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. Author manuscript; available in PMC: 2025 Sep 16.
Published in final edited form as: Microbiota Host. 2025 Jul 24;3(1):e250004. doi: 10.1530/mah-25-0004

Indole dysbiosis and mucosal inflammation

Ji Yeon Kim 1, Ian M Cartwright 1,2, Sean P Colgan 1,2
PMCID: PMC12435487  NIHMSID: NIHMS2098460  PMID: 40958961

Abstract

The inflammatory bowel diseases (IBD) coincide with shifts in the composition of the microbiota. Since the gastrointestinal (GI) epithelium is anatomically positioned to provide a selective barrier between the microbiota and host lamina propria, this barrier is essential for intestinal homeostasis. Decades-old studies have appreciated that byproducts of the microbiota provide an essential communication network to the host. More recent work has identified microbial-derived metabolites that support multiple functions within the GI mucosa. One such family of metabolites are the indoles, tryptophan-derived molecules that signal within the microbiota and importantly, provide anti-inflammatory properties within the host mucosa. Here, we review the topic of indole production and signaling in the healthy and diseased mucosa.

Keywords: tryptophan, colitis, inflammatory bowel disease, microbiota, tyrosine, epithelia

Graphical Abstract

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Introduction

The inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are relapsing-remitting chronic inflammatory disorders of the gastrointestinal (GI) tract. IBD appears to develop in some genetically susceptible individuals in response to antigenic triggers of unknown origin. While the etiology of IBD is incompletely understood, compelling evidence has shown that a combination of multiple factors, including genetics, environment, immune dysfunction and shifts in the gut microbiota, contribute to the onset and progression of IBD (Plichta, et al. 2019). These changes to the GI microbiome, including both the composition and the metabolites generated by the microbes, have garnered significant recent attention (Bernardi, et al. 2024; Colgan, et al. 2023). In this short review, we will explore how one such microbe-derived metabolite, namely indole, contributes to overall GI health and how shifts in this metabolite might contribute to overall disease.

Gut microbiota

The gut microbiota consists of the constellation of microorganisms, including bacteria, fungi, and viruses, in coexistence with eukaryotic organisms. Advances in technologies, especially those allowing more precise identification of microbial components, have made it possible to understand the interactions between microbial communities in finer and finer detail. Studies in the past 20 years have identified a precise and consistent role for microbial communities as essential for health, and shifts in this microbial landscape are strongly associated with mucosal disease (Sender, et al. 2016). Some believe that our microbiota profile is as unique as our fingerprint and only recently have we begun to define the components that mold this microbial population(Group, et al. 2009; Heintz and Mair 2014; Kumar, et al. 2016).

The density and diversity of gut microbiota vary along the length of the GI tract (Sommer and Backhed 2016). The human microbiota develops after birth and its mature composition is determined by multiple variables, including gestational age, type of birth delivery, infant feeding, weaning period, and exposure to antibiotics. Within the first years of life, the microbiota stabilizes under the ultimate influences of diet, genetics, and gut physiology. The microbiota plays a critical function in the digestion and production of essential nutrients and metabolites. The microbiota also contributes to shaping the mucosal immune system to protect the host from colonization and invasion of pathogens (Sommer and Backhed 2016). As we will discuss below, the composition of gut microbiota changes with perturbations in the intestinal environment and these changes can contribute to conditions such as IBD (Holmes, et al. 2011; Kinross, et al. 2011).

