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Production of Indole and Indole-Related Compounds by the Intestinal Microbiota and Consequences for the Host: The Good, the Bad, and the Ugly

Naouel Tennoune, Mireille Andriamihaja, François Blachier

Microorganisms · 2022 · Review · CC BY

doi:10.3390/microorganisms10050930

Abstract

The intestinal microbiota metabolic activity towards the available substrates generates myriad bacterial metabolites that may accumulate in the luminal fluid. Among them, indole and indole-related compounds are produced by specific bacterial species from tryptophan. Although indole-related compounds are, first, involved in intestinal microbial community communication, these molecules are also active on the intestinal mucosa, exerting generally beneficial effects in different experimental situations. After absorption, indole is partly metabolized in the liver into the co-metabolite indoxyl sulfate. Although some anti-inflammatory actions of indole on liver cells have been shown, indoxyl sulfate is a well-known uremic toxin that aggravates chronic kidney disease, through deleterious effects on kidney cells. Indoxyl sulfate is also known to provoke endothelial dysfunction. Regarding the central nervous system, emerging research indicates that indole at excessive concentrations displays a negative impact on emotional behavior. The indole-derived co-metabolite isatin appears, in pre-clinical studies, to accumulate in the brain, modulating brain function either positively or negatively, depending on the doses used. Oxindole, a bacterial metabolite that enters the brain, has shown deleterious effects on the central nervous system in experimental studies. Lastly, recent studies performed with indoxyl sulfate report either beneficial or deleterious effects depending once again on the dose used, with missing information on the physiological concentrations that are reaching the central nervous system. Any intervention aiming at modulating indole and indole-related compound concentrations in the biological fluids should crucially take into account the dual effects of these compounds according to the host tissues considered.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The colonic epithelial cells are polarized cells that face, on their luminal side, a complex mixture of microorganisms and molecules. These molecules include several bacterial components and myriad bacterial metabolites that are metabolic intermediaries and final products derived from the colonic bacterial metabolic activity that may accumulate in the intestinal luminal content. These bacterial metabolites have attracted increasing interest due to their capacity to interact with different aspects of colonic epithelial cell metabolism and physiology, and their potential implication in the development or modulation of pathological processes that occur in the colonic and rectal mucosae, notably chronic inflammatory bowel disease. These diseases have been associated with changes in the colonic bacterial metabolite profiles, raising the possibility of causal links between such changes and the modulation of the risk of colorectal inflammation. Among bacterial metabolites, those derived from various amino acids released from dietary and endogenous proteins present in the intestinal content represent a family of molecules, whose concentrations can vary according to many parameters, notably and interestingly including dietary habits.

Several amino acid-derived bacterial metabolites can be absorbed through the intestinal epithelial cells and metabolized by the host tissues, giving rise to the so-called co-metabolites, which thus result from the joint activities of the intestinal microbiota and host cells. The effects of co-metabolites on the different host peripheral tissues in different physiological or pathological situations represent an important issue to establish the overall consequences on the host of the production of bacterial metabolites.

In such a context, the present paper aims to provide the state of the art regarding the production from L-tryptophan of indole and indole-related compounds by the intestinal microbiota, the effects of indolic compounds on the intestinal mucosa, the metabolism of indole by the host, and the effects of indole and co-metabolites on peripheral organs. For the sake of clarity and concision, this review does not concern the effects on the host of other tryptophan-derived bacterial metabolites such as tryptamine, an inducer for the release of 5-hydroxytryptamine (serotonin) by enteroendocrine cells; this latter compound is able to stimulate gastrointestinal motility by acting on the neurons of the enteric nervous system, as detailed in recent reviews on that topic.

2. The Amino Acid L-tryptophan Is Used by the Intestinal Microbiota to Produce Indole and Indole-Related Compounds That Are Recovered in the Large Intestine Fluid

L-tryptophan is one of the nine indispensable amino acids that must be provided in the diet to meet the body’s requirements. L-tryptophan, in addition to its role as a precursor for protein synthesis in host tissues, is also a precursor for numerous compounds with biological activities, including the neurotransmitters serotonin and tryptamine, the hormone melatonin, and the vitamin-like compounds niacin and nicotinic acid. In humans, the tryptophan requirement is 4.0 mg/kg body weight/day. The mean amount of tryptophan provided from all sources is 0.91 g/day, thus representing a usual consumption equal to 13.0 mg/kg body weight/day; thus, this value is well above the requirement. In addition to being used by the different organs and tissues of the host body, a minor part of available tryptophan, approximately 5%, is metabolized by the gut microbes. Exogenous tryptophan used by the gut microbes mainly originates from the undigested, or not fully digested, proteins, which are transferred from the small to the large intestine. In fact, based on a regular Western diet, 6–12 g of proteins and peptides from both dietary and endogenous origin escape digestion in the small intestine, thus reaching the colonic lumen (Figure 1). This quantity of nitrogenous materials can be usefully compared to the dietary protein consumption in Western countries, which averages 85 g per day.

Bacterial proteases and peptidases release amino acids, including tryptophan, from available dietary and endogenous luminal protein, and since amino acids are little absorbed by the colonic epithelial cells, they are mainly used by the large intestine microbes in the course of their metabolic activity.

Intestinal bacteria convert tryptophan mainly into indole through the action of the bacterial enzyme tryptophanase; the latter is induced by tryptophan itself. Of note, in mammals, indole originates exclusively from bacterial metabolic activity since host cells do not have the metabolic capacity for the production of this compound. Indole is synthesized from various Gram-positive and Gram-negative bacterial species, including Escherichia coli, Proteus Vulgaris, Clostridium spp., and Bacteroides spp.. Tryptophan can also be converted directly or indirectly by the intestinal microbiota into several indole-related compounds, including indole-3-pyruvate, indole-3-lactate, indole-3-propionate, indole-3-acetamide, indole-3-acrylate, indole acetaldehyde, indole-3-acetate, indole-3-aldehyde, 3-methyl-indole (skatole), and indole-3-acetaldehyde. However, the precise metabolic pathways involved in the stepwise conversion of tryptophan into these minor indolic compounds by the intestinal microbiota in the large intestine remain unclear. Regarding the bacterial species involved in their production, indole-3-propionate has been shown to be produced by Clostridium sporogenes. Skatole is known to be produced by Clostridium spp. and Bacteroides spp.. Other indolic compounds are produced by Bacteroides species, Peptostreptococcus spp. Lactobacillus spp., and Bifidobacterium spp..

The fecal indole content has been measured in volunteers, but huge inter-individual differences exist between volunteers, ranging from 0.30 to 6.64 millimolar concentrations. Such a large range is presumably due to differences in intestinal microbiota composition between volunteers and to different levels of dietary protein consumption. Incidentally, since indole appears to be absorbed through the colonic epithelium, the concentration of indole in the colon is likely higher than that recorded in the feces, with concentrations higher in the distal large intestine than in the more proximal parts.

Fecal skatole concentration in healthy individuals averages 0.04 mM, but the concentration in the colonic content is again presumably higher since skatole is absorbed through the gut epithelium, and then released in the circulation. In the pig model, skatole colonic concentration averages 0.23 mM. Skatole concentration increases in the large intestine after a high-meat diet, or when luminal fermentation increases as a result of longer intestinal stasis. In rodents, indole-3-propionate is found only in blood recovered from animals with intestinal microbiota, but not in blood originating from germ-free animals, thus reinforcing the view that this metabolite originates from the intestinal microbiota’s metabolic activity.

