiphilic amino acid derivatives as antioxidant carriers: A new class of protective agents. J. Med. Chem. 2006;49:2812-2820.

    Not in our library10.1021/jm060027e

  138. 138.

    Mandelbaum-Shavit F., Barak V., Saheb-Tamimi K., Grossowicz N. Susceptibility of Legionella pneumophila grown extracellularly and in human monocytes to indole-3-propionic acid. Antimicrob. Agents Chemother. 1991;35:2526-2530.

    Not in our library10.1128/aac.35.12.2526

  139. 139.

    Grossowicz N. Phytohormones as specific inhibitors of Legionella pneumophila growth. Isr. J. Med. Sci. 1990;26:187-190.

    Not in our library

  140. 140.

    Chelala C.A., Margolin P. Bactericidal photoproducts in medium containing riboflavin plus aromatic compounds and MnCl2. Can. J. Microbiol. 1983;29:670-675.

    Not in our library10.1139/m83-109

  141. 141.
    Associations of serum indolepropionic acid, a gut microbiota metabolite, with type 2 diabetes and low-grade inflammation in high-risk individuals · 2018
    No notice
  142. 142.

    Nystrom S., Govender M., Yap S.H., Kamarulzaman A., Rajasuriar R., Larsson M. HIV-infected individuals on ART With impaired immune recovery have altered plasma metabolite profiles. Open Forum Infect. Dis. 2021;8:ofab288.

    Not in our library10.1093/ofid/ofab288

  143. 143.

    Jeffrey A.M., Williams G.M. Risk assessment of DNA-reactive carcinogens in food. Toxicol. Appl. Pharmacol. 2005;207:628-635.

    Not in our library10.1016/j.taap.2005.03.024

  144. 144.

    Hecht S.S. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat. Rev. Cancer. 2003;3:733-744.

    Not in our library10.1038/nrc1190

  145. 145.

    Athreya K., Xavier M.F. Antioxidants in the treatment of cancer. Nutr. Cancer. 2017;69:1099-1104.

    Not in our library10.1080/01635581.2017.1362445

  146. 146.

    Harris I.S., DeNicola G.M. The Complex Interplay between Antioxidants and ROS in cancer. Trends Cell Biol. 2020;30:440-451.

    Not in our library10.1016/j.tcb.2020.03.002

  147. 147.

    Karbownik M., Reiter R.J., Cabrera J., Garcia J.J. Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage. Mutat. Res. 2001;474:87-92.

    Not in our library10.1016/s0027-5107(00)00164-0

  148. 148.

    Owumi S.E., Adedara I.A., Oyelere A.K. Indole-3-propionic acid mitigates chlorpyrifos-mediated neurotoxicity by modulating cholinergic and redox-regulatory systems, inflammatory stress, apoptotic responses and DNA damage in rats. Environ. Toxicol. Pharmacol. 2022;89:103786.

    Not in our library10.1016/j.etap.2021.103786

  149. 149.

    Karbownik M., Garcia J.J., Lewinski A., Reiter R.J. Carcinogen-induced, free radical-mediated reduction in microsomal membrane fluidity: Reversal by indole-3-propionic acid. J. Bioenerg. Biomembr. 2001;33:73-78.

    Not in our library10.1023/a:1005628808688

  150. 150.

    Tolan D., Gandin V., Morrison L., El-Nahas A., Marzano C., Montagner D., Erxleben A. Oxidative stress induced by Pt(IV) Pro-drugs based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position. Sci. Rep. 2016;6:29367.

    Not in our library10.1038/srep29367

  151. 151.

    Zhang Z., Bi C., Buac D., Fan Y., Zhang X., Zuo J., Zhang P., Zhang N., Dong L., Dou Q.P. Organic cadmium complexes as proteasome inhibitors and apoptosis inducers in human breast cancer cells. J. Inorg. Biochem. 2013;123:1-10.

    Not in our library10.1016/j.jinorgbio.2013.02.004

  152. 152.

    Tabassum S., Zaki M., Ahmad M., Afzal M., Srivastav S., Srikrishna S., Arjmand F. Synthesis and crystal structure determination of copper(II)-complex: In vitro DNA and HSA binding, pBR322 plasmid cleavage, cell imaging and cytotoxic studies. Eur. J. Med. Chem. 2014;83:141-154.

    Not in our library10.1016/j.ejmech.2014.06.018

  153. 153.
    Gut microbiota-derived indole 3-propionic acid protects against radiation toxicity via retaining acyl-CoA-binding protein · 2020
    No notice
  154. 154.

    Dugger B.N., Dickson D.W. Pathology of Neurodegenerative Diseases. Cold Spring Harb. Perspect. Biol. 2017;9:a028035.

