Tryptophan metabolism at the crossroads of the neuro-immuno-microbial axis: implications for precision medicine in chronic diseases

Abstract

Tryptophan metabolism connects the nervous, immune, and microbial systems and influences the onset and progression of chronic diseases such as cancer, neurodegeneration, and autoimmunity. This review summarizes the three major metabolic routes: the kynurenine pathway, the serotonin pathway, and microbial indole production. It outlines how their metabolites shape neural activity, immune regulation, and host–microbiota interactions. We further discuss the relevance of these metabolites as biomarkers and their potential therapeutic implications. By integrating recent insights into tryptophan-associated signaling networks, this review provides a concise framework for understanding their roles in chronic disease and guiding future precision medicine strategies.

1. Introduction

Tryptophan is an essential amino acid required for protein synthesis and for maintaining metabolic and immune homeostasis (Zheng et al., 2025). Unlike plants and microorganisms, mammals cannot synthesize tryptophan de novo and must obtain it from the diet. In humans, dietary tryptophan is mainly metabolized through three pathways: the kynurenine pathway, the serotonin pathway, and microbial indole production (Roager and Licht, 2018; Madella et al., 2022; El-Azaz et al., 2023). Its metabolic fate is shaped not only by dietary intake but also by competition with other amino acids, gut microbial activity, and interactions with other nutrients.

The kynurenine pathway accounts for most tryptophan degradation, while the serotonin pathway and microbial indole production contribute additional metabolic outputs (Figure 1) (Savitz, 2020; Tanaka et al., 2021; Tanaka et al., 2022). Interactions among these pathways link metabolic regulation with immune responses and neural function. Commensal microbes further diversify tryptophan metabolism by generating indole derivatives such as indole-3-acetic acid (IAA), indole-3-carbaldehyde (I3A), and tryptamine. Several of these metabolites have emerging value as biomarkers for disease stratification and therapy monitoring. Tryptophan metabolism connects the nervous, immune, and microbial systems, influencing the development and progression of chronic diseases such as cancer, neurodegenerative disorders, and autoimmune conditions (Figure 2) (Cellini et al., 2020; Mondanelli et al., 2020; Bellucci et al., 2021; Mandarano et al., 2021).

Figure 1.

The kynurenine pathway of tryptophan metabolism. Key enzymes, metabolites, and cofactors involved in the pathway are shown. 3-HAA, 3-hydroxyanthranilic acid; 3-HK, 3-hydroxykynurenine; AA, anthranilic acid; ACMSD, aminocarboxymuconate semialdehyde decarboxylase; AHR, aryl hydrocarbon receptor; IDO, indoleamine 2,3-dioxygenase; KA, kynurenic acid; KAT, kynurenine aminotransferase; KMO, kynurenine monooxygenase; KYN, kynurenine; KYNU, kynureninase; NAD+, nicotinamide adenine dinucleotide; Pic, picolinic acid; QA, quinolinic acid; QPRT, quinolinate phosphoribosyltransferase; TDO, tryptophan 2,3-dioxygenase; Tryptophan, tryptophan; XA, xanthurenic acid.

Figure 2.

Overview of kynurenine pathway, intestinal flora, and mitochondrial function.

A better understanding of its regulation is essential for developing targeted therapies. Emerging strategies, such as enzyme inhibitors, receptor modulators, and microbiota-targeted therapies, offer potential solutions for precision medicine in chronic diseases. Future research should focus on refining these therapeutic approaches and exploring novel strategies to restore metabolic balance. This review synthesizes how these pathways form a neuro–immune–microbial axis and how their dysregulation contributes to chronic disease.

2. Molecular mechanisms and signaling hubs

Dysregulation of tryptophan metabolism has been implicated in the development of chronic diseases, making its enzymes, metabolites, and receptors potential therapeutic targets. Key metabolites of the kynurenine pathway (KP), such as kynurenine (KYN), act as agonists for the aryl hydrocarbon receptor (AHR).

KP metabolites have dual effects on glutamatergic neurotransmission. They specifically target the N-methyl-D-aspartate receptor(NMDAR). These metabolites can exert either neuroprotective effects or neurotoxic effects. Dysregulation of this pathway is intimately linked to multiple neuropsychiatric and neurological disorders, including schizophrenia, major depressive disorder, cognitive impairment, neuropathic pain, and neurodegenerative diseases (Jovanovic et al., 2020; Muneer, 2020). For example, inhibiting the key enzyme kynurenine 3-monooxygenase(KMO) promotes the metabolic flux toward the neuroprotective kynurenic acid(KYNA), which effectively alleviates neuropathic pain and its accompanying depressive-like behavior in preclinical models. Likewise, a pathological shift within the KP toward the neurotoxic metabolite 3-hydroxykynurenine(3-HK) is implicated in glaucomatous neurodegeneration, highlighting the potential of KMO inhibition as a novel therapeutic strategy (Fiedorowicz et al., 2021). Notably, the active form of vitamin B₆, pyridoxal 5’-phosphate(PLP)—an essential cofactor for multiple tryptophan-metabolizing enzymes—represents a critical regulator of metabolic crosstalk at the host-microbiome interface (Cellini et al., 2020).

Microbial metabolism of tryptophan constitutes a major axis through which the gut microbiota influences host health. Tryptophan-derived microbial metabolites modulate intestinal barrier integrity, immune homeostasis, and neural activity, primarily via activation of pathways such as the AHR (Roth et al., 2021). Dietary supplementation with tryptophan or its precursors has been demonstrated to ameliorate symptoms of inflammatory bowel disease(IBD), enhance sleep quality, improve mood states, and may potentially prevent hypertension in offspring induced by maternal chronic kidney disease(CKD), likely through modulation of the microbiota-metabolite-AHR axis (Hsu et al., 2020). This paradigm offers novel therapeutic avenues for targeted modulation of tryptophan metabolism to promote health, utilizing probiotics, prebiotics, and postbiotics.

2.1. Fine regulation of the kynurenine pathway

The KP is the primary route for tryptophan degradation and plays a critical role in glioma progression. In gliomas, abnormal activation of the KP supports tumor growth by providing energy and biosynthetic resources through metabolic reprogramming. Moreover, the KP generates immunosuppressive metabolites that contribute to tumor progression and immune evasion (Figure 3a) (Ha et al., 2014; Thakur et al., 2020).

Figure 3.

Panorama of metabolic regulation and therapeutic targets of the KP in gliomas. (a) Mechanisms of aberrant activation of the KP in the glioma microenvironment; (b) Mechanisms of metabolic flow and neuroprotective-neurotoxicity balance regulated by enzyme activity at the midstream branching point of the KP; (c) Positive-negative balance of KP metabolites in gliomas tilt mechanism; (d) therapeutic strategies to target KP fine-tuning nodes.