3. Indole and Indolic Compounds Are Involved in Intestinal Microbial Community Communication

Among amino acid-derived bacterial metabolites, indole has attracted growing interest since this compound is involved in bacterial physiology and metabolism in relationship with antibiotic resistance, virulence factors, sporulation, and biofilm formation. Indeed, indole is a bacterial signal involved in the communication between bacteria within the same species and between bacteria of different species. It acts as an inter-and intra-cellular signal in bacterial ecosystems (Figure 1). Indole diminishes the related virulence of L. monocytogenes by reducing cell motility and aggregation. Indole influences host cell invasion by non-indole-producing species, such as Salmonella enterica and P. aeruginosa, and the fungal species Candida albicans In addition, indole reduces E. coli motility. In another study, indole was shown to display bacteriostatic effects on lactic acid bacteria, while affecting their survival. Of note, indole mitigates cytotoxicity by Klebsellia spp. by suppressing toxin production.

4. Indole and Indolic Compounds Exert Beneficial Effects on the Intestinal Mucosa

Several indolic compounds, including indole-3-acetate, indole-3-propionate, indole-3-aldehyde, indole-3-acetaldehyde, and indole acrylate, bind to the aryl hydro carbon receptor, which is present in different cell types of the host, including cells present in the intestinal mucosa, notably intestinal epithelial cells and immune cells. The binding of indolic compounds to AhR participates in the maintenance of the intestinal mucosa homeostasis by acting on the control of the intestinal epithelium renewal, its barrier function, and the activity of several intestinal immune cell types. AhR can also be activated by dietary compounds, but bacterial metabolites appear to play a preponderant role in the AhR activation. Only a few commensal bacteria have been identified as able to produce AhR ligands, such as Peptostreptococcus russellii and Lactobacillus spp..

Among the indolic compounds, indole-3-propionate, when given by the oral route, exerts beneficial effects on the intestinal barrier function when the latter is experimentally altered in rodent models, such as via radiation injury, or rodents fed a high-fat diet. In addition, indole-3-propionate reduces intestinal permeability and inflammation in a rodent model. In such an experimental context, it is of interest to note that circulating indole-3-propionate acid is reduced in patients suffering from ulcerative colitis when compared with their healthy counterparts, whereas an increased level of this bacterial metabolite is associated with remission.

In a model of experimental colitis induced in mice, other indolic compounds given by the oral route, namely indole-3-pyruvate, indole-3-aldehyde, and indole-3-ethanol, protect against increased intestinal permeability observed in this model. Indole itself, when given by the oral route, decreases mucosal inflammation and injury in a model of enteropathy in rodents. In mice, microbiota-derived indole-3-aldehyde contributes to aryl hydrocarbon receptor-dependent IL-22 gene transcription, allowing the survival of mixed microbial communities, while providing colonization resistance to the fungal species C. albicans, and protecting the mucosa from inflammation. Indole-3-acrylate diminishes in mice intestinal inflammation and upregulates Mucin 2 gene expression.

Protective effects of microbiota-derived aryl hydrocarbon receptor agonists on the intestinal mucosa have been suggested by both experimental and clinical data, with presumed consequences for the risk of metabolic syndrome. In this latter study, metabolic syndrome was found to be associated with an impaired capacity of the gut microbiota to produce from tryptophan aryl hydrocarbon agonist receptors; this impaired capacity is paralleled by increased gut permeability and decreased secretion of GLP-1 from enteroendocrine cells.

Regarding the effects of indole on intestinal epithelial cells, exposure of human enterocytes to indole, but not to other indole-like compounds, increases the expression of genes involved in the intestinal epithelial barrier function and mucin production. Interestingly, these effects were paralleled by an effect of indole on the expression of different cytokines, with decreased expression of the pro-inflammatory IL-8, and increased expression of the regulatory cytokine IL-10. However, in this study, the expression of several genes linked to inflammation was also found to be increased, making the indole effect on the intestinal epithelial cells more complicated than it appears at first sight.

Moreover, oral administration of an indole-containing capsule to rodents results in an increased expression in colonocytes of genes coding for tight junction proteins between epithelial cells. Following these results, indole was found to increase transepithelial resistance in in vitro experiments using colonocyte monolayers, thus reinforcing the view that indole ameliorates the basal barrier function. Thus, indole and several indolic compounds exert beneficial effects on the intestinal mucosa in different situations (Figure 1). Overall, the protective effects of bacterial metabolites derived from tryptophan on intestinal mucosa may contribute to the beneficial effects of tryptophan supplementation observed in animal models of colitis.

However, surprisingly, indole used at a 2.5 millimolar concentration affects the respiration of colonocytes by diminishing mitochondrial oxygen consumption, and thus mitochondrial ATP production. This last effect was accompanied by transient oxidative stress in colonocytes, which was followed by an increase in the expression of antioxidant enzymes, presumably as an adaptive process against the deleterious effect of excessive indole exposure.

Little is known about the effects of skatole on intestinal cells, but high concentrations of skatole induce cell death in human colonocytes.

In in vitro experiments performed with immortalized and primary mouse colonic enteroendocrine L cells, indole modulates the secretion of glucagon-like peptide-1 (GLP-1). Since GLP-1 slows down gastric emptying, stimulates insulin secretion by pancreatic beta cells, and diminishes appetite, it would be of major interest to study in vivo the effects of indole on these physiological parameters.

5. After Absorption, Indole Is Partly Metabolized into Indoxyl Sulfate in the Liver

Indole, after absorption in the portal vein, has been shown to exert some anti-inflammatory effects on liver cells (Figure 1). In a rodent model, indole reduces the production of pro-inflammatory mediators by the liver. In a model of obese mice, indole reduces hepatic damage and the associated inflammatory response. The indolic compound indole-3-acetic acid alleviates, in mice, the high-fat diet-induced hepatotoxicity. This latter bacterial metabolite reduces the expression of fatty acid synthase in hepatocytes.

The indole that reaches the liver cells is partly metabolized by several cytochrome (CYP) family enzymes, including, notably, CYP2E1. Several molecules are produced from indole, with indoxyl sulfate being the main co-metabolite produced (Figure 1). As can be anticipated, subjects who consumed a high-protein diet showed overall greater indoxyl sulfate urinary excretion than those who consumed a low-protein diet. In addition, in a randomized, parallel, double-blind trial in overweight volunteers, protein supplementation provoked an increased concentration of indoxyl sulfate in urine. CYP enzymes are presumably involved in the conversion of indole to indoxyl, an intermediate in the synthesis of indoxyl sulfate. CYP2E1 represents the major enzymatic isoform responsible for the oxidation of indole to indoxyl. CYP2E1 is detected in the colonic epithelium. However, data obtained with human colonocytes of the HT-29 Glc-/+ line, chosen because these cells have retained metabolic features that are characteristic of healthy colonocytes (such as the capacity to oxidize butyrate and acetate, show that the capacity of these cells to convert indole to indoxyl sulfate is modest but measurable, and the vast majority of indoxyl sulfate is presumably produced within the liver (Figure 1).