    Not in our library10.1101/cshperspect.a028035

  155. 155.

    van der Plas E., Schultz J.L., Nopoulos P.C. The Neurodevelopmental Hypothesis of Huntington’s Disease. J. Huntingtons Dis. 2020;9:217-229.

    Not in our library10.3233/jhd-200394

  156. 156.

    Behl C., Davis J.B., Lesley R., Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994;77:817-827.

    Not in our library10.1016/0092-8674(94)90131-7

  157. 157.

    Pappolla M.A., Matsubara E., Vidal R., Pacheco-Quinto J., Poeggeler B., Zagorski M., Sambamurti K. Melatonin treatment enhances abeta lymphatic clearance in a transgenic mouse model of amyloidosis. Curr. Alzheimer Res. 2018;15:637-642.

    Not in our library10.2174/1567205015666180411092551

  158. 158.

    Bendheim P.E., Poeggeler B., Neria E., Ziv V., Pappolla M.A., Chain D.G. Development of indole-3-propionic acid (OXIGON) for Alzheimer′s disease. J. Mol. Neurosci. 2002;19:213-217.

    Not in our library10.1007/s12031-002-0036-0

  159. 159.

    Chyan Y.J., Poeggeler B., Omar R.A., Chain D.G., Frangione B., Ghiso J., Pappolla M.A. Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid. J. Biol. Chem. 1999;274:21937-21942.

    Not in our library10.1074/jbc.274.31.21937

  160. 160.

    Dragicevic N., Copes N., O′Neal-Moffitt G., Jin J., Buzzeo R., Mamcarz M., Tan J., Cao C., Olcese J.M., Arendash G.W., et al. Melatonin treatment restores mitochondrial function in Alzheimer’s mice: A mitochondrial protective role of melatonin membrane receptor signaling. J. Pineal Res. 2011;51:75-86.

    Not in our library10.1111/j.1600-079x.2011.00864.x

  161. 161.

    Huang Y.L., Lin C.H., Tsai T.H., Huang C.H., Li J.L., Chen L.K., Li C.H., Tsai T.F., Wang P.N. Discovery of a metabolic signature predisposing high risk patients with mild cognitive impairment to converting to Alzheimer’s disease. Int. J. Mol. Sci. 2021;22:10903.

    Not in our library10.3390/ijms222010903

  162. 162.

    Morshedi D., Rezaei-Ghaleh N., Ebrahim-Habibi A., Ahmadian S., Nemat-Gorgani M. Inhibition of amyloid fibrillation of lysozyme by indole derivatives--possible mechanism of action. FEBS J. 2007;274:6415-6425.

    Not in our library10.1111/j.1742-4658.2007.06158.x

  163. 163.

    Mimori S., Kawada K., Saito R., Takahashi M., Mizoi K., Okuma Y., Hosokawa M., Kanzaki T. Indole-3-propionic acid has chemical chaperone activity and suppresses endoplasmic reticulum stress-induced neuronal cell death. Biochem. Biophys. Res. Commun. 2019;517:623-628.

    Not in our library10.1016/j.bbrc.2019.07.074

  164. 164.

    Mangalam A., Poisson L., Nemutlu E., Datta I., Denic A., Dzeja P., Rodriguez M., Rattan R., Giri S. Profile of circulatory metabolites in a relapsing-remitting animal model of multiple sclerosis using global metabolomics. J. Clin. Cell. Immunol. 2013;4.

    Not in our library10.4172/2155-9899.1000150

  165. 165.

    Gaetani L., Boscaro F., Pieraccini G., Calabresi P., Romani L., Di Filippo M., Zelante T. Host and Microbial Tryptophan metabolic profiling in multiple sclerosis. Front. Immunol. 2020;11:157.

    Not in our library10.3389/fimmu.2020.00157

  166. 166.

    Cavero I., Lefevre-Borg F., Roach A.G. Effects of mianserin, desipramine and maprotiline on blood pressure responses evoked by acetylcholine, histamine and 5-hydroxytryptamine in rats. Br. J. Pharmacol. 1981;74:143-148.

    Not in our library10.1111/j.1476-5381.1981.tb09966.x

  167. 167.
    Gut-Derived Metabolite Indole-3-Propionic Acid Modulates Mitochondrial Function in Cardiomyocytes and Alters Cardiac Function · 2021
    Not checked
  168. 168.

    Zhu C., Sawrey-Kubicek L., Beals E., Rhodes C.H., Houts H.E., Sacchi R., Zivkovic A.M. Human gut microbiome composition and tryptophan metabolites were changed differently by fast food and Mediterranean diet in 4 days: A pilot study. Nutr. Res. 2020;77:62-72.

    Not in our library10.1016/j.nutres.2020.03.005

  169. 169.