2.1.1. Impact of dysregulation in gliomas

One key regulatory step in the kynurenine pathway is the uptake of tryptophan and kynurenine (KYN) via transporters such as L-type amino acid transporter(LAT1) and ASCT2, which are often overexpressed in glioma. Targeting these transporters to deprive tumors of essential substrates offers a potential strategy to inhibit tumor growth (Bröer et al., 2016; Cormerais et al., 2018). The subsequent initial oxygenation step, catalyzed by the key rate-limiting enzymes IDO1 and TDO2, converts Tryptophan to L-KYN. IDO1 expression exhibits significant heterogeneity across glioma subtypes (Sordillo et al., 2017), positively correlates with increasing tumor grade. It is modulated by isocitrate dehydrogenase (IDH) mutation status, which showing marked upregulation in IDH-wildtype tumors (Rocha et al., 2025). TDO2 demonstrates constitutive overexpression in high-grade gliomas, particularly glioblastoma(GBM), serving as an independent biomarker for tumor aggressiveness and poor prognosis (Riess et al., 2020; Wang et al., 2025). Critically, KYN produced by TDO2 directly activates the AHR as a ligand, driving tumor cell proliferation, invasion, and stem-like properties (Adams et al., 2012). Consequently, IDO1 inhibitors enhance anti-tumor immunity and show strong synergy when combined with immune checkpoint blockade (Guangzhao et al., 2025). Furthermore, post-translational modifications (PTMs)—such as phosphorylation and acetylation—have been demonstrated to dynamically regulate IDO1 stability and function, while enhancing TDO2 enzymatic activity, thereby providing an additional layer of fine control over KP flux initiation.

As outlined in Part 1, L-KYN sits at a critical branch point, destined for conversion into either neuroprotective or neurotoxic metabolites. Here, we focus on how glioma-specific enzyme expression alters this balance (Figure 3b). Kynurenine aminotransferases (KATs) catalyze the irreversible transamination of L-KYN to generate kynurenic acid(KYNA). Beyond its role as a potent NMDAR antagonist, KYNA exerts direct anti-tumor effects by suppressing glioma cell proliferation and migration, and exhibits synergy with chemotherapeutics like temozolomide (TMZ) (Badawy, 2017). Conversely, KMO catalyzes the conversion to 3-HK, which is subsequently metabolized into neurotoxic metabolites—3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QA) (Venkatesan et al., 2020). KMO is markedly overexpressed and enzymatically hyperactive in astrocytomas. Its metabolites promote tumor progression and exacerbate neuronal injury through three convergent mechanisms: glutamate receptor hyperactivation, induction of oxidative stress, and DNA damage. Inhibiting KMO effectively redirects metabolic flux toward KYNA production, alleviating neuropathological symptoms and inhibiting tumors in preclinical models (Dudzinska et al., 2019).

In gliomas, the metabolite balance shifts toward neurotoxicity and tumor progression, with a decrease in protective metabolites and an increase in neurotoxic or oncogenic species (Figure 3c) (Moffett et al., 1993)le prognostic indicator (Krupa et al., 2025). AA accumulates in gliomas and contributes to disease progression through its context-dependent pro- and anti-inflammatory properties. Meanwhile, the enzyme ACMSD Kynureninase(KYNU) catalyzes the production of anthranilic acid(AA), whose high expression is significantly associated with a shorter overall survival in glioma patients and is a reliabacts as a critical “molecular switch” by diverting its substrate(ACMS) toward picolinic acid(PIC) and away from the neurotoxic metabolite quinolinic acid(QUIN) (Brundin et al., 2016; Fargher et al., 2025).

QUIN promotes tumors through two mechanisms: it converts to NAD⁺ via quinolinic acid phosphoribosyltransferase (QPRT), providing glioma cells with energy and substrates for DNA repair, thus supporting survival and proliferation; additionally, QUIN induces tumor-associated macrophages (TAMs) to polarize toward the immunosuppressive M2 type, aiding immune evasion (Wang et al., 2010; Basak et al., 2023; Wang et al., 2025). In addition, xanthurenic acid(XA), a downstream metabolite of 3-HK, can inhibit tetrahydrobiopterin(BH₄) synthesis, interfere with neurotransmitter balance, and exhibit a unique inhibitory effect on tumor cell motility in GBM (Staats Pires et al., 2020). This metabolic imbalance results from upregulated activity of tumor-promoting enzymes (IDO1, TDO2, KMO, KYNU) alongside downregulated protective enzymes(KATs, ACMSD). Downregulation of ACMSD expression, commonly observed in gliomas, leads to a significant shift in metabolic flux toward QUIN and nicotinamide adenine dinucleotide (NAD⁺) synthesis pathways (Moffett et al., 2020; Dhuguru et al., 2023; Huang et al., 2025).

2.1.2. Therapeutic implications for targeting KP

Therapies targeting KP nodes are being developed. IDO1 inhibitors reduce KYN and T cell exhaustion, restoring anti-tumor immune responses (Figure 3d) (Kang et al., 2025; Li et al., 2025). In addition, dual IDO/TDO inhibitors can simultaneously target IDO1 and TDO2, overcoming compensatory upregulation after single enzyme inhibition, such as HIF-1α-mediated TDO2 escape phenomena (Wu et al., 2023). Targeting KP branch enzymes can restore the neuroprotective-neurotoxic balance. Inhibition of KMO with CHDI-340246 shifts metabolism from QUIN to KYNA, thus ameliorating motor deficits in HD models (Beaumont et al., 2016). The strategy of restoring or expressing ACMSD function can effectively reduce the cyclization of ACMS to QUIN, reduce the production of neurotoxic metabolites, and inhibit the energy supply of the tumor (Tufail et al., 2024). Further strategies aim to antagonize toxic metabolites directly. Inhibiting quinolinic acid phosphoribosyltransferase (QPRT) with compounds like UPF648 blocks QUIN’ s conversion to NAD⁺. Moreover, co-inhibiting QPRT and NAMPT (e.g., with FK866) synergistically blocks NAD⁺ synthesis, inducing lethal energy depletion in tumor cells and enhancing therapeutic efficacy (Kudo et al., 2024). Multi-target drug design addresses KP complexity. The dual inhibitor RY103, which targets both IDO1/TDO2 and the KYN-AHR-AQP4 axis, has been shown to suppress tumor invasion and migration in GBM models (Liang et al., 2021). To address the compensatory mechanisms and multifunctionality of the KP network—which often render single-agent therapies ineffective—combination strategies targeting multiple nodes are being pursued to enhance efficacy and overcome resistance (Garg et al., 2024). Thus, the multi-target therapeutic strategies discussed herein have shown promise in advancing neuro-oncological treatment for gliomas, and early-stage research suggests their potential application in other conditions involving KP dysregulation.