6. Indoxyl Sulfate Is a Recognized Uremic Toxin That Exerts Deleterious Effects on Tubular Kidney Cells and Accelerates Chronic Kidney Disease

Indoxyl sulfate after production in the liver is released in the peripheral blood and then excreted in urine. Indoxyl sulfate concentrations in the blood can be increased from micromolar concentrations in healthy individuals, up to 1.1 millimolar in severe chronic kidney disease. Indoxyl sulfate belongs to the family of uremic toxins that may accumulate in body fluids leading to the so-called uremic syndrome. Indeed, indoxyl sulfate at excessive concentrations aggravates chronic kidney disease in patients. In healthy individuals, indoxyl sulfate is almost entirely bound to proteins in the blood (approximately 93% of this co-metabolite is in bound form). The main binding protein in the blood is albumin, with two binding sites for indoxyl sulfate. Circulating IS in free form is then efficiently excreted in the urine by proximal tubular cells through basolateral organic anion transporters.

However, in patients with chronic kidney disease, only 85% of this co-metabolite is protein-bound, and thus a higher part of indoxyl sulfate is in free form. As kidney function declines, indoxyl sulfate total concentration increases in the blood and this elevation contributes to further progression of chronic kidney disease. In a cohort study, it was found that blood indoxyl sulfate concentrations are higher in patients with chronic kidney failure progression than in stabilized patients. Then, indoxyl sulfate concentration in blood has been proposed as an indicator of chronic kidney disease progression in dialyzed patients.

In experimental in vitro and in vivo studies, indoxyl sulfate has been shown to have deleterious effects on kidney cells when present in excess (Figure 1). This co-metabolite increases the expression of inflammation-associated genes in cultured proximal renal tubular cells. This effect coincides with a capacity of indoxyl sulfate to increase the net production of reactive oxygen species in the proximal tubular cells, and oxidative stress in these cells. In addition, this compound reduces the glutathione concentration in renal tubular cells. Taking into account the central role of reduced glutathione in the process of excessive reactive oxygen species disposal, it is plausible that a reduced intracellular concentration of glutathione will render renal tubular cells even more vulnerable to oxidative stress. The fact that indoxyl sulfate also reduces the superoxide scavenging activity in the kidneys of normal and uremic rodents contributes to the sensitivity of the kidney cells to oxidative stress. Indeed, superoxide is one of the reactive oxygen species that is deleterious to cells when its intracellular concentration exceeds a threshold value. These effects are of major importance when considering that reactive oxygen species are elevated in renal tubular cells in the process of chronic kidney disease progression.

Indoxyl sulfate in excess is involved in renal fibrosis. Briefly, renal fibrosis results notably from excessive accumulation of extracellular matrix after renal insult. Administration of indoxyl sulfate in experimental models of chronic kidney disease leads to glomerular sclerosis and interstitial fibrosis. These effects of indoxyl sulfate can be explained by its capacity to promote the transformation of kidney fibroblasts into matrix-producing phenotype, thus increasing collagen deposition, a process that is linked to interstitial fibrosis. This proposition is reinforced by the fact that indoxyl sulfate increases the expression of genes implicated in kidney fibrosis.

7. Indoxyl Sulfate Is Deleterious for Other Cell Types including Colonocytes and Endothelial Cells

Indoxyl sulfate may be toxic for colonocytes. The way of entry of this compound into colonocytes is most likely from the blood to the basolateral side of polarized cells. Indeed, as expected, the indoxyl sulfate concentration in the colonic content is in the low micromolar range. At micromolar concentrations, indoxyl sulfate is cytotoxic for the intestinal epithelial cells, inducing oxidative stress and impairing cell migration. At higher concentrations (millimolar), indoxyl sulfate reduces mitochondrial oxygen consumption in colonocytes, induces a transient increase in the reactive oxygen species’ net production, and rapidly but transiently increases the secretion of the pro-inflammatory IL-8 and, after a 48 h exposure, tumor necrosis factor-alpha (TNF-α).

Finally, indoxyl sulfate can be included in the family of uremic endotheliotoxins, meaning that this compound induces endothelial dysfunction, one central element implicated in cardiovascular morbidity and mortality, taking into account that the risk of cardiovascular dysfunctions is associated with chronic kidney disease. From in vivo and in vitro preclinical studies, indoxyl sulfate has been shown to promote both pro-thrombotic processes, notably through mechanisms involving the aryl hydrocarbon receptor and pro-oxidant processes. Clinical data obtained in patients with chronic kidney disease indicate that indoxyl sulfate is likely to represent one of the links between impaired renal function and adverse cardiovascular events, notably regarding hemostatic disorders and thrombotic events

8. Indole and Indolic Compounds Are Active on the Central Nervous System

There is emerging evidence of the influence of indole and indolic compounds on brain metabolism, physiology, and host behavior.

8.1. Indole in Excess Shows Adverse Effects on Behavior

Chronic overproduction of indole in rats monocolonized with E. coli generating indole has been shown to enhance anxiety-like behavior and depression in these animals. This latter study also found that giving intra-cecal indole to conventional rats activated a cerebral nucleus called the dorsal vagal complex. By comparing mice mono-associated with a non-indole-producing E. coli strain, or with an indole-producing E. coli strain, it was found that chronic high indole production by the intestinal microbiota increased the vulnerability to the adverse effects of chronic stress on overall emotional behavior. In humans, a study has revealed that children with autism spectrum disorders reported lower levels of indole and increased levels of 3-methylindole in fecal samples in comparison to healthy children. These two indoles have been linked to bacteria of the genus Clostridium, which are more prevalent in these patients. A rise in plasma indole derived from intestinal microbiota metabolic activity is associated with hepatic encephalopathy, neuropsychiatric trouble caused by hepatic dysfunction, and changes in the individual’s state of consciousness, conduct, and personality. Furthermore, the findings of the observational prospective NutriNet-Santé Study revealed a positive link between urine indole and indolic compounds’ concentrations and recurrent depressive symptoms. This correlation raises the hypothesis that the synthesis of these compounds by the gut microbiota in excessive amounts may play a role in the emergence of mood disorders in humans.

Some information on the effects of indolic compounds on the central nervous system are available. Isatin, oxindole, and indoxyl sulfate are the most studied indolic metabolites for their neuroactive effects (Figure 1).

8.2. Isatin Can Enter the Brain and Affect Behavior and Brain Function

Isatin (1H-indole-2,3-dione) is a co-metabolite produced by the host from indole. Isatin is detected in different brain regions. Systemic administration of isatin to rodents leads to an accumulation of this compound in the brain. In addition, administration of indole in the large intestine results in an accumulation of isatin in the brain, thus suggesting that this compound is able to enter the brain by still unknown processes. The hippocampus and cerebellum have the largest concentrations of isatin in the rat brain, whereas the prefrontal cortex and brainstem have the lowest quantities. The impact of isatin on rodent behavior and brain function, either beneficial or deleterious, appears to depend on the doses used. Intraperitoneal treatment of isatin up to 20 mg/kg body weight promotes an increase in anxiety-like behavior in rats and mice. Isatin affects anxiety-like behavior via acting on monoaminergic receptors. Furthermore, at 10 mg/kg, isatin reduces the anxiolytic effect of intracerebroventricular atrial natriuretic peptide (ANP) injection. Because ANP has a role in the control of the hypothalamic-pituitary-adrenal (HPA) axis, it is plausible that isatin anxiogenic action would be mediated through this axis. Indeed, isatin (20 mg/kg) causes a 50% rise in plasma cortisol in rhesus monkeys. Higher amounts of isatin, over 40 mg/kg when given intraperitoneally, result in a reduction in locomotor activity in the open field test and mobility in the forced swimming test in rats, indicating that isatin may exert a sedative effect.