    Du H., Rao Y., Liu R., Deng K., Guan Y., Luo D., Mao Q., Yu J., Bo T., Fan Z., et al. Proteomics and metabolomics analyses reveal the full spectrum of inflammatory and lipid metabolic abnormalities in dyslipidemia. Biomed. Chromatogr. 2021;35:e5183.

    Not in our library10.1002/bmc.5183

  170. 170.

    Cason C.A., Dolan K.T., Sharma G., Tao M., Kulkarni R., Helenowski I.B., Doane B.M., Avram M.J., McDermott M.M., Chang E.B., et al. Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes. J. Vasc. Surg. 2018;68:1552-1562.

    Not in our library10.1016/j.jvs.2017.09.029

  171. 171.

    Zhong V.W., Van Horn L., Greenland P., Carnethon M.R., Ning H., Wilkins J.T., Lloyd-Jones D.M., Allen N.B. Associations of processed meat, unprocessed red meat, poultry, or fish intake with incident cardiovascular disease and all-cause mortality. JAMA Intern. Med. 2020;180:503-512.

    Not in our library10.1001/jamainternmed.2019.6969

  172. 172.

    Wang Z., Bergeron N., Levison B.S., Li X.S., Chiu S., Jia X., Koeth R.A., Li L., Wu Y., Tang W.H.W., et al. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur. Heart J. 2019;40:583-594.

    Not in our library10.1093/eurheartj/ehy799

  173. 173.

    Wu W., Zhang L., Xia B., Tang S., Liu L., Xie J., Zhang H. Bioregional alterations in gut microbiome contribute to the plasma metabolomic changes in pigs fed with inulin. Microorganisms. 2020;8:111.

    Not in our library10.3390/microorganisms8010111

  174. 174.

    Behera J., Ison J., Voor M.J., Tyagi N. Probiotics stimulate bone formation in obese mice via histone methylations. Theranostics. 2021;11:8605-8623.

    Not in our library10.7150/thno.63749

  175. 175.

    Mach F., Baigent C., Catapano A.L., Koskinas K.C., Casula M., Badimon L., Chapman M.J., De Backer G.G., Delgado V., Ference B.A., et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur. Heart J. 2020;41:111-188.

    Not in our library10.1093/eurheartj/ehz455

  176. 176.

    Russo G., Piscitelli P., Giandalia A., Viazzi F., Pontremoli R., Fioretto P., De Cosmo S. Atherogenic dyslipidemia and diabetic nephropathy. J. Nephrol. 2020;33:1001-1008.

    Not in our library10.1007/s40620-020-00739-8

  177. 177.

    Rinella M.E. Nonalcoholic fatty liver disease: A systematic review. JAMA. 2015;313:2263-2273.

    Not in our library10.1001/jama.2015.5370

  178. 178.

    Sehgal R., Ilha M., Vaittinen M., Kaminska D., Mannisto V., Karja V., Tuomainen M., Hanhineva K., Romeo S., Pajukanta P., et al. Indole-3-Propionic Acid, a Gut-Derived Tryptophan Metabolite, associates with Hepatic Fibrosis. Nutrients. 2021;13:3509.

    Not in our library10.3390/nu13103509

  179. 179.

    Liu F., Sun C., Chen Y., Du F., Yang Y., Wu G. Indole-3-propionic Acid-aggravated CCl4-induced Liver Fibrosis via the TGF-beta1/Smads Signaling Pathway. J. Clin. Transl. Hepatol. 2021;9:917-930.

    Not in our library10.14218/jcth.2021.00032

  180. 180.

    Meldrum D.R., Morris M.A., Gambone J.C. Obesity pandemic: Causes, consequences, and solutions-but do we have the will? Fertil. Steril. 2017;107:833-839.

    Not in our library10.1016/j.fertnstert.2017.02.104

  181. 181.

    Cooke A.A., Connaughton R.M., Lyons C.L., McMorrow A.M., Roche H.M. Fatty acids and chronic low grade inflammation associated with obesity and the metabolic syndrome. Eur. J. Pharmacol. 2016;785:207-214.

    Not in our library10.1016/j.ejphar.2016.04.021

  182. 182.

    Zhao L., Wu H., Qiu M., Sun W., Wei R., Zheng X., Yang Y., Xin X., Zou H., Chen T., et al. Metabolic Signatures of Kidney Yang Deficiency Syndrome and Protective Effects of Two Herbal Extracts in Rats Using GC/TOF MS. Evid. Based. Complement. Alternat. Med. 2013;2013:540957.

    Not in our library10.1155/2013/540957

  183. 183.

    Bornfeldt K.E., Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14:575-585.

    Not in our library10.1016/j.cmet.2011.07.015

  184. 184.

    La Sala L., Prattichizzo F., Ceriello A. The link between diabetes and atherosclerosis. Eur. J. Prev. Cardiol. 2019;26:15-24.