Gut Microbiota-derived Metabolites

Gut microbiota produces a variety of metabolites, such as short-chain fatty acids (SCFAs), secondary bile acids, and microbial-derived tryptophan metabolites (Zhang and Davies 2016). The compositions of gut microbiota can be altered by diets, which could influence the relative amounts of SCFAs (Tan, et al. 2014). Dietary fibers and resistant starches are the primary substrates for bacterial fermentation, which produces various end products, including SCFAs (acetate, propionate, and butyrate) and gases (H2, CO2, and CH4) in the colon (Holmes et al. 2011). These SCFAs have been identified as contributing to various physiological processes, including maintaining intestinal epithelial barrier function, regulating the immune system, and protecting the host from pathogens (Kelly, et al. 2015; Louis and Flint 2009; Wang, et al. 2020a). In addition to SCFAs, secondary bile acids, converted from primary bile acids by colonic bacteria, can contribute to anti-inflammatory effects on the intestinal mucosa, helping maintain intestinal homeostasis and regulate intestinal inflammation (Thomas, et al. 2022). Additionally, tryptophan metabolites, including kynurenine, serotonin, and indole, have been shown to influence immune responses and mucosal homeostasis in the intestine, which will be discussed in more detail in this review (Brommage 2015; Israelyan and Margolis 2019; Yu, et al. 2024)

Tryptophan Metabolism

Tryptophan is an essential aromatic amino acid that humans cannot synthesize endogenously and must be consumed from protein-rich foods such as meat, fish, and eggs (Friedman 2018). Some dietary tryptophan is utilized as a substrate to synthesize protein. In contrast, the rest of dietary tryptophan is metabolized through 3 different pathways, including the kynurenine pathway, the serotonin pathway, and bacterial metabolism.

The kynurenine pathway is the major pathway (95%) through which the body catabolizes dietary tryptophan (Taleb 2019). Tryptophan is metabolized to kynurenine with the first and rate-limiting step regulated by tryptophan 2,3-dioxygenase (TDO) in the liver and indoleamine 2,3-dioxygenase (IDO) in the extrahepatic tissues (Badawy and Guillemin 2019). Kynurenine is further converted to kynurenine derivatives, including kynurenic acid, anthranilic acid, 3-hydroxykynurenine, and quinolinic acid. The final product, quinolinic acid, is converted to nicotinamide adenine dinucleotide (NAD) in the final step of the kynurenine pathway (Damerell, et al. 2025). Previous research has found that some of these derivatives may have anti-inflammatory characteristics, while others may have pro-inflammatory characteristics (Yu et al. 2024).

In addition to the kynurenine pathway, approximately 1–2% of diet-derived tryptophan is metabolized via the serotonin pathway in the central nervous system (CNS) and GI tract. Only a small portion of total serotonin is produced in the CNS (Israelyan and Margolis 2019), while the majority of serotonin is synthesized by enterochromaffin cells in the GI tract (Mawe and Hoffman 2013). Two isoforms of tryptophan hydroxylase, including tryptophan hydroxylase 1 in the gut and tryptophan hydroxylase 2 in the CNS, are involved in the serotonin pathway (Israelyan and Margolis 2019; Kanova and Kohout 2021). Tryptophan is initially metabolized to 5-hydroxytryptophan, further to serotonin (5-hydroxytryptamine), and finally to melatonin (Aaldijk and Vermeiren 2022; Akram, et al. 2024). Furthermore, serotonin can be further converted to 5-hydroxyindoleacetic acid (5-HIAA) (Aaldijk and Vermeiren 2022). Serotonin plays a significant role in both the CNS and GI tract. In the CNS, serotonin functions as a neurotransmitter that regulates stress, anxiety, and mood (Jones, et al. 2020). In the GI tract, it influences gut motility, microbial balance, and secretion of digestive enzymes (Brommage 2015; Israelyan and Margolis 2019).

Bacterial Metabolism of Tryptophan

Although most diet-derived tryptophan is absorbed in the small intestine, 4–6% of tryptophan is metabolized to indole and its derivatives in the colonic microbiota. Several studies have demonstrated the essential role of gut microbiota in indole production. One study reported that germ-free (GF) mice showed 27 times lower concentrations of indole and indoxyl sulfate in feces than specific pathogen-free (SPF) mice (Shimada, et al. 2013). Another study found that the concentration of indole metabolite tryptamine was significantly decreased in GF mice (Ge, et al. 2017). Taken together, the production of indole and its derivatives is dependent on commensal gut bacteria.