Intraperitoneal injection of isatin (100 mg/kg) improved parkinsonian symptoms in a parkinsonian rat model induced by a 6-hydroxydopamine lesion. Isatin intraperitoneal administration (100 mg/kg) increased dopamine concentration in the striatum of rats in the model of Parkinson’s disease induced by the Japanese encephalitis virus. Isatin can inhibit, in a dose-dependent manner, the monoamine oxidase activities in extracts obtained from the rat brain. It has been suggested that the effects of isatin, which is anxiogenic at low doses and sedative at high doses, would be related to the monoaminergic systems in the brain. Because of the affinity of isatin for ANP peptide receptors and their role in the stress axis, these receptors seem to represent one significant target in the mechanism of action of isatin on the central nervous system physiology and the anxiety-like behaviors.

8.3. Oxindole Can Enter the Brain and Exert Deleterious Effects on the Brain

The intraperitoneal injection of oxindole results in its accumulation in the brain, thus indicating that this compound may, like isatin, enter the brain by a still unknown process. Oral administration in rodents of neomycin, a broad-spectrum antibiotic, decreases the brain oxindole content, thus suggesting that oxindole is originating, at least partly, from the intestinal microbiota metabolic activity. Interestingly, oxindole was recently found in human fecal samples, thus confirming that the intestinal microbes are a source of this metabolite. Among the bacterial metabolites present in human stool, oxindole was found to be one of the dominant aryl hydrocarbon receptor activators. In vitro experiments on rat hippocampus slices demonstrate that oxindole may interact with voltage-gated sodium channels, increasing the threshold for producing action potentials and therefore drastically reducing neuron excitability. These results led several authors to propose that oxindole may share some characteristics with known neurodepressant compounds. Of note, unlike isatin, oxindole has relatively low monoamine oxidase inhibitory activity.

8.4. Indoxyl Sulfate, Depending on the Dose Used, May Exert Both Beneficial and Deleterious Effects on Brain

Concerning indoxyl sulfate, this co-metabolite is detected in the mammalian brain. Indoxyl sulfate is also detected in the cerebrospinal fluid of mice, and animals with no intestinal microbiota display a low level of this compound in this fluid when compared with normal mice hosting microbes. By comparing volunteers suffering from depression with healthy participants, 22 urine metabolites were identified, and their abundances differed between the two groups of subjects. The Hamilton Depression Scale questionnaire score was used to measure the severity of depression. According to this investigation, the urine indoxyl sulfate concentration in individuals suffering from severe depression was lower than that in healthy counterparts. In volunteers, serum indoxyl sulfate concentrations have been associated with psychic anxiety and the related functional magnetic resonance imaging-based neurological signature.

In a mouse model of experimental autoimmune encephalomyelitis, indoxyl sulfate delivered daily (10 mg/kg) intraperitoneally modulates astrocyte activity and exerts an anti-inflammatory action on the central nervous system via the aryl hydrocarbon receptor. Conversely, when rats were exposed orally to indoxyl sulfate used at higher doses (100 and 200 mg/kg), impairment of spatial memory and reduced locomotor and exploratory activities were observed. In this latter study, after indoxyl sulfate administration, this compound was mainly recovered in the brainstem. Another study found that a single intraperitoneal injection of indoxyl sulfate at an even greater dose (800 mg/kg) caused histological changes in the brain compatible with neuronal necrosis. In this latter study, indoxyl sulfate, when used in a 15–60 micromolar range, induced radical oxygen species production in primary astrocytes, and cell death in hippocampal neurons. At a 10-micromolar concentration, indoxyl sulfate induces apoptosis through oxidative stress in human astrocytes. Unfortunately, little information is available on the physiological concentrations of indoxyl sulfate and of the other indole-related compounds that reach the central nervous system.

9. Conclusions and Perspectives

Indole and indole-related compounds are, first, involved in intestinal microbial community communication, regulating important aspects of bacterial physiology. These molecules are also known to be active on the intestinal mucosa, exerting overall beneficial effects in different experimental situations, notably in inflammatory situations. After absorption, indole is partly metabolized in the liver into the co-metabolite indoxyl sulfate. Indoxyl sulfate is well known to be one of the uremic toxins that can seriously aggravate chronic kidney disease, notably through deleterious effects on kidney cells. Regarding the central nervous system, emerging research indicates that indole at excessive concentrations displays a negative impact on emotional behavior in different experimental situations. From a limited number of experimental studies, the indolic compounds isatin, oxindole, and indoxyl sulfate also appear to affect the central nervous system activity.

Any intervention, either of dietary, microbial, and/or pharmacological origin, which aims at modulating indole and indole-related compounds in the biological fluids, notably in the colonic lumen, should crucially take into account the dual effects of these compounds, either beneficial or deleterious, according to the host tissues considered, and the physiological or pathophysiological context (Figure 1). For instance, given the deleterious effect of indoxyl sulfate on kidney cells in chronic kidney disease patients, it can be envisaged in that situation to either decrease the production of indole by the colonic microbiota, and/or to decrease indoxyl sulfate production by the liver, and/or to increase its removal from blood by an appropriate dialysis system.

In order to answer questions related to the effects of indolic compounds on the colonic epithelium, further research is needed to explore advantages from the utilization of colonic organoids for determining the effects of bacterial metabolites on the different phenotypes among intestinal epithelial cells. Additional pre-clinical studies are needed to document further the effects of indolic compounds on host tissues, thus paving the way for future clinical studies.

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    Not in our library10.1111/j.1365-2982.2009.01370.x

  21. 21.
    The aryl hydrocarbon receptor as a mediator of host-microbiota interplay · 2020
    No notice
  22. 22.
    Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health · 2019
    No notice
  23. 23.
    Tryptophan Dietary Impacts Gut Barrier and Metabolic Diseases · 2019
    No notice
  24. 24.

    Jensen M.T., Cox R.P., Jensen B.B. 3-Methylindole (skatole) and indole production by mixed populations of pig fecal bacteria. Appl. Environ. Microbiol. 1995;61:3180-3184.

    Not in our library10.1128/aem.61.8.3180-3184.1995

  25. 25.

    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

  26. 26.

    Cook K.L., Rothrock M.J., Loughrin J.H., Doerner K.C. Characterization of skatole-producing microbial populations in enriched swine lagoon slurry. FEMS Microbiol. Ecol. 2007;60:329-340.

    Not in our library10.1111/j.1574-6941.2007.00299.x

  27. 27.

    Whitehead T.R., Price N.P., Drake H.L., Cotta M.A. Catabolic pathway for the production of skatole and indoleacetic acid by the acetogen Clostridium drakei, Clostridium scatologenes, and swine manure. Appl. Environ. Microbiol. 2008;74:1950-1953.