2.2. Interaction mechanism between the microbiota and tryptophan axis

2.2.1. Microbiota’s role in tryptophan metabolism

The gut microbiota plays a pivotal role in regulating tryptophan metabolism, influencing both host and microbial interactions. Beyond the host-driven kynurenine and serotonin pathways, microbial metabolism of tryptophan generates indole derivatives that are essential for maintaining intestinal barrier integrity, immune function, and neurological health. Approximately 1-5% of dietary Tryptophan is metabolized by specific bacterial communities in the colon, producing a variety of structurally diverse indole compounds. The production of these metabolites exhibits significant species dependence (Jamshed et al., 2022). For example, Bacteroides spp. primarily produce IAA, while Lactobacillus acidophilus, Lactobacillus murinus, and Lactobacillus reuteri produce I3A (Taleb, 2019; Scott et al., 2020). Spore-forming bacteria like Clostridium sporogenes synthesize indolepropionic acid(IPA) (Peng et al., 2024). Indole derivatives from microorganisms exert local effects in the intestine, but metabolites like IPA and I3A can also cross the blood-brain barrier(BBB) and impact the central nervous system (Hu et al., 2025).

2.2.2. Gut microbiota and neuroactive effects

The neuroactive effects of tryptophan metabolites depend largely on whether they can cross the BBB. Because the BBB tightly controls molecular exchange, only metabolites that can traverse this interface exert direct effects in the central nervous system. The transport mechanisms vary significantly: some metabolites rely on specific active transporters, while others passively diffuse, and this differential access critically shapes their respective roles in neurological health and disease. The neuroactive effects of these KP metabolites are contingent upon their distinct interactions with the BBB. The key metabolite, L-KYN, crosses the blood-brain barrier (BBB) through LAT1, the same transporter it shares with its precursor, Tryptophan (Hsu et al., 2020). This access allows for the local production of downstream metabolites within the brain itself. For instance, once across the BBB, L-KYN can be converted by astrocytic kynurenine aminotransferases (KATs) to form KYNA, which, being a polar organic acid, has limited back-diffusion and thus accumulates locally. In contrast, the neurotoxic metabolite QUIN is transported across the BBB by an active, saturable system, leading to its accumulation under inflammatory conditions when peripheral production is high. Conversely, the neuroprotective KYNA has limited permeability, underscoring the importance of its in situ synthesis within the CNS for its neuromodulatory functions.

2.2.3. Impact on AHR activation and gut health

Microbial indoles engage the AHR pathway to regulate epithelial integrity and immune tolerance, as summarized in the general mechanism. Here we focus on their disease-specific consequences. The absence of specific probiotics, especially those that produce IPA(such as Faecalibacterium prausnitzii) and I3A-producing lactobacilli, leads to depletion of protective metabolites, resulting in decreased levels of IPA and I3A, insufficient AHR activation, weakened intestinal barrier function, and exacerbated immune imbalance (Huang et al., 2023; Xu et al., 2024). In addition, pro-inflammatory factors released by intestinal inflammation inhibit the growth of probiotics while upregulating the expression of host IDO1, accelerating the degradation of Tryptophan along the KP and further reducing the substrate of Tryptophan metabolized into indole derivatives in the microbiota (Kaur et al., 2025). As inflammation worsens, oxidative stress and bile acid changes also inhibit the colonization of indole-producing bacteria. The lack of IPA not only damages the local immune defense of the intestine but also inhibits its ability to cross the blood-brain barrier, leading to insufficient activation of AHR in the central nervous system and thereby affecting the anti-inflammatory response of astrocytes. For example, in neuroinflammatory models such as MS, IPA deficiency promotes disease progression (Zelic et al., 2021). Clinical studies have shown that IPA levels in IBD patients are positively correlated with cognitive function scores (Sârb et al., 2025), further confirming the pivotal role of the microbiota-Tryptophan metabolic axis in gut-brain communication.

However, in chronic disease states, the ability of gut microbiota to metabolize tryptophan and produce AHR ligands is significantly impaired. Studies have shown that fecal AHR agonist activity and the concentrations of key indole ligands such as IAA are significantly reduced in patients with metabolic syndrome (MetS) and patients in remission of inflammatory bowel disease (IBD) (Lamas et al., 2016). This deficiency is not only related to dysbiosis of gut microbiota composition, but is also directly regulated by the host’s genetic background. For example, the deletion of the IBD susceptibility gene CARD9 alters the gut microbiota, leading to a reduction in AHR ligand-producing bacteria (such as Lactobacillus reuteri), thereby weakening AHR signaling and increasing susceptibility to colitis (Niu et al., 2025). This indicates that disruption of the “host gene-microbiota function-AHR ligand production” axis is a common pathological basis for many chronic diseases.

2.2.4. Dysbiosis and disease pathogenesis

Based on the above mechanism, intervention strategies targeting the microbiota-tryptophan axis show great therapeutic potential. Supplementing with probiotics that produce indole metabolites or directly administering indole derivatives can effectively restore AHR/PXR activation and improve intestinal barrier damage and inflammatory responses in IBD models. In addition, increasing dietary Tryptophan intake or using AHR agonists can reverse neurodeficiencies associated with dysbiosis, especially in AD models, where IPA exerts neuroprotective effects through the CPR30/AMPK/SIRT1 pathway and has antioxidant effects (Rakshe et al., 2024). Short-chain fatty acids, such as butyric acid, also indirectly promote the diversion of Tryptophan to indole metabolism in the microbiota by inhibiting IDO1 expression and STAT1 phosphorylation, further enhancing the AHR signaling pathway (Pant et al., 2023).

In summary, the microbiota-tryptophan axis regulates the AHR/PXR signaling network through microbial-derived indole metabolites, serving as a core regulatory mechanism for intestinal barrier defense and immune balance. The disruption of this axis, such as dysbiosis, indole deficiency, AHR inhibition, barrier damage, immune imbalance, exacerbated inflammation, and worsening microbiota, is a common pathological basis for many chronic diseases. Restoring homeostasis within the tryptophan metabolic network may offer potential targets for intervention in cross-system diseases, though further research is needed to confirm their applicability across various conditions.

2.3. The synergistic network of microbial metabolites: integrating short-chain fatty acids and tryptophan derivatives

2.3.1. Short-chain fatty acids and their immunomodulatory effects

The impact of the gut microbiota on host physiology is mediated by a complex network of metabolites, among which short-chain fatty acids (SCFAs) and tryptophan-derived indoles represent two pivotal communicative channels. While often studied in parallel, their functions are deeply intertwined, creating a synergistic system that maintains host homeostasis.