To date, 85 indole-producing bacterial species and more than 51 bacteria species that can produce tryptophan catabolites have been described in previous reviews (Lee and Lee 2010; Roager and Licht 2018). These bacteria are primarily members of the genera Bacteroides, Clostridium, Escherichia, Eubacterium, Lactobacillus, and Peptostreptococcus (Roager and Licht 2018). The production of indole and its derivatives begins with the transport through the tryptophan permease (TnaB) (Yanofsky, et al. 1991). Once imported, bacterial enzymes metabolize tryptophan, producing indole and its derivatives (Fig. 1).

Figure 1.

Figure 1.

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Bacterial tryptophan metabolism. TnaA, Tryptophanase; TrpD, Tryptophan decarboxylase; ArAT, Aromatic amino acid aminotransferase; TMO, Tryptophan monooxygenase; MAO, Monoamine oxidase; ID, Indole pyruvate decarboxylase; IaaO, Indole acetaldehyde oxidase; ILDH, Indole lactate dehydrogenase; ILD, Indole lactate dehydratase; fldAIBC, phenyl lactate dehydratase gene cluster; ACD,Acyl-CoA dehydrogenase; IaaH, Indole acetamide hydrolase; IaaD, Indoleacetate decarboxylase. Created in BioRender: Kim J (2025) https://BioRender.com/s58r840.

Several enzymatic reactions are involved in tryptophan metabolism by gut microbiota. First, tryptophan is catabolized to indole by indole-producing bacteria expressing tryptophanase (TnaA) (Yanofsky et al. 1991). Tryptophan is then converted to tryptamine, a β-arylamine neurotransmitter, by Clostridium sporogenes and Ruminococcus ganvus, which express tryptophan decarboxylase (TrpD). As shown in Figure 1, tryptamine is further catabolized to indole acetaldehyde (IAAld) by monoamine oxidase, which degrades monoamine from tryptamine (Mustala, et al. 1969; Williams, et al. 2014). Ultimately, IAAld is oxidized to indole acetic acid (IAA) by IAAld oxidase (Schütz, et al. 2003).

Tryptophan is also converted indole acetamide (IAM), indole acetate (IAA), skatole, and indole aldehyde (IAld). IAM is first formed from tryptophan by tryptophan monooxygenase (IaaM) and subsequently converted to indole acetate (IAA) by indole acetamide hydrolase (IaaH) (Tsavkelova, et al. 2012). One of the final products in this reaction, skatole, is synthesized from the decarboxylation of IAA by Bacteroides spp, Firmicutes spp, Lactobacillus spp (Honeyfield and Carlson 1990; Russell, et al. 2013; Whitehead, et al. 2008). The other final product, IAld, is generated by Lactobacillus acidophilus, Lactobacillus murinus, and Lactobacillus reuteri (Cervantes-Barragan, et al. 2017; Wilck, et al. 2017; Zelante, et al. 2013).

A fourth reaction is the conversion from tryptophan to indole pyruvate, indole lactate, indole acrylate, and indole propionate. Aromatic amino acid aminotransferase (ArAT)-expressing bacteria metabolize tryptophan to indole pyruvate, a precursor for multiple indole metabolites. Indole pyruvate is then converted into indole lactate (ILA) via indole lactate dehydrogenase (ILDH) (Jean and DeMoss 1968). ILA is further converted into indole acrylate (IA) through the phenyl lactate dehydratase gene cluster (fldAIBC) (Dodd, et al. 2017; Wlodarska, et al. 2017). Finally, IA is converted to indole propionate by acyl-CoA dehydrogenase (Acd) (Dodd et al. 2017). Indole pyruvate can also be converted into IAAld via indole pyruvate decarboxylase, which is subsequently oxidized to IAA by IAAld oxidase (Schütz et al. 2003).