    Not in our library10.1128/aem.02458-07

  28. 28.

    Wlodarska M., Luo C., Kolde R., d’Hennezel E., Annand J.W., Heim C.E., Krastel P., Schmitt E.K., Omar A.S., Creasey E.A., et al. Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation. Cell Host Microbe. 2017;22:25-37.e26.

    Not in our library10.1016/j.chom.2017.06.007

  29. 29.

    Darkoh C., Chappell C., Gonzales C., Okhuysen P. A rapid and specific method for the detection of indole in complex biological samples. Appl. Environ. Microbiol. 2015;81:8093-8097.

    Not in our library10.1128/aem.02787-15

  30. 30.
    Indoxyl Sulfate—Review of Toxicity and Therapeutic Strategies · 2016
    No notice
  31. 31.

    Huc T., Konop M., Onyszkiewicz M., Podsadni P., Szczepańska A., Turło 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

  32. 32.

    Whitt D.D., Demoss R.D. Effect of microflora on the free amino acid distribution in various regions of the mouse gastrointestinal tract. Appl. Microbiol. 1975;30:609-615.

    Not in our library10.1128/am.30.4.609-615.1975

  33. 33.

    Yokoyama M.T., Carlson J.R. Microbial metabolites of tryptophan in the intestinal tract with special reference to skatole. Am. J. Clin. Nutr. 1979;32:173-178.

    Not in our library10.1093/ajcn/32.1.173

  34. 34.

    Witte F., Pajic A., Menger F., Tomasevic I., Schubert D.C., Visscher C., Terjung N. Preliminary Test of the Reduction Capacity for the Intestinal Adsorption of Skatole and Indole in Weaning Piglets by Pure and Coated Charcoal. Anim. Open Access J. MDPI. 2021;11:2720.

    Not in our library10.3390/ani11092720

  35. 35.

    Claus R., Raab S. Influences on skatole formation from tryptophan in the pig colon. Adv. Exp. Med. Biol. 1999;467:679-684.

    Not in our library10.1007/978-1-4615-4709-9_87

  36. 36.

    Yoshihara I., Maruta K. Gas Chromatographic Microdetermination of Indole and Skatole in Gastrointestinal Contents of Domestic Animals. Agric. Biol. Chem. 1977;41:2083-2085.

    Not in our library10.1080/00021369.1977.10862811

  37. 37.

    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

  38. 38.

    Kim J., Park W. Indole: A signaling molecule or a mere metabolic byproduct that alters bacterial physiology at a high concentration? J. Microbiol. 2015;53:421-428.

    Not in our library10.1007/s12275-015-5273-3

  39. 39.

    Lee J.-H., Lee J. Indole as an intercellular signal in microbial communities. FEMS Microbiol. Rev. 2010;34:426-444.

    Not in our library10.1111/j.1574-6976.2009.00204.x

  40. 40.

    Vega N.M., Allison K.R., Samuels A.N., Klempner M.S., Collins J.J. Salmonella typhimurium intercepts Escherichia coli signaling to enhance antibiotic tolerance. Proc. Natl. Acad. Sci. USA. 2013;110:14420-14425.

    Not in our library10.1073/pnas.1308085110

  41. 41.

    Rattanaphan P., Mittraparp-Arthorn P., Srinoun K., Vuddhakul V., Tansila N. Indole signaling decreases biofilm formation and related virulence of Listeria monocytogenes. FEMS Microbiol. Lett. 2020;367:fnaa116.

    Not in our library10.1093/femsle/fnaa116

  42. 42.

    Li G., Young K.D. Indole production by the tryptophanase TnaA in Escherichia coli is determined by the amount of exogenous tryptophan. Microbiology. 2013;159:402-410.

    Not in our library10.1099/mic.0.064139-0

  43. 43.

    Bansal T., Englert D., Lee J., Hegde M., Wood T.K., Jayaraman A. Differential effects of epinephrine, norepinephrine, and indole on Escherichia coli O157:H7 chemotaxis, colonization, and gene expression. Infect. Immun. 2007;75:4597-4607.

    Not in our library10.1128/iai.00630-07

  44. 44.

    Nowak A., Libudzisz Z. Influence of phenol, p-cresol and indole on growth and survival of intestinal lactic acid bacteria. Anaerobe. 2006;12:80-84.

    Not in our library10.1016/j.anaerobe.2005.10.003

  45. 45.

    Ledala N., Malik M., Rezaul K., Paveglio S., Provatas A., Kiel A., Caimano M., Zhou Y., Lindgren J., Krasulova K., et al. Bacterial Indole as a Multifunctional Regulator of Klebsiella oxytoca Complex Enterotoxicity. mBio. 2022;13:e03752-21.

    Not in our library10.1128/mbio.03752-21

  46. 46.

    Pernomian L., Duarte-Silva M., de Barros Cardoso C.R. The Aryl Hydrocarbon Receptor (AHR) as a Potential Target for the Control of Intestinal Inflammation: Insights from an Immune and Bacteria Sensor Receptor. Clin. Rev. Allergy Immunol. 2020;59:382-390.

    Not in our library10.1007/s12016-020-08789-3

  47. 47.
    Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles · 2015
    No notice
  48. 48.

    Hubbard T.D., Murray I.A., Perdew G.H. Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. Drug Metab. Dispos. Biol. Fate Chem. 2015;43:1522-1535.

    Not in our library10.1124/dmd.115.064246

  49. 49.

    Lamas B., Richard M.L., Leducq V., Pham H.P., Michel M.L., Da Costa G., Bridonneau C., Jegou S., Hoffmann T.W., Natividad J.M., et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 2016;22:598-605.

    Not in our library10.1038/nm.4102

  50. 50.

    Zelante T., Iannitti R.G., Cunha C., De Luca A., Giovannini G., Pieraccini G., Zecchi R., D’Angelo C., Massi-Benedetti C., Fallarino F., et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372-385.

    Not in our library10.1016/j.immuni.2013.08.003

  51. 51.
    Gut microbiota-derived indole 3-propionic acid protects against radiation toxicity via retaining acyl-CoA-binding protein · 2020
    No notice
  52. 52.

    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. Off. J. Eur. Gastrointest. Motil. Soc. 2018;30:e13178.

    Not in our library10.1111/nmo.13178

  53. 53.

    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

  54. 54.

    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

  55. 55.

    Scott S.A., Fu J., Chang P.V. Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA. 2020;117:19376-19387.

    Not in our library10.1073/pnas.2000047117

  56. 56.

    Whitfield-Cargile C.M., Cohen N.D., Chapkin R.S., Weeks B.R., Davidson L.A., Goldsby J.S., Hunt C.L., Steinmeyer S.H., Menon R., Suchodolski J.S., et al. The microbiota-derived metabolite indole decreases mucosal inflammation and injury in a murine model of NSAID enteropathy. Gut Microbes. 2016;7:246-261.

    Not in our library10.1080/19490976.2016.1156827

  57. 57.

    Natividad J.M., Agus A., Planchais J., Lamas B., Jarry A.C., Martin R., Michel M.L., Chong-Nguyen C., Roussel R., Straube M., et al. Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome. Cell Metab. 2018;28:737-749.e734.

    Not in our library10.1016/j.cmet.2018.07.001

  58. 58.

