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Cited by 132Tryptophan and brain disordersAmino Acid Enzymes and MetabolismNeuroscience and Neuropharmacology Research

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Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders

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Li, Dan, Yu, Shuang, Long, Yu, Shi, Ai, Deng, Jie, Ma, Yin, Wen, Jing, Li, Xiaoqiu, Liu, Songyu, Zhang, Yulu, Wan, Jinyan, Li, Nan, Ao, Rui·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2022.985378PMC PMC9496178
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Abstract

Neurological and psychiatric disorders are a category of chronic diseases that are widespread and pose serious mental and physical health problems for patients. The substrates, products, and enzymes of Tryptophan metabolism all contribute to the development of neurological and psychiatric disorders. This paper deals with three metabolic pathways of tryptophan that produce a series of metabolites called tryptophan Catabolics (TRYCATs). These metabolites are involved in pathological processes such as excitotoxicity, neuroinflammation, oxidative stress, and mitochondrial damage and are closely associated with neurological and psychiatric disorders such as Alzheimer’s disease and depression. Here, we review the elements that affect how tryptophan metabolism is regulated, including inflammation and stress, exercise, vitamins, minerals, diet and gut microbes, glucocorticoids, and aging, as well as the downstream regulatory effects of tryptophan metabolism, including the regulation of glutamate (Glu), immunity, G-protein coupled receptor 35 (Gpr35), nicotinic acetylcholine receptor (nAChR), aryl hydrocarbon receptor (AhR), and dopamine (DA). In order to advance the general understanding of tryptophan metabolism in neurological and psychiatric disorders, this paper also summarizes the current situation and effective drugs of tryptophan metabolism in the treatment of neurological and psychiatric disorders and considers its future research prospects.

