Addiction and the kynurenine pathway: A new dancing couple?

Morales-Puerto, Nuria; Giménez-Gómez, Pablo; Pérez-Hernández, Mercedes; Abuin-Martínez, Cristina; Biedma-Elduayen, Leticia Gil de; Vidal, Rebeca; Gutiérrez-López, Marı́a Dolores; O’Shea, Esther; Colado, María Isabel

doi:10.1016/j.pharmthera.2021.107807

Cited by 32 publications

(25 citation statements)

References 179 publications

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“…The "samples" represent the number of samples contained in a parent node, whereas the "value" represents the number of samples of its left and right child nodes. -Puerto et al, 2021). Moreover, given that the imbalance of neuroprotective and neurotoxic kynurenine pathway metabolites is associated with the pathogenesis of neuropsychiatric disorders (Myint et al, 2007;Muneer, 2020;Zhu et al, 2021a), the disturbances of tryptophan metabolism along the kynurenine pathway may contribute to the cooccurrence of alcohol exposure and mental disorders in the context of addiction (Neupane et al, 2015;Jiang et al, 2020;Vidal et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Combining Metabolomics and Interpretable Machine Learning to Reveal Plasma Metabolic Profiling and Biological Correlates of Alcohol-Dependent Inpatients: What About Tryptophan Metabolism Regulation?

Zhu

Huang

et al. 2021

Front. Mol. Biosci.

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Alcohol dependence (AD) is a condition of alcohol use disorder in which the drinkers frequently develop emotional symptoms associated with a continuous alcohol intake. AD characterized by metabolic disturbances can be quantitatively analyzed by metabolomics to identify the alterations in metabolic pathways. This study aimed to: i) compare the plasma metabolic profiling between healthy and AD-diagnosed individuals to reveal the altered metabolic profiles in AD, and ii) identify potential biological correlates of alcohol-dependent inpatients based on metabolomics and interpretable machine learning. Plasma samples were obtained from healthy (n = 42) and AD-diagnosed individuals (n = 43). The plasma metabolic differences between them were investigated using liquid chromatography-tandem mass spectrometry (AB SCIEX® QTRAP 4500 system) in different electrospray ionization modes with scheduled multiple reaction monitoring scans. In total, 59 and 52 compounds were semi-quantitatively measured in positive and negative ionization modes, respectively. In addition, 39 metabolites were identified as important variables to contribute to the classifications using an orthogonal partial least squares-discriminant analysis (OPLS-DA) (VIP > 1) and also significantly different between healthy and AD-diagnosed individuals using univariate analysis (p-value < 0.05 and false discovery rate < 0.05). Among the identified metabolites, indole-3-carboxylic acid, quinolinic acid, hydroxy-tryptophan, and serotonin were involved in the tryptophan metabolism along the indole, kynurenine, and serotonin pathways. Metabolic pathway analysis revealed significant changes or imbalances in alanine, aspartate, glutamate metabolism, which was possibly the main altered pathway related to AD. Tryptophan metabolism interactively influenced other metabolic pathways, such as nicotinate and nicotinamide metabolism. Furthermore, among the OPLS-DA-identified metabolites, normetanephrine and ascorbic acid were demonstrated as suitable biological correlates of AD inpatients from our model using an interpretable, supervised decision tree classifier algorithm. These findings indicate that the discriminatory metabolic profiles between healthy and AD-diagnosed individuals may benefit researchers in illustrating the underlying molecular mechanisms of AD. This study also highlights the approach of combining metabolomics and interpretable machine learning as a valuable tool to uncover potential biological correlates. Future studies should focus on the global analysis of the possible roles of these differential metabolites and disordered metabolic pathways in the pathophysiology of AD.

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Section: Discussionmentioning

confidence: 99%

Combining Metabolomics and Interpretable Machine Learning to Reveal Plasma Metabolic Profiling and Biological Correlates of Alcohol-Dependent Inpatients: What About Tryptophan Metabolism Regulation?

Zhu

Huang

et al. 2021

Front. Mol. Biosci.

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“…No clinical study was found regarding the serum or CSF level of KYNs in patients with SUD. The TRP-KYN metabolic pathway is considered to play an important role in SUD and was discussed as a potential target for SUD therapy [17]. Patients with cocaine use disorder (CUD) frequently develop MDD.…”

Section: Substance Use Disordermentioning

confidence: 99%

“…The TRP-KYN pathway is involved in migraine headache and is one of the potential targets as anti-migraine drugs [16]. Modulation of the pathway was found to reduce or prevent substance abuse [17]. Furthermore, AhR also participates in the gut-brain axis.…”

Section: Introductionmentioning

confidence: 99%

Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway

et al. 2021

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The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases and psychiatric disorders. The presence of positive feedback loops facilitates amplifying the immune responses vice versa. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses and chronic diseases. KYN, kynurenic acid, xanthurenic acid and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2,3-dioxygenases and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric disorders, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia and autism spectrum disorder.

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“…Like other viruses, SARS-CoV2 immunopathology and disease progression are a function of factors that drive virus pathogenesis and host vulnerability ( Ezeomah et al, 2020 ; Mangalmurti and Hunter, 2020 ). For example, host proteins involved in the pathogenesis of SARS-CoV2 infections, in parallel to host immune signaling, impact the kynurenine pathway, a major regulator of serotonergic and glutamatergic systems involved in SUDs and neuropsychiatric disorders; in tandem, kynurenine functionality is tightly regulated by inflammatory events ( Anastasio et al, 2020 ; Attademo and Bernardini, 2021 ; Klempin et al, 2018 ; Linker et al, 2019 ; Morales-Puerto et al, 2021 ; Singer et al, 2012 ). Given that patient cytokine patterns and interferon responses correlate to Covid-19 disease severity and neurological complications, dysregulation of serotonergic and glutaminergic signaling could generate a cascade of pathophysiology that contributes to the escalation of SUDs ( Galani et al, 2021 ; Kohno et al, 2019 ; Lucerne and Kiraly, 2021 ; Nennig and Schank, 2017 ; Solomon, 2021 ).…”

Section: Covid-19 and Substance Use Disorder (Sud) Syndemicmentioning

confidence: 99%