    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

  59. 59.
    Commensal Bacteria-Dependent Indole Production Enhances Epithelial Barrier Function in the Colon · 2013
    No notice
  60. 60.

    Armand L., Fofana M., Couturier-Becavin K., Andriamihaja M., Blachier F. Dual effects of the tryptophan-derived bacterial metabolite indole on colonic epithelial cell metabolism and physiology: Comparison with its co-metabolite indoxyl sulfate. Amino Acids. 2022.

    Not in our library10.1007/s00726-021-03122-4

  61. 61.

    Hashimoto T., Perlot T., Rehman A., Trichereau J., Ishiguro H., Paolino M., Sigl V., Hanada T., Hanada R., Lipinski S., et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012;487:477-481.

    Not in our library10.1038/nature11228

  62. 62.

    Kim C.J., Kovacs-Nolan J.A., Yang C., Archbold T., Fan M.Z., Mine Y. l-Tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis. J. Nutr. Biochem. 2010;21:468-475.

    Not in our library10.1016/j.jnutbio.2009.01.019

  63. 63.

    Kurata K., Kawahara H., Nishimura K., Jisaka M., Yokota K., Shimizu H. Skatole regulates intestinal epithelial cellular functions through activating aryl hydrocarbon receptors and p38. Biochem. Biophys. Res. Commun. 2019;510:649-655.

    Not in our library10.1016/j.bbrc.2019.01.122

  64. 64.
    Bacterial Metabolite Indole Modulates Incretin Secretion from Intestinal Enteroendocrine L Cells · 2014
    No notice
  65. 65.

    Holst J.J. The physiology of glucagon-like peptide 1. Physiol. Rev. 2007;87:1409-1439.

    Not in our library10.1152/physrev.00034.2006

  66. 66.

    Beaumont M., Neyrinck A.M., Olivares M., Rodriguez J., de Rocca Serra A., Roumain M., Bindels L.B., Cani P.D., Evenepoel P., Muccioli G.G., et al. The gut microbiota metabolite indole alleviates liver inflammation in mice. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2018;32:lb359.

    Not in our library10.1096/fj.201800544

  67. 67.

    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

  68. 68.
    Indole-3-Acetic Acid Alleviates Nonalcoholic Fatty Liver Disease in Mice via Attenuation of Hepatic Lipogenesis, and Oxidative and Inflammatory Stress · 2019
    No notice
  69. 69.

    Krishnan S., Ding Y., Saedi N., Choi M., Sridharan G.V., Sherr D.H., Yarmush M.L., Alaniz R.C., Jayaraman A., Lee K. Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. Cell Rep. 2018;23:1099-1111.

    Not in our library10.1016/j.celrep.2018.03.109

  70. 70.

    Gillam E.M., Notley L.M., Cai H., De Voss J.J., Guengerich F.P. Oxidation of indole by cytochrome P450 enzymes. Biochemistry. 2000;39:13817-13824.

    Not in our library10.1021/bi001229u

  71. 71.

    King L.J., Parke D.V., Williams R.T. The metabolism of [2-14C] indole in the rat. Biochem. J. 1966;98:266-277.

    Not in our library10.1042/bj0980266

  72. 72.

    Poesen R., Mutsaers H.A., Windey K., van den Broek P.H., Verweij V., Augustijns P., Kuypers D., Jansen J., Evenepoel P., Verbeke K., et al. The Influence of Dietary Protein Intake on Mammalian Tryptophan and Phenolic Metabolites. PLoS ONE. 2015;10:e0140820.

    Not in our library10.1371/journal.pone.0140820

  73. 73.

    Beaumont M., Portune K.J., Steuer N., Lan A., Cerrudo V., Audebert M., Dumont F., Mancano G., Khodorova N., Andriamihaja M., et al. Quantity and source of dietary protein influence metabolite production by gut microbiota and rectal mucosa gene expression: A randomized, parallel, double-blind trial in overweight humans. Am. J. Clin. Nutr. 2017;106:1005-1019.

    Not in our library10.3945/ajcn.117.158816

  74. 74.

    Banoglu E., Jha G.G., King R.S. Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. Eur. J. Drug Metab. Pharmacokinet. 2001;26:235-240.

    Not in our library10.1007/bf03226377

  75. 75.

    Bulus H., Oguztuzun S., Guler Simsek G., Kilic M., Ada A.O., Gol S., Kocdogan A.K., Kaygin P., Bozer B., Iscan M. Expression of CYP and GST in human normal and colon tumor tissues. Biotech. Histochem. Off. Publ. Biol. Stain Comm. 2019;94:1-9.

    Not in our library10.1080/10520295.2018.1493220

  76. 76.

    Rosenberg D.W., Mankowski D.C. Induction of cyp2e-1 protein in mouse colon. Carcinogenesis. 1994;15:73-78.

    Not in our library10.1093/carcin/15.1.73

  77. 77.

    Andriamihaja M., Chaumontet C., Tome D., Blachier F. Butyrate metabolism in human colon carcinoma cells: Implications concerning its growth-inhibitory effect. J. Cell. Physiol. 2009;218:58-65.

    Not in our library10.1002/jcp.21556

  78. 78.

    Leschelle X., Delpal S., Goubern M., Blottiere H.M., Blachier F. Butyrate metabolism upstream and downstream acetyl-CoA synthesis and growth control of human colon carcinoma cells. Eur. J. Biochem. 2000;267:6435-6442.

    Not in our library10.1046/j.1432-1327.2000.01731.x

  79. 79.

    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.. Ren. Physiol. 2019;316:F1211-F1217.

    Not in our library10.1152/ajprenal.00298.2018

  80. 80.

    Vanholder R., Schepers E., Pletinck A., Nagler E.V., Glorieux G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: A systematic review. J. Am. Soc. Nephrol. JASN. 2014;25:1897-1907.

    Not in our library10.1681/asn.2013101062

  81. 81.

    Vanholder R., Baurmeister U., Brunet P., Cohen G., Glorieux G., Jankowski J., European Uremic Toxin Work G. A bench to bedside view of uremic toxins. J. Am. Soc. Nephrol. JASN. 2008;19:863-870.

    Not in our library10.1681/asn.2007121377

  82. 82.

    Cheng T.H., Ma M.C., Liao M.T., Zheng C.M., Lu K.C., Liao C.H., Hou Y.C., Liu W.C., Lu C.L. Indoxyl Sulfate, a Tubular Toxin, Contributes to the Development of Chronic Kidney Disease. Toxins. 2020;12:684.

    Not in our library10.3390/toxins12110684

  83. 83.

    Devine E., Krieter D.H., Ruth M., Jankovski J., Lemke H.D. Binding affinity and capacity for the uremic toxin indoxyl sulfate. Toxins. 2014;6:416-429.

    Not in our library10.3390/toxins6020416

  84. 84.

    Viaene L., Annaert P., de Loor H., Poesen R., Evenepoel P., Meijers B. Albumin is the main plasma binding protein for indoxyl sulfate and p-cresyl sulfate. Biopharm. Drug Dispos. 2013;34:165-175.

    Not in our library10.1002/bdd.1834

  85. 85.

    Enomoto A., Takeda M., Tojo A., Sekine T., Cha S.H., Khamdang S., Takayama F., Aoyama I., Nakamura S., Endou H., et al. Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J. Am. Soc. Nephrol. JASN. 2002;13:1711-1720.

