The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases

Tsuji, Akira; Ikeda, Yuka; Yoshikawa, Sayuri; Taniguchi, Kurumi; Sawamura, Haruka; Morikawa, Sae; Nakashima, Moeka; Asai, Tomoko; Matsuda, Satoru

doi:10.3390/ijms24065742

Cited by 38 publications

(14 citation statements)

References 129 publications

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“…Furthermore, the tryptophan metabolism was selectively upregulated in NASH leading to increased levels of tryptophan, kynurenine and Indoleacrylic acid ( Figure 7 A,B). Because kynurenine and its metabolites have immunosuppressive effects [ 18 ], we determined the immune response in these mice. Therefore, we used the MELC technology for high-content immunohistochemistry, which was used to visualize 30 antibodies ( Supplementary Table S4 ) describing the major immune cell types [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

Differential Lipidomics, Metabolomics and Immunological Analysis of Alcoholic and Non-Alcoholic Steatohepatitis in Mice

Dorochow,

Kraus,

Chenaux-Repond

et al. 2023

IJMS

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Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) are the leading causes of liver disease worldwide. To identify disease-specific pathomechanisms, we analyzed the lipidome, metabolome and immune cell recruitment in livers in both diseases. Mice harboring ASH or NASH had comparable disease severities regarding mortality rate, neurological behavior, expression of fibrosis marker and albumin levels. Lipid droplet size was higher in NASH than ASH and qualitative differences in the lipidome were mainly based on incorporation of diet-specific fatty acids into triglycerides, phosphatidylcholines and lysophosphatidylcholines. Metabolomic analysis showed downregulated nucleoside levels in both models. Here, the corresponding uremic metabolites were only upregulated in NASH suggesting stronger cellular senescence, which was supported by lower antioxidant levels in NASH as compared to ASH. While altered urea cycle metabolites suggest increased nitric oxide synthesis in both models, in ASH, this depended on increased L-homoarginine levels indicating a cardiovascular response mechanism. Interestingly, only in NASH were the levels of tryptophan and its anti-inflammatory metabolite kynurenine upregulated. Fittingly, high-content immunohistochemistry showed a decreased macrophage recruitment and an increased polarization towards M2-like macrophages in NASH. In conclusion, with comparable disease severity in both models, higher lipid storage, oxidative stress and tryptophan/kynurenine levels were seen in NASH, leading to distinct immune responses.

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Section: Resultsmentioning

confidence: 99%

Differential Lipidomics, Metabolomics and Immunological Analysis of Alcoholic and Non-Alcoholic Steatohepatitis in Mice

Dorochow,

Kraus,

Chenaux-Repond

et al. 2023

IJMS

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“…A lot of previous studies reported that Trp metabolites act as AhR agonists [ 19 , 20 , 33 , 41 , 42 ]. The primary Trp metabolism is known to be the kynurenine pathway that accounts for greater than 90% of the peripheral metabolism of Trp in mammals [ 43 , 44 ], and Trp is metabolized to Kyn via its metabolizing enzyme, indoleamine 2,3 dioxygenase (IDO)-1, which is reported to affect the Th17/Treg balance [ 32 ]. This increase in Kyn was reported to lead to an increase in Tregs [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Immunoregulatory Effects of Elemental Diet and Its Ingredient, Tryptophan, via Activation of the Aryl Hydrocarbon Receptor in Mice

Kubota,

Imai,

Aoyagi

et al. 2024

IJMS

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Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation and its treatment varies widely; however, when inflammation is high, a complete nutrient containing pre-digested elemental diet (ED) is used to preserve the intestinal tract. In this study, we investigated the mechanisms underlying the effectiveness of EDs for IBD using mice. C57BL/6 mice were orally treated with the ED (5 mL/day) and its ingredient L-tryptophan (Trp) (1–100 mg/kg), respectively. Flow cytometry analysis revealed that treatment with the ED and Trp (10 and 100 mg/kg) significantly increased the percentage of splenic CD4+-/CD25+-/Foxp3+ regulatory T cells (Tregs). In the 2% DSS-induced colitis-mouse model, Trp administration (100 mg/kg) led to a significant decrease in TNF-α and increase in IL-10 in the serum as well as a significant decrease in the inflammation score. Furthermore, the aryl hydrocarbon receptor (AhR) agonistic activity, which is a key function of Treg induction, of Trp and 15 Trp metabolites was characterized using a highly sensitive DR-EcoScreen cell assay. Five Trp metabolites, including L-kynurenine, acted as AhR agonists, while Trp did not. Taken together, these results suggest that the ED treatment has a Trp-dependent immunoregulatory effect, and several Trp metabolites that activate the AhR might contribute to induction of remission in patients with IBD.

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“…Tryptophan is mainly broken down through the kynurenine pathway, which donates electrons to the tricarboxylic acid (TCA) cycle and converts a significant portion of the tryptophan into various bioactive metabolites [ 55 , 56 ]. These metabolites are suspected to have antioxidant, anti-inflammatory, and/or neuroprotective properties [ 57 , 58 , 59 , 60 ]. Hypoxia could alter the activity of the kynurenine pathway, potentially affecting tryptophan metabolism and its downstream effects on improving immune function and neuronal health in OHT patients.…”

Section: Discussionmentioning

confidence: 99%

Distinct Metabolic Profiles of Ocular Hypertensives in Response to Hypoxia

Langbøl,

Rovelt,

Saruhanian

et al. 2023

IJMS

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Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs). The main risk factor is elevated intraocular pressure (IOP), but the actual cause of the disease remains unknown. Emerging evidence indicates that metabolic dysfunction plays a central role. The aim of the current study was to determine and compare the effect of universal hypoxia on the metabolomic signature in plasma samples from healthy controls (n = 10), patients with normal-tension glaucoma (NTG, n = 10), and ocular hypertension (OHT, n = 10). By subjecting humans to universal hypoxia, we aim to mimic a state in which the mitochondria in the body are universally stressed. Participants were exposed to normobaric hypoxia for two hours, followed by a 30 min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and in recovery. Plasma samples were analyzed using a non-targeted metabolomics approach based on liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), and univariate analysis using the Wilcoxon signed-rank test and false discovery rate (FDR) correction. Unique metabolites involved in fatty acid biosynthesis and ketone body metabolism were upregulated, while metabolites of the kynurenine pathway were downregulated in OHT patients exposed to universal hypoxia. Differential affection of metabolic pathways may explain why patients with OHT initially do not suffer or are more resilient from optic nerve degeneration. The metabolomes of NTG and OHT patients are regulated differently from control subjects and show dysregulation of metabolites important for energy production. These dysregulated processes may potentially contribute to the elevation of IOP and, ultimately, cell death of the RGCs.

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The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases

Cited by 38 publications

References 129 publications

Differential Lipidomics, Metabolomics and Immunological Analysis of Alcoholic and Non-Alcoholic Steatohepatitis in Mice

Differential Lipidomics, Metabolomics and Immunological Analysis of Alcoholic and Non-Alcoholic Steatohepatitis in Mice

Immunoregulatory Effects of Elemental Diet and Its Ingredient, Tryptophan, via Activation of the Aryl Hydrocarbon Receptor in Mice

Distinct Metabolic Profiles of Ocular Hypertensives in Response to Hypoxia

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