SCFAs are produced by microbial fermentation of dietary fiber and exert profound immunomodulatory effects. A key mechanism is their function as histone deacetylase(HDAC) inhibitors, which epigenetically regulates gene expression in immune cells (Qu et al., 2023). For instance, SCFAs, particularly butyrate and propionate, promote the differentiation of IL-10-producing regulatory B cells (Bregs) and have been shown to alleviate disease severity in models of rheumatoid arthritis by this mechanism. Furthermore, SCFAs are crucial for B cell metabolism, fueling their activation and antibody production through enhanced glycolysis, oxidative phosphorylation, and fatty acid synthesis.

2.3.2. Synergistic effects between SCFAs and tryptophan derivatives

The interplay between SCFAs and the tryptophan-AHR axis is multifaceted. SCFAs can indirectly promote the tryptophan-indole pathway by inhibiting the expression of the host’s IDO1 enzyme, thereby increasing the bioavailability of tryptophan for gut microbes (Yi et al., 2025). Conversely, AHR activation by indole derivatives can enhance the integrity of the gut barrier, an environment that SCFAs also help to maintain. This creates a positive feedback loop: a healthy barrier supports a SCFA-producing microbiota, which in turn shunts more tryptophan toward the production of AHR ligands that further fortify the barrier.

This metabolic cross-talk is evident in disease pathogenesis. Dysbiosis often leads to a concurrent deficiency in both SCFAs and AHR ligands. For example, in metabolic syndrome, the observed decline in microbial AHR agonist production occurs alongside broader microbial disturbances (Natividad et al., 2018). Therapeutic strategies that simultaneously target both metabolite families—such as a diet rich in both fermentable fiber(for SCFAs) and tryptophan(for indoles)—or next-generation probiotics designed to produce both SCFAs and indoles, may yield superior efficacy in restoring immune and metabolic homeostasis in chronic diseases ranging from IBD to metabolic syndrome.

2.4. Mitochondrial-metabolite crosstalk

2.4.1. Impact of tryptophan metabolites on mitochondrial function

Tryptophan metabolites from the KP and microbiota-derived indoles influence mitochondria both as metabolic regulators and as direct modulators of mitochondrial structure and signaling. By affecting survival, apoptosis, and autophagy, they help determine cellular energy balance. This metabolit mitochondria interaction is central to neurodegeneration, tumor metabolic reprogramming, and inflammation. Metabolites of the canine urea cycle, especially QUIN, are potent neurotoxic metabolites that directly interfere with mitochondrial function, causing dysfunction and cell damage (Platten et al., 2021).

2.4.2. Role of QUIN and KYNA in neurodegenerative diseases

QUIN promotes the generation of significant levels of reactive oxygen species (ROS) and interferes with intracellular calcium balance, resulting in an increased permeability of the mitochondrial membrane. QUIN acts as a potent redox cycler and a direct inhibitor of the mitochondrial electron transport chain (ETC), particularly at complexes I and II (Zhao et al., 2019). This inhibition causes a substantial leak of electrons, which reduce molecular oxygen to generate superoxide anions (O₂^-), the primary mitochondrial ROS. The resulting oxidative damage further impairs ETC function, creating a vicious cycle of ROS production. Concurrently, QUIN depletes glutathione (GSH) and inhibits antioxidant enzymes like superoxide dismutase (SOD), crippling the cellular defense system and amplifying the oxidative insult (Bansal et al., 2019; Krishnamurthy et al., 2024). The disruption of calcium homeostasis is a hallmark of QUIN toxicity. By acting as an agonist of N-methyl-D-aspartate receptors (NMDARs), QUIN triggers excessive Ca²⁺ influx into neurons. The resultant cytosolic Ca²⁺ overload is rapidly buffered by mitochondria, leading to mitochondrial Ca²⁺ overload (Madreiter-Sokolowski et al., 2020). This overload is a critical trigger for the prolonged opening of the mitochondrial permeability transition pore (mPTP). Sustained mPTP opening collapses the mitochondrial membrane potential (ΔΨm), uncouples oxidative phosphorylation, and causes osmotic swelling, outer membrane rupture, and the release of pro-apoptotic factors such as cytochrome c, thereby initiating caspase-dependent apoptosis. This mechanism may play a significant role in neurodegenerative conditions such as Huntington’s disease (HD) and Alzheimer’s disease (AD), as well as in ischemia-reperfusion injury, based on current evidence, though further studies are needed to fully establish its involvement (Wadan et al., 2025).

In contrast, the neuroprotective metabolite KYNA exhibits antioxidant properties and can partially antagonize QUIN-induced mitochondrial oxidative stress and dysfunction (Saliba et al., 2025). By inhibiting KMO, which promotes metabolic flux toward KYNA production, it has been shown in preclinical models to protect mitochondria and reduce neurological damage (Beggiato et al., 2014).

2.4.3. Microbial metabolites and mitochondrial health

Microbial-derived indole metabolites, especially IPA, exhibit significant mitochondrial protection and metabolic regulation effects. IPA enhances mitochondrial biogenesis by activating the peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) pathway (Li et al., 2025). IPA, as a potent inducer of PGC-1α, can significantly upregulate the expression and activity of PGC-1α by activating AMP-dependent protein kinase(AMPK) and silencing the deacetylase regulatory protein(SIRT1) (Majeed et al., 2021). Activated PGC-1α works synergistically with nuclear respiratory factors (NRF-1/2) and mitochondrial transcription factor A(TFAM) to drive mitochondrial DNA replication, ETC complex protein expression, and new mitochondrial generation, thereby enhancing the cell’s oxidative phosphorylation capacity and energy production (Liang et al., 2020). In addition, IPA promotes mitophagy by activating the SIRT1-PGC-1α axis, clearing damaged mitochondria and enhancing the expression of antioxidant enzymes, effectively alleviating oxidative damage to mitochondria and maintaining their healthy state (Liang et al., 2020). IPA also regulates the activity of key metabolic enzymes by optimizing substrate utilization and respiratory efficiency, promoting fatty acid β-oxidation and glucose oxidation, ensuring efficient substrate flow into the tricarboxylic acid cycle(TCA cycle), and supporting the efficient operation of the ETC (Liu et al., 2025).