    Not in our library10.1097/01.asn.0000022017.96399.b2

  86. 86.

    Fujii H., Goto S., Fukagawa M. Role of Uremic Toxins for Kidney, Cardiovascular, and Bone Dysfunction. Toxins. 2018;10:202.

    Not in our library10.3390/toxins10050202

  87. 87.

    Wang W., Hao G., Pan Y., Ma S., Yang T., Shi P., Zhu Q., Xie Y., Ma S., Zhang Q., et al. Serum indoxyl sulfate is associated with mortality in hospital-acquired acute kidney injury: A prospective cohort study. BMC Nephrol. 2019;20:57.

    Not in our library10.1186/s12882-019-1238-9

  88. 88.

    Tan X., Cao X., Zou J., Shen B., Zhang X., Liu Z., Lv W., Teng J., Ding X. Indoxyl sulfate, a valuable biomarker in chronic kidney disease and dialysis. Hemodial. Int. Int. Symp. Home Hemodial. 2017;21:161-167.

    Not in our library10.1111/hdi.12483

  89. 89.

    Sun C.Y., Hsu H.H., Wu M.S. p-Cresol sulfate and indoxyl sulfate induce similar cellular inflammatory gene expressions in cultured proximal renal tubular cells. Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc.-Eur. Ren. Assoc. 2013;28:70-78.

    Not in our library10.1093/ndt/gfs133

  90. 90.
    Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB · 2013
    No notice
  91. 91.

    Shimizu H., Yisireyili M., Higashiyama Y., Nishijima F., Niwa T. Indoxyl sulfate upregulates renal expression of ICAM-1 via production of ROS and activation of NF-kappaB and p53 in proximal tubular cells. Life Sci. 2013;92:143-148.

    Not in our library10.1016/j.lfs.2012.11.012

  92. 92.

    Motojima M., Hosokawa A., Yamato H., Muraki T., Yoshioka T. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int. 2003;63:1671-1680.

    Not in our library10.1046/j.1523-1755.2003.00906.x

  93. 93.

    Edamatsu T., Fujieda A., Itoh Y. Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells. PLoS ONE. 2018;13:e0193342.

    Not in our library10.1371/journal.pone.0193342

  94. 94.

    D’Autréaux B., Toledano M.B. ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis. Nat. Rev. Mol. Cell Biol. 2007;8:813-824.

    Not in our library10.1038/nrm2256

  95. 95.

    Owada S., Goto S., Bannai K., Hayashi H., Nishijima F., Niwa T. Indoxyl sulfate reduces superoxide scavenging activity in the kidneys of normal and uremic rats. Am. J. Nephrol. 2008;28:446-454.

    Not in our library10.1159/000112823

  96. 96.

    Peskin A.V. Cu,Zn-superoxide dismutase gene dosage and cell resistance to oxidative stress: A review. Biosci. Rep. 1997;17:85-89.

    Not in our library10.1023/a:1027343519591

  97. 97.

    Ratliff B.B., Abdulmahdi W., Pawar R., Wolin M.S. Oxidant Mechanisms in Renal Injury and Disease. Antioxid. Redox Signal. 2016;25:119-146.

    Not in our library10.1089/ars.2016.6665

  98. 98.

    Humphreys B.D. Mechanisms of Renal Fibrosis. Annu. Rev. Physiol. 2018;80:309-326.

    Not in our library10.1146/annurev-physiol-022516-034227

  99. 99.

    Miyazaki T., Ise M., Hirata M., Endo K., Ito Y., Seo H., Niwa T. Indoxyl sulfate stimulates renal synthesis of transforming growth factor-beta 1 and progression of renal failure. Kidney Int. Suppl. 1997;63:S211-S214.

    Not in our library

  100. 100.

    Milanesi S., Garibaldi S., Saio M., Ghigliotti G., Picciotto D., Ameri P., Garibotto G., Barisione C., Verzola D. Indoxyl Sulfate Induces Renal Fibroblast Activation through a Targetable Heat Shock Protein 90-Dependent Pathway. Oxidative Med. Cell. Longev. 2019;2019:2050183.

    Not in our library10.1155/2019/2050183

  101. 101.

    Shimizu H., Yisireyili M., Nishijima F., Niwa T. Stat3 contributes to indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence. Am. J. Nephrol. 2012;36:184-189.

    Not in our library10.1159/000341515

  102. 102.

    Gryp T., De Paepe K., Vanholder R., Kerckhof F.M., Van Biesen W., Van de Wiele T., Verbeke F., Speeckaert M., Joossens M., Couttenye M.M., et al. Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease. Kidney Int. 2020;97:1230-1242.

    Not in our library10.1016/j.kint.2020.01.028

  103. 103.

    Adesso S., Ruocco M., Rapa S.F., Piaz F.D., Raffaele Di Iorio B., Popolo A., Autore G., Nishijima F., Pinto A., Marzocco S. Effect of Indoxyl Sulfate on the Repair and Intactness of Intestinal Epithelial Cells: Role of Reactive Oxygen Species’ Release. Int. J. Mol. Sci. 2019;20:2280.

    Not in our library10.3390/ijms20092280

  104. 104.
    Indoxyl Sulfate, a Uremic Endotheliotoxin · 2020
    No notice
  105. 105.

    Belghasem M., Roth D., Richards S., Napolene M.A., Walker J., Yin W., Arinze N., Lyle C., Spencer C., Francis J.M., et al. Metabolites in a mouse cancer model enhance venous thrombogenicity through the aryl hydrocarbon receptor-tissue factor axis. Blood. 2019;134:2399-2413.

    Not in our library10.1182/blood.2019001675

  106. 106.

    Karbowska M., Kaminski T.W., Marcinczyk N., Misztal T., Rusak T., Smyk L., Pawlak D. The Uremic Toxin Indoxyl Sulfate Accelerates Thrombotic Response after Vascular Injury in Animal Models. Toxins. 2017;9:229.

    Not in our library10.3390/toxins9070229

  107. 107.

    Karbowska M., Kaminski T.W., Znorko B., Domaniewski T., Misztal T., Rusak T., Pryczynicz A., Guzinska-Ustymowicz K., Pawlak K., Pawlak D. Indoxyl Sulfate Promotes Arterial Thrombosis in Rat Model via Increased Levels of Complex TF/VII, PAI-1, Platelet Activation as Well as Decreased Contents of SIRT1 and SIRT3. Front. Physiol. 2018;9:1623.

    Not in our library10.3389/fphys.2018.01623

  108. 108.

    Dou L., Jourde-Chiche N., Faure V., Cerini C., Berland Y., Dignat-George F., Brunet P. The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells. J. Thromb. Haemost. JTH. 2007;5:1302-1308.

    Not in our library10.1111/j.1538-7836.2007.02540.x

  109. 109.
    Differential Effects of Indoxyl Sulfate and Inorganic Phosphate in a Murine Cerebral Endothelial Cell Line (bEnd.3) · 2014
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    Tumur Z., Shimizu H., Enomoto A., Miyazaki H., Niwa T. Indoxyl sulfate upregulates expression of ICAM-1 and MCP-1 by oxidative stress-induced NF-kappaB activation. Am. J. Nephrol. 2010;31:435-441.

