Tryptophan metabolism links brain, immune system, and gut microbes: implications for personalized treatment in chronic diseases

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).

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.

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).

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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).

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.

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.

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.