In summary, understanding how tryptophan metabolites interact with mitochondria offers a new approach to treating related diseases (Table 1). By inhibiting the production of toxic metabolites, using KMO inhibitors, enhancing ACMSD activity, reducing QUIN levels, and promoting the accumulation of neuroprotective KYNA, mitochondria can be protected from excitotoxicity and oxidative damage. Additionally, supplementing with beneficial microbiota metabolites like IPA or using IPA-producing probiotics can activate the PGC-1α pathway, improving mitochondrial function. This is particularly important for treating neurodegenerative diseases and metabolic syndrome.

Table 1.

Multidimensional regulatory mechanisms and translational applications of the tryptophan metabolic network in diseases.

Metabolites	Source and regulation	Molecular targets	Pathway	Physiological functions	Disease associations	Mechanism	References
IPA	Source: •C. sporogenes • F. prausnitzii Regulates: • Dietary fiber ↑→ production ↑ • Intestinal inflammation ↓→ production ↑	• AhR/PXR • PGC-1/AMPK/SIRT1	1. AhR→ZO-1/occludin↑→Barrier repair 2. PXR→NF-κB↓→inflammation suppression 3. AMPK/SIRT1→PGC-1α↑→mitochondrial biogenesis↑ 4. AhR→PPARγ↑→Treg differentiation↑(IL-10↑)	•Maintaining the integrity of intestinal epithelial tight junctions •inhibitionTh17differentiation •Crossing the blood-brain barrier •Activate astrocytesAhR→neuroinflammation↓ •Enhanced mitophagy	IBD Type 2 diabetes MS AD	•Intestinal barrier damage→Endotoxin translocation↑ •neuroinflammation↑→Microglial activation↑	(Pant et al., 2023; Rakshe et al., 2024; Hu et al., 2025; Sârb et al., 2025)
Indole-3-aldehyde (I3A)	Sources: • Lactobacillus reuteri • Lactobacillus acidophilus Regulation: • Tryptophanase-positive bacteria colonization ↑ → yield ↑ • Intestinal hypoxia → yield ↓	AhR	1. AhR → ILC3 activation → IL-22↑ → RegIIIγ↑ 2. AhR → STAT3↓ → Th17 differentiation↓ 3. AhR → mucin (MUC2)↑	•Strengthening the intestinal chemical barrier (Antimicrobial peptide secretion) •Maintain goblet cell function •PromoteIL-22Dependent epithelial repair	IBD Autoimmune hepatitis	•Thinning of the mucus layer→Pathogen invasion↑ • Th17/Treg imbalance → tissue damage↑	(Peng et al., 2024)
Quinolinic acid (QUIN)	Source: •HostIDO1/TDO (Inflammation induction) Regulation: • IFN-γ↑→IDO1↑→production↑ • KMO activity↑→QUIN/KYNA ratio↑	• NMDA receptors • Mitochondrial complex I	1.activationNMDA-R→Ca2+ internal flow↑→mPTPopen 2.inhibitionETC→ROS↑→mtDNAdamage 3.activationPARP→NAD+exhaustion	•Physiological concentration (≤100 nM): Neurotransmitter regulation •High concentrations: Excitotoxicity	AD Ischemic stroke	•Mitochondrial swelling→Cytochromecrelease→caspase-3Activation • Astrocyte mitochondrial fragmentation → ATP synthesis↓	(Beggiato et al., 2014; Zhao et al., 2019)
Kynurenic acid (KYNA)	source: •astrocytesKATsRegulation: • KMO inhibition → production ↑ inflammatory environment → KAT activity ↓	• NMDAreceptors • α7nAChRantagonists	1.Block NMDA-R→Excitotoxicity↓ 2.scavenging free radicals	•Neuroprotection •Antioxidant	Schizophrenia Huntington disease	• QUINToxicity not antagonized→Neuronal death ↑ •Glutamatergic signaling disorders	(Li et al., 2025)
Cross-regulatory mechanism	Imbalance in the microbiota-host metabolic axis	–	1. Inflammatory factors (IFN-γ/TNF-α) ↑ → IDO1 ↑ → KP shunt ↑ → Trp substrate ↓ 2. Indole-producing bacteria ↓ (F. prausnitzii/Lactobacillus) → IPA/I3A ↓ 3. Insufficient AhR/PXR activation → Barrier damage → Endotoxin translocation ↑ → Exacerbated inflammation	• Maintain Trp metabolic balance	IBD AD	IBD:stoolIPA↓→AhR↓→Barrier damage→LPS↑→IDO1↑→KP↑ • AD : IntestinalIPA↓→BBBPermeability↑→neuroinflammation↑→IDO1↑	(Lamas et al., 2016; Huang et al., 2023)

2.5. The serotonin pathway: bridging the gut and brain

While the KP is the major catabolic route, the serotonin pathway represents a critical anabolic branch of tryptophan metabolism with profound systemic influence. The synthesis of 5-HT is initiated by the rate-limiting enzyme tryptophan hydroxylase (TPH), which exists in two isoforms: TPH1, predominantly expressed in the gut enterochromaffin cells, and TPH2, primarily found in the central nervous system (CNS) (Imamdin and Van Der Vorst, 2023; Sinenko et al., 2023). This anatomical distinction underlies the concept of dual serotoninergic systems: over 90% of the body’s 5-HT is produced in the periphery (primarily in the gut), while CNS-derived 5-HT acts as a key neurotransmitter (Loh et al., 2024).

The gut microbiota is a pivotal regulator of peripheral 5-HT synthesis. Specific spore-forming microbes and metabolites from other commensals can directly stimulate colonic enterochromaffin cells to produce 5-HT (Loh et al., 2024). Gut-derived 5-HT cannot cross the blood-brain barrier but exerts extensive peripheral effects, including modulating gastrointestinal motility, platelet aggregation, and bone metabolism (Chang, 2024). Furthermore, through its actions on vagal afferents and immune cells, peripheral 5-HT plays a significant role in gut-brain axis communication (Chang, 2024).

Within the CNS, 5-HT is a quintessential neurotransmitter regulating mood, cognition, sleep, and appetite. Dysregulation of the central serotonin pathway is a cornerstone of neuropsychiatric disorders such as major depressive disorder, anxiety, and migraines (Zheng et al., 2025). The pathway is also intricately linked with the KP: inflammatory cytokines can shift tryptophan metabolism away from 5-HT synthesis and towards the KP, thereby reducing 5-HT bioavailability and contributing to inflammation-associated depressive symptoms. This crosstalk highlights the metabolic competition between the pathways and their collective impact on brain function and behavior.

3. Molecular mechanisms: metabolic switches and signaling hubs

The Try metabolic network plays a physiological protective role in maintaining homeostasis that transcends its pathological role. The metabolite-receptor interaction system formed by the co-evolution of microorganisms and their hosts builds a multi-organ defense system by precisely regulating epithelial integrity, neurovascular function, and energy metabolism balance (Chang, 2024). This section will systematically explain the core mechanism of tryptophan metabolites as endogenous protective mediators.