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    Yu M., Kim Y.J., Kang D.H. Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clin. J. Am. Soc. Nephrol. CJASN. 2011;6:30-39.

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    Kaminski T.W., Pawlak K., Karbowska M., Mysliwiec M., Pawlak D. Indoxyl sulfate—the uremic toxin linking hemostatic system disturbances with the prevalence of cardiovascular disease in patients with chronic kidney disease. BMC Nephrol. 2017;18:35.

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    Hung S.C., Kuo K.L., Wu C.C., Tarng D.C. Indoxyl Sulfate: A Novel Cardiovascular Risk Factor in Chronic Kidney Disease. J. Am. Heart Assoc. 2017;6:5022.

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    Indole, a Signaling Molecule Produced by the Gut Microbiota, Negatively Impacts Emotional Behaviors in Rats · 2018
    No notice
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    Mir H.D., Milman A., Monnoye M., Douard V., Philippe C., Aubert A., Castanon N., Vancassel S., Guerineau N.C., Naudon L., et al. The gut microbiota metabolite indole increases emotional responses and adrenal medulla activity in chronically stressed male mice. Psychoneuroendocrinology. 2020;119:104750.

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    Fecal Microbiota and Metabolome of Children with Autism and Pervasive Developmental Disorder Not Otherwise Specified · 2013
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    Riggio O., Mannaioni G., Ridola L., Angeloni S., Merli M., Carla V., Salvatori F.M., Moroni F. Peripheral and splanchnic indole and oxindole levels in cirrhotic patients: A study on the pathophysiology of hepatic encephalopathy. Am. J. Gastroenterol. 2010;105:1374-1381.

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    Philippe C., Szabo de Edelenyi F., Naudon L., Druesne-Pecollo N., Hercberg S., Kesse-Guyot E., Latino-Martel P., Galan P., Rabot S. Relation between Mood and the Host-Microbiome Co-Metabolite 3-Indoxylsulfate: Results from the Observational Prospective NutriNet-Sante Study. Microorganisms. 2021;9:716.

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    Medvedev A., Buneeva O., Glover V. Biological targets for isatin and its analogues: Implications for therapy. Biol. Targets Ther. 2007;1:151-162.

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    Glover V., Halket J.M., Watkins P.J., Clow A., Goodwin B.L., Sandler M. Isatin: Identity with the purified endogenous monoamine oxidase inhibitor tribulin. J. Neurochem. 1988;51:656-659.

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    Medvedev A., Igosheva N., Crumeyrolle-Arias M., Glover V. Isatin: Role in stress and anxiety. Stress. 2005;8:175-183.

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    Bhattacharya S.K., Chakrabarti A., Sandler M., Glover V. Anxiolytic activity of intraventricularly administered atrial natriuretic peptide in the rat. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 1996;15:199-206.

    Not in our library10.1016/0893-133x(95)00204-q

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    Abel E.L. Behavioral effects of isatin on open field activity and immobility in the forced swim test in rats. Physiol. Behav. 1995;57:611-613.

    Not in our library10.1016/0031-9384(94)00365-c

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    Zhou Y., Zhao Z.Q., Xie J.X. Effects of isatin on rotational behavior and DA levels in caudate putamen in Parkinsonian rats. Brain Res. 2001;917:127-132.

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    Hamaue N., Minami M., Terado M., Hirafuji M., Endo T., Machida M., Hiroshige T., Ogata A., Tashiro K., Saito H., et al. Comparative Study of the Effects of Isatin, an Endogenous MAO-Inhibitor, and Selegiline on Bradykinesia and Dopamine Levels in a Rat Model of Parkinson’s Disease Induced by the Japanese Encephalitis Virus. NeuroToxicology. 2004;25:205-213.

    Not in our library10.1016/s0161-813x(03)00100-1

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    Yuwiler A. The effect of isatin (tribulin) on metabolism of indoles in the rat brain and pineal: In vitro and in vivo studies. Neurochem. Res. 1990;15:95-100.

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    Carpenedo R., Mannaioni G., Moroni F. Oxindole, a sedative tryptophan metabolite, accumulates in blood and brain of rats with acute hepatic failure. J. Neurochem. 1998;70:1998-2003.

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    Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity · 2020
    No notice
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    Mannaioni G., Carpenedo R., Pugliese A.M., Corradetti R., Moroni F. Electrophysiological studies on oxindole, a neurodepressant tryptophan metabolite. Br. J. Pharmacol. 1998;125:1751-1760.

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    Crumeyrolle-Arias M., Tournaire M.C., Cane A., Launay J.M., Barritault D., Medvedev A. Inhibition of brain mitochondrial monoamine oxidases by the endogenous compound 5-hydroxyoxindole. Biochem. Pharmacol. 2004;67:977-979.

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    Wang G., Korfmacher W.A. Development of a biomarker assay for 3-indoxyl sulfate in mouse plasma and brain by liquid chromatography/tandem mass spectrometry. Rapid Commun. Mass Spectrom. RCM. 2009;23:2061-2069.

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    Chu C., Murdock M.H., Jing D., Won T.H., Chung H., Kressel A.M., Tsaava T., Addorisio M.E., Putzel G.G., Zhou L., et al. The microbiota regulate neuronal function and fear extinction learning. Nature. 2019;574:543-548.

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    Chen J.J., Zhou C.J., Zheng P., Cheng K., Wang H.Y., Li J., Zeng L., Xie P. Differential urinary metabolites related with the severity of major depressive disorder. Behav. Brain Res. 2017;332:280-287.

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    Brydges C.R., Fiehn O., Mayberg H.S., Schreiber H., Dehkordi S.M., Bhattacharyya S., Cha J., Choi K.S., Craighead W.E., Krishnan R.R., et al. Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature. Sci. Rep. 2021;11:21011.

    Not in our library10.1038/s41598-021-99845-1

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    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.

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    Karbowska M., Hermanowicz J.M., Tankiewicz-Kwedlo A., Kalaska B., Kaminski T.W., Nosek K., Wisniewska R.J., Pawlak D. Neurobehavioral effects of uremic toxin-indoxyl sulfate in the rat model. Sci. Rep. 2020;10:9483.

    Not in our library10.1038/s41598-020-66421-y

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    Indoxyl Sulfate Affects Glial Function Increasing Oxidative Stress and Neuroinflammation in Chronic Kidney Disease: Interaction between Astrocytes and Microglia · 2017
    No notice
  139. 139.

    Lin Y.-T., Wu P.-H., Tsai Y.-C., Hsu Y.-L., Wang H.Y., Kuo M.-C., Kuo P.-L., Hwang S.-J. Indoxyl Sulfate Induces Apoptosis through Oxidative Stress and Mitogen-Activated Protein Kinase Signaling Pathway Inhibition in Human Astrocytes. J. Clin. Med. 2019;8:191.

    Not in our library10.3390/jcm8020191

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    Puschhof J., Pleguezuelos-Manzano C., Martinez-Silgado A., Akkerman N., Saftien A., Boot C., de Waal A., Beumer J., Dutta D., Heo I., et al. Intestinal organoid cocultures with microbes. Nat. Protoc. 2021;16:4633-4649.

    Not in our library10.1038/s41596-021-00589-z

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