Dysbiosis of Indole Production in Active Mucosal Disease

It is well-established that the intestinal microbiota shifts in fundamental ways during active inflammation (Manichanh, et al. 2012). Microbial signals, such as those delivered by a mix of Clostridial species, induce mucosal tolerance by promoting regulatory T cell development and overall mucosal immunity (Atarashi, et al. 2013). Studies investigating dysbiosis in inflammatory bowel disease (IBD), for example, have identified a reduced abundance of butyrate-producing organisms (e.g., certain Faecalibacterium and Roseburia genera) and lower concentrations of fecal SCFAs associated with disease (Eeckhaut, et al. 2013; Machiels, et al. 2013; Sokol, et al. 2009). SCFAs are bacterial fermentation products that include acetate, propionate, and butyrate that exist at high concentrations (50–100mM) in the colonic lumen. Butyrate is the favored energy source for colonocytes, where >95% of luminal-derived butyrate is used within the colon (Donohoe, et al. 2011; Hamer, et al. 2008; Topping and Clifton 2001). Butyrate is predominantly transported and utilized by enterocytes, while propionate and acetate enter hepatic circulation (den Besten, et al. 2013). The loss of butyrate-producing microbiota and diminished mucosal response to butyrate in active IBD has led to the “starved gut hypothesis”, whereby disease-associated dysbiosis places significant demands on energy procurement within the mucosa, resulting in functional deficits including diminished wound healing (Colgan et al. 2023).

Less well understood is the dysbiosis associated with indole production in mucosal disease. Several studies have shown important associations with human disease. For example, Yu et al. identified an E. coli strain from individuals treated with the antibiotic tinidazole. This strain produced high levels of indole-3-lactic acid (ILA) that conferred protection in a DSS colitis model. Studies in humans revealed that fecal ILA levels negatively correlated with progression to IBD (Yu, et al. 2023). Other studies have provided important protective roles for indole propionate (IPA). For example, oral administration of IPA significantly diminished damage associated with a mouse model of UC. These findings were translated to human patients by profiling serum samples from, healthy controls, patients with active UC, and those with UC in clinical remission. This analysis revealed that serum IPA was decreased by nearly 60% in subjects with active UC compared to healthy controls. Notably, this IPA deficiency was normalized in UC patients in remission, strongly implicating IPA deficiency as a biomarker for active UC (Alexeev, et al. 2018). Other work identified several mucin-utilizing Peptostreptococcous sp. that enable robust production of indole acrylic acid (IA). Analysis of human stool sample metagenomes revealed a diminished capacity of IBD patients to utilize mucins and metabolize tryptophan to IA (Wlodarska et al. 2017). Finally, the incorporation of a model of psychological stress revealed the enrichment of a commensal Lactobacillus murinus that increased mucosal production of indole-3-acetate (IAA) and resulted in disruption of intestinal stem cell bioenergetics. These results were extended to human patients with major depressive disorder, where increased fecal IAA levels were correlated with intestinal dysfunction (Wei, et al. 2024). Thus, indole metabolism appears to reflect mucosal disease and provides opportunities to consider replacement therapies to promote disease remission and tissue homeostasis.

Mechanisms of Indole Derivatives in the Intestinal Mucosa

A. Aryl Hydrocarbon Receptor (AhR)

The aryl hydrocarbon receptor (AhR) is one of the members of the basic helix-loop-helix superfamily of transcription factors expressed by both immune cells and epithelial cells in barrier tissues such as gut, skin, and lung (Pernomian, et al. 2020; Wang, et al. 2020b). AhR is located in the cytoplasm when it is inactive. Once activated by ligands, including indole derivatives, AhRß translocates to the nucleus and forms a heterodimer with the AhR nuclear translocator (ARNT) binding to E-box domains on target gene promotor, leading to immunomodulatory effects (Sun, et al. 2020; Tian, et al. 2015).