3.1. The AHR-IL-22 axis

This section elaborates on a key downstream axis of the AHR signaling pathway, introduced in the overview, which is central to maintaining intestinal homeostasis.

Indole derivatives produced by the gut microbiota, such as IPA, act as high-affinity ligands for the AHR. These ligands activate AHR signaling in intestinal epithelial cells and type 3 innate lymphoid cells (ILC3s), helping to maintain a dynamic intestinal barrier defense (Aoki et al., 2018). Direct transcriptional regulation of AHR induces enhanced expression of ZO-1 and mucins (MUC2), significantly improving physical barrier function and limiting pathogen and toxin translocation. More importantly, AHR activation by ILC3s triggers the secretion of interleukin-22(IL-22), which binds to the IL-22 receptor on epithelial cells, activates the STAT3 phosphorylation cascade, drives goblet cell proliferation and mucus layer thickening, and promotes the proliferation of Lgr5+ intestinal stem cells to accelerate epithelial damage repair (Hou et al., 2021; Ishihara et al., 2022). Clinical studies have confirmed that AHR-agonistic indole levels in the feces of patients with IBD are significantly positively correlated with serum IL-22 concentrations(p < 0.01), and that their deficiency is directly associated with increased intestinal permeability(elevated plasma lactoferrin levels) and worsening disease activity index(CDAI) (Wang et al., 2023). Concurrently, the AHR-IL-22 axis establishes an immune tolerance microenvironment at the mucosal interface by inhibiting RORγt-mediated Th17 cell differentiation and proinflammatory factor (IL-17, TNF-α) release, while inducing Foxp3+ regulatory Treg cell expansion (Cui et al., 2024). Therefore, the microbiota-tryptophan-AHR-IL-22-ZO1 pathway constitutes the core regulatory loop of intestinal homeostasis, and its dysregulation is a common basis for the pathogenesis of IBD.

3.2. Metabolic defense of neurovascular units

In the brain, tryptophan metabolites provide neuroprotection by regulating the neurovascular unit (NVU). For example, 3-HKA promotes vascular remodeling. Following cerebral ischemia injury, activated microglia and infiltrating macrophages exhibit upregulation of KYNU expression, which catalyzes the conversion of 3-HK to 3-HKA (Kang et al., 2024). 3-HKA, as an endogenous agonist of the metabolic glutamate receptor 4(mGluR4), binds to mGluR4 on the surface of astrocytes, activating the calcium ion/calmodulin kinase II(CaMKII)-cAMP response element-binding protein(CREB) signaling axis, promoting the transformation of astrocytes from the pro-inflammatory A1 phenotype(C3+) to the neuroprotective A2 phenotype(S100A10+) (Chen et al., 2025). A2-type astrocytes release vascular endothelial growth factor(VEGF), brain-derived neurotrophic factor(BDNF), and transforming growth factor-β(TGF-β), which directly stimulate the proliferation and migration of vascular endothelial cells, promote angiogenesis in the penumbra, and enhance the reconstruction of tight junctions in the blood-brain barrier (Wang et al., 2022; Li et al., 2025). In a permanent middle cerebral artery occlusion(pMCAO) model, intraventricular injection of 3-HKA reduced infarct volume by 38% ± 5%(p < 0.001), accompanied by increased vascular density and neurological recovery (Li et al., 2025).

Consistent with its well-established neuroprotective role (as overviewed in Part 1), KYNA antagonizes NMDAR-mediated Ca²⁺influx in ischemia, thereby supporting neuronal survival (Juhász et al., 2025). In the ischemia-reperfusion model, KYNA levels in the hippocampal CA1 region were positively correlated with neuronal survival(r = 0.72), while KATII gene knockout mice exhibited exacerbated excitatory neuronal death (Wang et al., 2022). In addition, KYNA activates AHR in astrocytes, inducing the expression of phase II detoxification enzymes such as quinone oxidoreductase (NQO1), which synergistically clears ischemia-related ROS storms (Ross and Siegel, 2021). Therefore, the signaling pathway mediated by 3-HKA activation of metabolic glutamate receptor 4(mGluR4) that promotes the conversion of astrocytes to the neuroprotective A2 phenotype and ultimately induces angiogenesis, and the neuroprotective effects provided by KYNA through antagonizing NMDAR and exerting antioxidant effects, synergistically constitute a dual neurovascular protective mechanism. This endogenous mechanism provides potential therapeutic targets for the repair of stroke and neurodegenerative diseases.

3.3. Microecological regulation of metabolic homeostasis

Intestinal microbiota-derived indole compounds IPA and IAA stimulate GLP-1 secretion through two main pathways—the gut-pancreas axis—to regulate insulin/glucagon and directly act on the liver and adipose tissue to inhibit hepatic gluconeogenesis, improve insulin sensitivity, and promote fat thermogenesis, thereby achieving fine regulation of systemic glucose homeostasis and energy metabolism balance.

In the regulation of the gut-pancreatic axis, IPA and IAA activate G protein-coupled receptor 119(GPR119) on the surface of enteroendocrine L cells, stimulating the secretion of glucagon-like peptide-1 (GLP-1) through the cAMP/PKA signaling pathway (Drucker, 2001; Meier et al., 2002a; Gromada et al., 2004). GLP-1 promotes insulin synthesis and release by pancreatic beta cells in a glucose concentration-dependent manner, while inhibiting glucagon secretion by alpha cells (Carlessi et al., 2017). In lean and obese rat models, a high-protein diet significantly reduced the area under the blood glucose curve (AUC) during the oral glucose tolerance test (OGTT) in obese rats. The increase in GLP-1 AUC and elevated fasting insulin levels indicate that the high-protein diet improved the rats’ tolerance to diabetes (Reimer and Russell, 2008). IPA directly inhibits the transcription of key rate-limiting enzymes in hepatic gluconeogenesis, phosphoenolpyruvate carboxylase kinase(PEPCK) and glucose-6-phosphatase (G6Pase), through the AHR-peroxisome proliferator-activated receptor gamma (PPARγ) axis, thereby reducing endogenous glucose output (Untereiner et al., 2016). At the same time, AHR activation enhances tyrosine phosphorylation of insulin receptor substrate 1(IRS1), improving insulin signaling (Run et al., 2023). IAA activates the PXR, induces browning of white adipose tissue(WAT), upregulates uncoupling protein 1(UCP1) and genes related to mitochondrial biogenesis, and promotes thermogenic energy expenditure (Gong et al., 2024; Wang et al., 2025). Clinical studies have shown that serum IPA concentrations in patients with type 2 diabetes are significantly negatively correlated with the insulin resistance index (HOMA-IR)(p<-0.065), and low IPA levels independently predict the risk of developing diabetes (Ballanti et al., 2024).