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Figure 1 The three metabolic pathways of TRP. TRP is metabolized through three different pathways: KP, SP, and IP, with KP accounting for around 95% of TRP metabolism in the liver. Under the action of a series of enzymes, TRP generates metabolites such as KYN and KYNA via KP. Of these, only TRP, KYN, and 3-HK can enter the brain through the BBB, which in turn is involved in the neurotoxic and neuroprotective branches of TRP. A small proportion of TRP is metabolized in the gastrointestinal tract via SP and IP.
Figure 1 The three metabolic pathways of TRP. TRP is metabolized through three different pathways: KP, SP, and IP, with KP accounting for around 95% of TRP metabolism in the liver. Under the action of a series of enzymes, TRP generates metabolites such as KYN and KYNA via KP. Of these, only TRP, KYN, and 3-HK can enter the brain through the BBB, which in turn is involved in the neurotoxic and neuroprotective branches of TRP. A small proportion of TRP is metabolized in the gastrointestinal tract via SP and IP.CC BY · PubMed Central
Figure 2 Mechanism of upstream regulation of TRP metabolism. Inflammation and stress, exercise, vitamins, diet and gut microbes, minerals, glucocorticoids and aging can modulate tryptophan metabolism. Pro-inflammatory cytokines produced by macrophages can cross the BBB and regulate IDO-1 expression together with pro-inflammatory cytokines produced by astrocytes, microglia, neurons, and CD4+ T cells in the brain. The binding of central 5-HT1a and 5-HT2 receptor sites is also influenced by cytokines like IFN-γ, which affects Glu release. Glucocorticoids and aging can enhance the activity of IFN-γ. Exercise decreases IDO-1 activity via anti-inflammatory effects and lessens branched-chain amino acids’ competitive effect on TRP entrance into the brain through the BBB, both of which result in an increase in TRP concentrations in the brain. Vitamins are directly involved in regulating in TRP metabolism as cofactors and coenzymes. Gut microbes promoting gut homeostasis, which also contributes to TRP metabolites and ω-3-fatty acids. Vitamins and gut microbes, which jointly govern tryptophan metabolism, can both be controlled by dietary changes. Additionally, minerals are cofactors and enzymes of KP, and KP enzymes are very sensitive to them.
Figure 2 Mechanism of upstream regulation of TRP metabolism. Inflammation and stress, exercise, vitamins, diet and gut microbes, minerals, glucocorticoids and aging can modulate tryptophan metabolism. Pro-inflammatory cytokines produced by macrophages can cross the BBB and regulate IDO-1 expression together with pro-inflammatory cytokines produced by astrocytes, microglia, neurons, and CD4+ T cells in the brain. The binding of central 5-HT1a and 5-HT2 receptor sites is also influenced by cytokines like IFN-γ, which affects Glu release. Glucocorticoids and aging can enhance the activity of IFN-γ. Exercise decreases IDO-1 activity via anti-inflammatory effects and lessens branched-chain amino acids’ competitive effect on TRP entrance into the brain through the BBB, both of which result in an increase in TRP concentrations in the brain. Vitamins are directly involved in regulating in TRP metabolism as cofactors and coenzymes. Gut microbes promoting gut homeostasis, which also contributes to TRP metabolites and ω-3-fatty acids. Vitamins and gut microbes, which jointly govern tryptophan metabolism, can both be controlled by dietary changes. Additionally, minerals are cofactors and enzymes of KP, and KP enzymes are very sensitive to them.CC BY · PubMed Central
Figure 3 Regulatory mechanism of TRP metabolism on downstream signals. TRYCATs can achieve the regulation of Glu by acting on NMDAR, AMPAR, GABA, and KARs. For example, L-KYN, PIC and QUIN can exert immunosuppressive effects through different mechanisms, inhibiting the proliferation of CD4+ T cells, CD8+ T cells and natural killer (NK) cells. The specific activation of Gpr35 by KYNA can exert anti-inflammatory effects through negative regulation of NLRP3 and release of IL-23 and IL-17. α7-nACh receptors mediate large amounts of Ca2+ into neurons at resting or hyperpolarized membrane potentials, whereas NMDAR directs Ca2+ into neurons in a depolarized state. In addition, TRYCATs are the major endogenous ligands for AHR, which are released from the HSP90 complex and translocated to the nucleus when AHR binds to the ligand.
Figure 3 Regulatory mechanism of TRP metabolism on downstream signals. TRYCATs can achieve the regulation of Glu by acting on NMDAR, AMPAR, GABA, and KARs. For example, L-KYN, PIC and QUIN can exert immunosuppressive effects through different mechanisms, inhibiting the proliferation of CD4+ T cells, CD8+ T cells and natural killer (NK) cells. The specific activation of Gpr35 by KYNA can exert anti-inflammatory effects through negative regulation of NLRP3 and release of IL-23 and IL-17. α7-nACh receptors mediate large amounts of Ca2+ into neurons at resting or hyperpolarized membrane potentials, whereas NMDAR directs Ca2+ into neurons in a depolarized state. In addition, TRYCATs are the major endogenous ligands for AHR, which are released from the HSP90 complex and translocated to the nucleus when AHR binds to the ligand.CC BY · PubMed Central
Figure 4 TRP metabolism for neurological and psychiatric disorders.
Figure 4 TRP metabolism for neurological and psychiatric disorders.CC BY · PubMed Central

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Metadata

Authors
Li, D., Yu, S., Long, Y., Shi, A., Deng, J., Ma, Y., Wen, J., Li, X., Liu, S., Zhang, Y., Wan, J., Li, N., & Ao, R.
Affiliations
  • Chengdu University of Traditional Chinese Medicine (CN)
  • Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (CN)
Corresponding author
  • Li, Nan
  • Ao, Rui
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-09-08
Volume
13
Pages
985378-985378
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2022.985378
PMC
PMC9496178
OpenAlex
W4295865246
Cited by
129
References
136
Citations by year
2026: 27 · 2025: 52 · 2024: 32 · 2023: 18
FWCI
1.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Jiangxi University of Traditional Chinese Medicine (zdsys-202107)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
tryptophan metabolism, tryptophan catabolites, neurological disorders, mental illness, Alzheimer's disease, depression, excitotoxicity, neuroinflammation, oxidative stress, mitochondrial damage, gut microbiota, glucocorticoids, aging, glutamate, GPR35, nicotinic acetylcholine receptors, aryl hydrocarbon receptor, dopamine
MeSH terms
Mental Disorders, Dopamine, Glucocorticoids, Humans, Receptors, Nicotinic, Tryptophan, Vitamins, Receptors, Aryl Hydrocarbon, Glutamic Acid

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