AhR plays a crucial role in maintaining gut microbiota balance by promoting the dominance of commensal bacteria over pathogens (Busbee, et al. 2017; Busbee, et al. 2020; Romani, et al. 2014). The absence of AhR has been associated with increased dextran sodium sulfate (DSS)-induced colitis severity and susceptibility to infections, such as Citrobacter rodentium (Kiss, et al. 2011; Li, et al. 2011). Additionally, AhR is involved in the renewal of intestinal epithelium and the regulation of various immune cell types, which contributes to mucosal homeostasis (Hubbard, et al. 2015b).

While dietary compounds like flavonoids, resveratrol, curcumin, and berberine can activate AhR, bacterial metabolites, particularly indole and its derivatives, play a significant role in its activation (Hubbard, et al. 2015a; Hubbard et al. 2015b; Zhang, et al. 2003). For example, Peptostreptococcus russelii and Lactobacillus spp. produce IA and ILA, which are AhR agonists that contribute to immune modulation (Wlodarska et al. 2017; Zelante et al. 2013). Moreover, indole aldehyde (Iade) has been considered as potent AhR agonist, increasing interleukin-22 (IL-22) expression through AhR and enhancing the survival of microbial communities, thus protecting the mucosa against inflammation (Zelante et al. 2013).

In addition to Iade, IAA improves gut motility by activating AhR, leading to increased serotonin secretion and enhanced barrier function (Chen, et al. 2023). It has recently been shown that increased IAA production from polyphenol supplementation enhances AhR-mediated protection against murine colitis through increased expression of IL-22 and tight junction proteins, such as occludin and claudin-1, in the colon (Zhang, et al. 2023).

Indole derivatives like IA, produced by P.russellii, have demonstrated potential therapeutic effects by increasing AhR activation, enhancing goblet cell function, and increasing interleukin-10 (Wlodarska et al. 2017). Additionally, IA produced from Parabacteroides sitasonis has been shown to attenuate type 2 diabetes via activation of AhR, leading to repairing intestinal barrier and inflammation reduction (Liu, et al. 2023).

Furthermore, recent studies indicate that ILA ameliorates intestinal colitis (Xia, et al. 2023; Yu et al. 2023). ILA decreases CCL2/7 production in epithelial cells and reduces the accumulation of inflammatory macrophages by decreasing glycolysis and NFkB/HIF signaling pathways via AhR (Yu et al. 2023). Also, Li group found that ILA, derived from supplementation of Lactobacillus acidophilus, can attenuate intestinal inflammation and restore group innate lymphoid cells (ILC3) through AhR signaling in colitis from cesarean-born mice offspring (Xia et al. 2023).

B. Pregnane X Receptor

The Pregnane X receptor (PXR) is a nuclear receptor extensively expressed in the intestinal tract and plays a vital role in regulating mucosal integrity through its interaction with toll-like receptor 4 (TLR4) (Venkatesh, et al. 2014). PXR can be activated by a variety of endogenous and exogenous compounds, including several indole derivatives (Illes, et al. 2020; Koutsounas, et al. 2013; Venkatesh et al. 2014).

Of indole derivatives, IPA has been shown to contribute to modulating inflammatory responses through PXR. It has been demonstrated that IPA downregulates tumor necrosis factor-alpha (TNF-α) expression and promotes the expression of tight junction proteins, thus strengthening intestinal barrier function (Venkatesh et al. 2014). Another study reported that deletion of PXR in fibroblasts has been associated with increased neutrophil infiltration and cytokine production following DSS treatment. Interestingly, administration of IPA can mitigate inflammation and support recovery of the intestinal epithelium (Flannigan, et al. 2023). In addition to IPA, IAA can induce the production of interleukin-35 (IL-35)+ B cells via PXR, increasing the production of potent anti-inflammatory cytokine IL-35, which maintains intestinal homeostasis in high-fat-diet-fed mice (Su, et al. 2022).