4. Tryptophan metabolic network dysregulation and therapeutic targets: mechanisms and interventions in chronic diseases

Disruption of the tryptophan metabolic network plays a crucial role in the pathogenesis of chronic diseases, driving disease onset and progression by impairing immune function (Zhao et al., 2018), neuroprotection (Messaoud et al., 2019), and metabolic balance (Szelest et al., 2021; Stone and Williams, 2023). At the same time, the complexity and multifunctionality of the tryptophan metabolic network provide diverse intervention targets for the treatment of chronic diseases. This section will systematically analyze the molecular mechanisms of tryptophan metabolism disorders in autoimmune diseases and neurodegenerative diseases and discuss the challenges and opportunities in clinical practice from the perspective of mechanism discovery.

4.1. Metabolic imbalance in autoimmune diseases and neurodegenerative diseases

4.1.1. Role of tryptophan metabolism in systemic lupus erythematosus

In systemic lupus erythematosus (SLE), an inflammatory shift toward the kynurenine pathway depletes tryptophan, limiting the substrate available for serotonin synthesis and contributing to the high prevalence of mood disorders in these patients (Zhu et al., 2020; Eryavuz Onmaz et al., 2023). QUIN-driven excitotoxicity contributes to neuronal injury in NPSLE and stroke, whereas interventions that shift KP flux toward KYNA may alleviate these outcomes (Andrabi et al., 2011). In addition, studies have shown that IDO1 and IDO2 mRNA expression are most significantly upregulated in the spleen, and AHR is a necessary condition for the induction of IDO1 and IDO2 expression by 2,3,7,8-tetrachlorodibenzodioxin(TCDD) (Vogel et al., 2008). AHR regulates Blimp-1 expression through Bach2, inhibiting the differentiation of B cells into plasma cells in vitro (Vaidyanathan et al., 2017). This indicates that weakening AHR signal activation will reduce the clearance of autoreactive B cells, and that the inactivation of the IDO2-mediated B cell tolerance mechanism is a core component of SLE immune dysregulation.

4.1.2. Tryptophan metabolism in rheumatoid arthritis

Tryptophan metabolism disorder plays a crucial role in autoimmune diseases such as rheumatoid arthritis(RA). Recent clinical metabolomics studies have provided direct evidence for this: compared with healthy controls, the levels of multiple metabolites in the Tryptophan-KP in the serum of newly diagnosed RA patients were significantly downregulated, and the levels of these metabolites were negatively correlated with disease activity indices(DAS28) and autoantibodies(anti-CCP) (Wu et al., 2025). More importantly, this metabolic disorder is associated with key immune imbalances: decreased tryptophan and kynurenine levels are associated with increased Th17/Treg ratios and Tfh/Tfr ratios (Zheng et al., 2024). This indicates that IDO1-mediated downregulation of the Tryptophan-KP is a key driver of immune tolerance disruption in rheumatoid arthritis. Preclinical studies have shown that L-Kyn-activated AHR promotes the differentiation of immature CD4+ Th cells into regulatory Treg cell phenotypes, while inhibiting differentiation into Th17 cells that produce IL-17 (Mezrich et al., 2010; Liu et al., 2017). This provides a new theoretical basis for correcting immune imbalances in RA by regulating tryptophan metabolism.

4.1.3. Tryptophan metabolism in stroke and neurodegenerative diseases

In stroke and age-related neurodegenerative diseases, disorders in the KP and Tryptophan metabolism have a critical impact on neuronal function and disease progression (Huang et al., 2023). In the pathological process of stroke, due to the lack of KMO expression in astrocytes, the main astrocytic product of tryptophan catabolism is KYNA (Guillemin et al., 2005). As a metabolite of tryptophan, KYNA exerts its neuroregulatory function by regulating multiple neurotransmitter systems. Studies have shown that low nanomolar concentrations of KYNA can inhibit glutamate release in the caudate nucleus region of the striatum and have a widespread effect on the extracellular levels of acetylcholine, GABA, and dopamine (Amori et al., 2009; Zmarowski et al., 2009; Wu et al., 2010; Majeed et al., 2021). In vivo experiments further confirmed that fluctuations in KYNA levels directly regulate the release dynamics of glutamine, acetylcholine, and dopamine.

4.1.4. Impact of aging on tryptophan metabolism

There is also a causal relationship between age-related neurodegeneration and tryptophan metabolism disorders. In aged mice(24 months old), the levels of SIRT1 protein in the hippocampus were significantly reduced (Quintas et al., 2012). Tryptophan supplementation may reduce the mRNA levels of pro-inflammatory cytokine genes and enhance mitochondrial function by increasing the mRNA levels of mitochondrial transcription factor A, nuclear respiratory factor 1, mitochondrial transcription factor B1, AMPKα1, AMPKα2, Sirt1, and PGC1α mRNA levels, as well as the protein expression of phosphorylated AMPK, Sirt1, and PGC1α, thereby enhancing mitochondrial function (Liu et al., 2023). Mitochondria are the core hub of aging regulation, and strategies to enhance their function can slow down the aging process in multiple ways, providing key targets for anti-aging interventions.

4.2. Therapeutic interventions targeting the tryptophan metabolic network

The complexity and compensatory potential of the tryptophan metabolic network necessitate diverse therapeutic strategies. A critical lesson from clinical trials, such as the failure of the IDO1 inhibitor epacadostat (Garber, 2018). It is crucial to develop a biomarker approach that can be applied to different tissues in order to realize the full potential of tryptophan metabolism networks in precision medicine. This requires establishing a biomarker screening and validation system with high specificity, sensitivity, and wide applicability from the perspectives of multi omics data integration, disease mechanism analysis, and individualized treatment decision-making. The core of this system lies in integrating multi-level data from the genome, epigenome, transcriptome, proteome, and metabolome, combined with medical imaging omics and liquid biopsy information, using artificial intelligence and machine learning models to identify driving biological features closely related to clinical outcomes and treatment responses (Alagarswamy et al., 2024). On this basis, candidate biomarkers must undergo rigorous mechanism validation and clinical association testing to ensure that they accurately reflect the pathological and physiological status of specific tissues, such as the level of quinoline acid(QA) in neuroinflammation or IDO1 activity in the tumor microenvironment (Wang et al., 2024). Furthermore, these biomarkers can be used for dynamic monitoring of treatment response and guiding patient stratification, thereby providing support for personalized treatment decisions, such as selecting KMO inhibitors for patients with high KMO expression or supplementing specific probiotics for patients with intestinal microbiota derived indole metabolite deficiency (Catani et al., 2025). Despite facing challenges such as organizational heterogeneity and standardized detection, by promoting the deep integration of computational science and clinical practice, and conducting long-term longitudinal research verification, this multi omics biomarker based strategy will greatly promote cross tissue precision therapy for tryptophan metabolism networks.