    Not in our library10.1177/2047487319878373

  185. 185.

    Patterson E., Ryan P.M., Cryan J.F., Dinan T.G., Ross R.P., Fitzgerald G.F., Stanton C. Gut microbiota, obesity and diabetes. Postgrad. Med. J. 2016;92:286-300.

    Not in our library10.1136/postgradmedj-2015-133285

  186. 186.

    Abildgaard A., Elfving B., Hokland M., Wegener G., Lund S. The microbial metabolite indole-3-propionic acid improves glucose metabolism in rats, but does not affect behaviour. Arch. Physiol. Biochem. 2018;124:306-312.

    Not in our library10.1080/13813455.2017.1398262

  187. 187.
    The meaning of blood pressure · 2018
    No notice
  188. 188.

    Ning B., Chen Y., Waqar A.B., Yan H., Shiomi M., Zhang J., Chen Y.E., Wang Y., Itabe H., Liang J., et al. Hypertension enhances advanced atherosclerosis and induces cardiac death in watanabe heritable hyperlipidemic rabbits. Am. J. Pathol. 2018;188:2936-2947.

    Not in our library10.1016/j.ajpath.2018.08.007

  189. 189.

    Pulakazhi Venu V.K., Saifeddine M., Mihara K., Tsai Y.C., Nieves K., Alston L., Mani S., McCoy K.D., Hollenberg M.D., Hirota S.A. The pregnane X receptor and its microbiota-derived ligand indole 3-propionic acid regulate endothelium-dependent vasodilation. Am. J. Physiol. Endocrinol. Metab. 2019;317:E350-E361.

    Not in our library10.1152/ajpendo.00572.2018

  190. 190.

    Patterson R.A., Stankewicz H.A. Penicillin Allergy. 2021.

    Not in our library

  191. 191.
    Clostridioides difficile Biology: Sporulation, Germination, and Corresponding Therapies for C. difficile Infection · 2018
    No notice
  192. 192.

    Brown S.A., Riviere J.E. Comparative pharmacokinetics of aminoglycoside antibiotics. J. Vet. Pharmacol. Ther. 1991;14:1-35.

    Not in our library10.1111/j.1365-2885.1991.tb00801.x

  193. 193.

    Behr C., Kamp H., Fabian E., Krennrich G., Mellert W., Peter E., Strauss V., Walk T., Rietjens I., van Ravenzwaay B. Gut microbiome-related metabolic changes in plasma of antibiotic-treated rats. Arch. Toxicol. 2017;91:3439-3454.

    Not in our library10.1007/s00204-017-1949-2

  194. 194.

    Wilkins T., Sequoia J. Probiotics for gastrointestinal conditions: A summary of the evidence. Am. Fam. Physician. 2017;96:170-178.

    Not in our library

  195. 195.

    Sebastian Domingo J.J. Review of the role of probiotics in gastrointestinal diseases in adults. Gastroenterol. Hepatol. 2017;40:417-429.

    Not in our library10.1016/j.gastre.2016.12.001

  196. 196.

    Kim H.K., Rutten N.B., Besseling-van der Vaart I., Niers L.E., Choi Y.H., Rijkers G.T., van Hemert S. Probiotic supplementation influences faecal short chain fatty acids in infants at high risk for eczema. Benef. Microbes. 2015;6:783-790.

    Not in our library10.3920/bm2015.0056

  197. 197.

    Primec M., Klemenak M., Di Gioia D., Aloisio I., Bozzi Cionci N., Quagliariello A., Gorenjak M., Micetic-Turk D., Langerholc T. Clinical intervention using Bifidobacterium strains in celiac disease children reveals novel microbial modulators of TNF-alpha and short-chain fatty acids. Clin. Nutr. 2019;38:1373-1381.

    Not in our library10.1016/j.clnu.2018.06.931

  198. 198.

    Abildgaard A., Elfving B., Hokland M., Wegener G., Lund S. Probiotic treatment reduces depressive-like behaviour in rats independently of diet. Psychoneuroendocrinology. 2017;79:40-48.

    Not in our library10.1016/j.psyneuen.2017.02.014

  199. 199.

    Savino F., Cordisco L., Tarasco V., Palumeri E., Calabrese R., Oggero R., Roos S., Matteuzzi D. Lactobacillus reuteri DSM 17938 in infantile colic: A randomized, double-blind, placebo-controlled trial. Pediatrics. 2010;126:e526-e533.

    Not in our library10.1542/peds.2010-0433

  200. 200.

    Szajewska H., Gyrczuk E., Horvath A. Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: A randomized, double-blind, placebo-controlled trial. J. Pediatr. 2013;162:257-262.

    Not in our library10.1016/j.jpeds.2012.08.004

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