C. Antioxidant Activity

Indole and indole derivatives are potent antioxidants (Jasiewicz, et al. 2021). In the healthy intestine, cells regulate the balance between the production and elimination of reactive oxygen species (ROS) as a result of antioxidant defenses (Tian, et al. 2017). However, during active inflammation, oxidative stress downregulates the antioxidant signaling pathway and mitochondrial function and leads to gene dysregulation, cellular and molecular damage (i.e., DNA damage, lipid peroxidation, and protein modifications)(Bourgonje, et al. 2020). Oxidative stress plays a critical role in the onset and development of IBD (Guan and Lan 2018). ROS levels can be modulated by an antioxidant defense system, which includes endogenous enzymatic antioxidants (i.e., superoxide dismutase, catalase, and glutathione peroxidase), endogenous non-enzymatic antioxidants (i.e., glutathione, thioredoxin, irisin and indole derivatives), and exogenous antioxidants (i.e., vitamin C, polyphenols, polysaccharide) (Chyan, et al. 1999; Li, et al. 2024; Wang, et al. 2020c). Most of this system has been studied for antioxidants other than indole derivatives. Much of our understanding of indole and indole derivative antioxidant capacity has been focused on melatonin for diseases such as Alzheimer’s disease, with little attention to intestinal disease (Chyan et al. 1999; Gurer-Orhan, et al. 2016).

Indole derivatives have been recently shown to exert antioxidant effects in intestinal diseases. For instance, our lab found that indole derivatives such as IPA can inhibit myeloperoxidase activity, leading to the reduction of tissue damage and tissue chemokine expression in murine colitis (Alexeev, et al. 2021; Cartwright, et al. 2024). Moreover, IAA contributes to reducing colitis severity by increasing Foxp3+T cells through the production of R-quaol from Bifidobacterium pseudolongum, a metabolite produced from soybean isoflavones with antioxidant effects (Li et al. 2024).

D. Bystander Tissue Damage

The mucosal inflammatory response is characterized by the accumulation of neutrophils (polymorphonuclear leukocytes; PMN) at sites of injury. When PMN are not cleared efficiently from tissue, they can drive chronic inflammation. This is especially true in diseases such as UC and CD, where a hallmark of these conditions is the crypt abscess, histologically demonstrated as accumulated PMN within the crypts of the intestine (Chin and Parkos 2007). When PMN are not effectively cleared from the tissue, their continued presence can contribute to bystander tissue damage, an unintentional injury in host tissue as a result of the immune response (Wera, et al. 2016; Wright, et al. 2010). During inflammation, PMN antimicrobial functions, while aimed at eliminating pathogens, can unintentionally damage surrounding host cells. A primary mechanism by which PMN responds to bacterial insults is through the activation of myeloperoxidase (MPO), which comprises ~5% of the PMN dry weight (Schultz and Kaminker 1962). Within the phagosome of the PMN, MPO generates hypochlorous acid (HOCl) from hydrogen peroxide and halides, mainly chlorine (Chami, et al. 2018; Strzepa, et al. 2017). While the majority of HOCl is confined to the phagosome during active inflammation, MPO can be secreted into the extracellular space during PMN degranulation (Lacy 2006).