4.2.1. Enzyme inhibitors

Rational drug design targeting key enzymes has advanced, though not without challenges. The failure of the highly selective IDO1 inhibitor epacadostat in a phase III melanoma trial(ECHO-301) highlighted several hurdles: compensatory upregulation of TDO2/KMO via HIF-1α-mediated metabolic reprogramming, continuous AHR activation by alternative micro environmental ligands, and a lack of predictive biomarkers for patient selection (Long et al., 2019). This has contributed to the development of next-generation inhibitors, such as the allosteric IDO1 inhibitor LY3381916, which shows promise in blocking the substrate channel and overcoming conformational resistance, though further validation through clinical trials is required (Dorsey et al., 2018). Beyond IDO1/TDO2, inhibition of downstream branchpoint enzymes is also promising. For instance, the KMO inhibitor CHDI-340246 potently and dose-dependently modulates the KP in transgenic Huntington’s disease models, inhibiting the formation of 3-HK and QUIN while elevating neuroprotective KYNA levels in the brain (Kudo et al., 2024; Tufail et al., 2024).

4.2.2. Metabolite supplementation and receptor modulation

Direct administration of key metabolites offers a complementary approach to restore metabolic balance. In ischemic stroke, supplementation with 3-hydroxykynurenine(3-HK) has demonstrated significant therapeutic potential. In a middle cerebral artery occlusion(MCAO) model, 3-HK treatment reduced infarct volume and promoted long-term neurological recovery (Wang et al., 2022). Its mechanism involves multi-dimensional neurovascular unit reconstruction: it enhances angiogenesis and blood-brain barrier integrity by activating the VEGF signaling pathway, while simultaneously driving the polarization of astrocytes from a neurotoxic A1 to a neuroprotective A2 phenotype by inhibiting NF-κB and activating STAT3 (Wang et al., 2022; Li et al., 2025). This exemplifies the potential of metabolite-based therapy to orchestrate complex repair processes.

4.2.3. Microbiome-targeted therapies

Precision modulation of the gut microbiota represents a powerful strategy to influence host tryptophan metabolism. Engineered probiotics that overexpress tryptophanase(tnaA) can significantly increase the production of indole derivatives like IPA (Li et al., 2011). Furthermore, specific AHR-activating ligands derived from the microbiome or diet have shown efficacy in ameliorating colitis in models such as DSS, TNBS, and T-cell transfer (Monteleone et al., 2011; Zelante et al., 2013; Goettel et al., 2016; Islam et al., 2017). The beneficial effects of these compounds are associated with elevated IL-22 levels and are attenuated by IL-22 blockade or AHR antagonism, confirming the critical role of the microbiota-AHR-IL-22 axis in their mechanism of action (Zelante et al., 2013; Bai et al., 2019).

When considering dietary Tryptophan supplementation or high-Tryptophan diets as a therapeutic strategy, two key confounding factors are paramount. First, bioavailability is limited by competition at the intestinal transporter level; high levels of other LNAAs can significantly reduce Tryptophan uptake into circulation and across the blood-brain barrier, thereby limiting its availability for both host and microbial metabolism. Second, the source and matrix of the diet introduce confounding compounds. For example, high-protein diets may provide more Tryptophan but also increase competing LNAAs, while complex plant-based diets provide additional AHR ligands and fibers that independently modulate the microbial ecosystem and host immunity. Therefore, a holistic view of the dietary composition, rather than focusing on a single nutrient, is essential for predicting intervention outcomes.

4.2.4. Natural products with multi-target activity

Natural products often exert synergistic effects through multi-target regulation. Shikimic acid(SA), for example, inhibits Staphylococcus aureus biofilm formation by modulating sarA and agrA transcription and exerts cardioprotective effects via antioxidant and anti-inflammatory mechanisms (Bai et al., 2019; Alwaili et al., 2025). More notably, artemisinin and its derivatives have proven to be effective anticancer agents. They activate the mitochondrial ROS-JNK pathway to induce apoptosis while concurrently downregulating IDO1 expression. Artemisinin dimers can target heme-dependent IDO1 for degradation, reducing tumor KYN levels by approximately 75% and synergizing with anti-PD-1 therapy (Stockwin et al., 2009; Berdelle et al., 2011; Xia et al., 2025). These findings highlight the potential of natural products in multi-target cancer and infection treatments.

5. Challenges and future perspectives

Future challenges in applying insights from tryptophan metabolism to clinical practice mainly involve technical and biological hurdles. One challenge is the limited ability to detect metabolites in specific tissues over time, especially for metabolites like kynurenine. To address this, combining spatial metabolomics with single-cell transcriptomics is necessary to better understand metabolic changes at a cellular level.

Another challenge is the complexity of host-microbiome interactions in metabolism. Current models do not fully integrate microbial and host metabolic data. Developing better models that combine metabolomic, microbiomic, and enzymatic data will be crucial for understanding how metabolic changes affect disease and treatment responses.

Therapeutic strategies are also limited by metabolic redundancy and individual variability. Single-target therapies may not be effective due to compensatory mechanisms. Dual-target inhibitors and combination therapies are needed to address this complexity. Additionally, variations in microbiome composition affect treatment outcomes, so precision medicine must account for these differences.

Emerging technologies offer solutions to these challenges. Engineering metabolites and using probiotics to enhance beneficial microbial metabolites could lead to new treatments. AI-driven models can help identify new therapeutic targets and improve drug development. (Xia et al., 2025a; Xia et al., 2025b; Xia et al., 2025c; Xia et al., 2025d)

Looking ahead, research should focus on validating tissue-specific biomarkers and integrating spatial metabolomics with artificial intelligence technology to refine treatment strategies (Chen et al., 2024). Understanding dietary factors and tryptophan bioavailability will also be important for developing personalized treatments. These efforts will help advance precision medicine, particularly in cancer, neurology, and immunology.

Funding Statement

The author(s) declared financial support was received for this work and/or its publication. This work was supported by the National Key Research and Development Program of China(2022YFD1802104).

Author contributions

H-HX: Visualization, Writing – original draft, Writing – review & editing. J-ZH: Supervision, Funding acquisition, Writing – review & editing, Writing – original draft.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcimb.2025.1707850/full#supplementary-material