MPO-derived HOCl is one of the most potent oxidizing agents that reacts with lipids, DNA, amino acids and proteins (Kettle and Winterbourn 1997; Piechota-Polanczyk and Fichna 2014; Pullar, et al. 2000; Simmonds and Rampton 1993; Spickett and Pitt 2020; Winterbourn and Kettle 2013). One of the major targets of HOCl are tyrosine residues in proteins, leading to the formation of a chlorinated product, 3-chlorotyrosine (3-Cl-Tyr) (Domigan, et al. 1995; Gaut, et al. 2001). A presence of chlorinated tyrosine is considered a biomarker of MPO activity within tissue. It has been demonstrated that 3-Cl-Tyr levels in the tissue correlate with disease severity and can be used as a biomarker in inflammatory conditions (Afshinnia, et al. 2017; Alexeev et al. 2021; Cartwright et al. 2024; Chami et al. 2018; Fu, et al. 2000; Kettle 1996; Knutson, et al. 2013). In addition, 3-Cl-Tyr can be used to indicate the HOCl involvement in tissue damage (Liu, et al. 2020). Most recently, it was demonstrated that MPO chlorinates tyrosines in epithelial tight junction proteins, resulting in epithelial barrier defects (Figure 2). It was shown that epithelial occludin, one of the transmembrane tight junction proteins important for barrier function, is highly enriched for surface tyrosine residues and that these residues are targeted for chlorinated by MPO in vitro and in vivo. This chlorination of occludin extended to patients with active IBD relative to healthy controls (Cartwright et al. 2024). The full impact of amino acid chlorination has not been fully delineated; however, it has been recently shown that chlorination within tight junctions disrupts barrier function in both endothelial and epithelial cells (Blaschuk, et al. 2002; Cartwright et al. 2024) (Fig. 2). Further research into the full impact of 3-Cl-Tyr on cellular function during inflammation is needed.

Figure 2.

Figure 2.

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Mechanism of indole and its derivatives on inhibiting bystander tissue damage. During inflammation, excessive activated neutrophils release myeloperoxidase, which produces hypochlorous acid (HOCl). HOCl chlorinates tyrosine residues within tight junction proteins, such as occludin, exerting bystander tissue damage. One of indole derivatives, indole propionic acid, has been shown to attenuate bystander tissue damage through inhibiting myeloperoxidase. MPO, myeloperoxidase; Cl-Tyr, chloro-tyrosine. Created in BioRender: Kim J (2025) https://BioRender.com/s58r840.

It has recently been shown that microbial-derived tryptophan metabolites, specifically indole and IPA, are potent MPO inhibitors. These compounds work by causing the accumulation of the redox intermediate MPO-II, which lacks chlorinating activity (Ximenes, et al. 2005). This occurs through their role as competing substrates for MPO-I, the only redox intermediate of MPO to oxidize chloride and binding to MPO, as shown by NMR (Alexeev et al. 2021; Ximenes et al. 2005). Since MPO-II is not reactivated to native MPO, it could be argued that overall oxidative stress is diminished by indole compounds. There have been several in vivo studies which have shown treatment with indole, IPA, or other indole derivatives decreased inflammation through the inhibition of MPO (Alexeev et al. 2018; Alexeev et al. 2021; Cartwright et al. 2024; Patnaik, et al. 2020). Unlike inhibition of NADPH oxidase in the PMN, inhibition of MPO does not appear to diminish the ability of PMN such as superoxide generation, migration to sites of inflammation, or oxidative burst capacity (Nauseef, et al. 1983; Wientjes and Segal 1995). Indeed, inhibition to NADPH oxidase or superoxide dismutase enhances colitis and IBD severity through the lack of an oxidative burst or the inability to decrease oxidative stress (Campbell, et al. 2014; Narayanan, et al. 1998). Indole and indole derivatives are of interest therapeutically because they not only inhibit MPO but also have other antioxidant properties (Cartwright, et al. 2022; Kumar, et al. 2020). This is an important feature because MPO inhibition has been associated with increases in free radicals (Klebanoff 2005).

E. Dopamine Receptor D2 (DRD2)

Dopamine receptors are G-protein-coupled receptors, expressed in the brain, intestinal mucosa and various innate and adaptive immune cells (Li, et al. 2019; Vidal and Pacheco 2020). Although dopamine receptors primarily play a critical role in regulating physiological and behavioral processes such as emotion, motor activity, and hormone secretion, recent research reports a role of DRD in modulating colon physiology (Moyer, et al. 2011; Tolstanova, et al. 2015). For instance, dopamine receptor D2 (DRD2) activation through agonists such as quinpirole or cabergoline has demonstrated anti-inflammatory effects by reducing vascular permeability, which attenuates colitis symptoms in mice (Tolstanova et al. 2015). In addition to DRD2, dopamine receptor D5 (DRD5) activation has been shown to promote distal colonic mucus secretion, indicating the importance of DRD activation for the colonic mucosal barrier (Li et al. 2019). However, understanding dopamine receptor effects on colonic physiology and inflammation remains unclear, and their ligands are not fully understood.

Recently, activation of DRD2 in the intestinal epithelium by indole-3-ethanol (IEt), indole-3-pyruvate (Ipy), and Iade, has been shown to confer protection against enterohaemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium by reducing bacterial adherence through modulation of host cell actin dynamics (Scott, et al. 2024).

Therapeutic Implications

The observed dysbiosis associated with active mucosal disease has contributed to some clinical progress. For example, fecal microbiota transplantation (FMT) has become a commonplace treatment for antibiotic-resistant Clostridium difficiile colitis (CdC), where original studies revealed that up to 90% of patients were cured with a single treatment (van Nood, et al. 2013). The healing properties of FMT are not well understood. While it would seem reasonable to assume that FMT simply “resets” the microbiome in CdC, the real answer may be more complicated. For instance, a study in a small cohort of CdC patients revealed that delivery of FMT samples filtered to remove all bacteria shows nearly equivalent efficacy (Ott, et al. 2017), thereby implicating a non-bacterial source for the resolution of disease (e.g., microbial metabolites). In this light, it may be interesting to consider the contribution of microbial-derived metabolites such as indoles within such therapies.

Conclusion

In this review, we summarize changes in indole metabolism associated with active inflammation in diseases such as IBD and mechanisms of indole and its derivatives in intestinal mucosa (Figs. 2 & 3). It remains to be determined whether inflammation-associated dysbiosis is cause or effect in IBD and other related disorders. It is clear that the inflammatory tissue microenvironment becomes less tolerant to strict anaerobes (e.g., butyrate-producing Bacteroidetes and Firmicutes) and shifts toward a less diverse microbiota that promotes facultative anaerobes (e.g., more virulent Proteobacteria) (Zeng, et al. 2017). While we do not know the nature of the loss of indole-producing microbes in inflammation, it is interesting to speculate that the loss of antioxidant properties that accompany indole production could result in increased oxidative stress, thereby selecting against strict anaerobes.

Figure 3.

Figure 3.

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Mechanisms of indole and its derivatives in intestine. Indole and its derivatives play an important role in intestinal homeostasis through multiple mechanisms. They activate the aryl hydrocarbon receptor to enhance goblet cell function and gut motility, upregulate the expression of tight junction protein expression, interleukin-22 and interleukin-10, and reduce the accumulation of inflammatory macrophages. Also, they activate pregnane X receptor and lead to an increase in interleukin-35 through the induction of interleukin-35+ B cells and a decrease in tumor necrosis factor-alpha expression. Furthermore, they are potent antioxidants capable of increasing Foxp3+ T cells. Finally, they activate dopamine receptor 2 to decrease the expression of a host regulatory protein to decrease pathogen attachment. TnaA, Tryptophanase; TrpD, Tryptophan decarboxylase; ArAT, Aromatic amino acid aminotransferase; TMO, Tryptophan monooxygenase; AhR, Aryl hydrocarbon receptor; PXR, Pregnane X receptor; IL-22, Interleukin-22; IL-10, Interleukin-10; TNF-α, tumor necrosis factor alpha; IL-35, Interleukin-35; DRD2; Dopamine receptor 2. Created in BioRender: Kim J (2025) https://BioRender.com/s58r840.

Acknowledgements

This work was supported by NIH grants DK1047893, DK50189, DK095491, DK103639 and VA Merit BX002182.

Footnotes

The authors declare no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

JK and SC conceived the study. JK, IC and SC wrote and edited the paper.

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