Peripheral and central kynurenine pathway abnormalities in major depression

Paul, Elisabeth; Schwieler, Lilly; Erhardt, Sophie; Boda, Sandra; Trepci, Ada; Kämpe, Robin; Asratian, Anna; Holm, Lovisa; Yngve, Adam; Dantzer, Robert; Heilig, Markus; Hamilton, J. Paul; Samuelsson, Martin

doi:10.1016/j.bbi.2022.01.002

Cited by 67 publications

(29 citation statements)

References 66 publications

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“…Picolinic acid is also known to have antiviral effects on HIV and other viruses, such as herpes simplex, 73 which are known to contribute to CNS inflammation in PLHIV. Our data do not support previous findings of lower levels of picolinic acid in depressed patients, 75 including in PLHIV. 39 Altogether, these findings suggest a protective role of tryptophan, plasma metabolites of serotonin, and indoles on psychiatric symptoms in PLHIV, while kynurenine metabolites showed an opposite effect.…”

Section: Discussioncontrasting

confidence: 99%

Microbiome-Related Indole and Serotonin Metabolites are Linked to Inflammation and Psychiatric Symptoms in People Living with HIV

Vadaq

Zhang

Meeder

et al. 2022

Int J�Tryptophan�Res

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Background: People living with HIV (PLHIV) exhibit dysregulation of tryptophan metabolism. Altered gut microbiome composition in PLHIV might be involved. Mechanistic consequences within the 3 major tryptophan metabolism pathways (serotonin, kynurenine, and indoles), and functional consequences for platelet, immune and behavioral functions are unknown. We investigated plasma tryptophan metabolites, gut microbiome composition, and their association with platelet function, inflammation, and psychiatric symptoms. Methods: This study included 211 PLHIV on long-term antiretroviral treatment (ART). Plasma tryptophan pathway metabolites were measured using time-of-flight mass spectrometry. Bacterial composition was profiled using metagenomic sequencing. Platelet reactivity and serotonin levels were quantified by flowcytometry and ELISA, respectively. Circulating inflammatory markers were determined using ELISA. Symptoms of depression and impulsivity were measured by DASS-42 and BIS-11 self-report questionnaires, respectively. Results: Plasma serotonin and indole metabolites were associated with gut bacterial composition. Notably, species enriched in PLHIV were associated with 3-methyldioxyindole. Platelet serotonin concentrations were elevated in PLHIV, without effects on platelet reactivity. Plasma serotonin and indole metabolites were positively associated with plasma IL-10 and TNF-α concentrations. Finally, higher tryptophan, serotonin, and indole metabolites were associated with lower depression and anxiety, whereas higher kynurenine metabolites were associated with increased impulsivity. Conclusion: Our results suggest that gut bacterial composition and dysbiosis in PLHIV on ART contribute to tryptophan metabolism, which may have clinical consequences for immune function and behavior.

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Section: Discussioncontrasting

confidence: 99%

Microbiome-Related Indole and Serotonin Metabolites are Linked to Inflammation and Psychiatric Symptoms in People Living with HIV

Vadaq

Zhang

Meeder

et al. 2022

Int J�Tryptophan�Res

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“…The products of tryptophan metabolism via the kynurenine pathway include both quinolinic acid and kynurenic acid. As an agonist of NMDA receptors, QA leads to increased potential neurotoxic metabolites and releases large amounts of glutamate [ 70 ], and KYNA, a potentially neuroprotective compound [ 71 ], that aggravates depression at low levels [ 72 , 73 ]. In addition to affecting excitatory neurotransmission by acting directly on glutamate receptors, QA and KYNA indirectly modulate glutamate function.…”

Section: Discussionmentioning

confidence: 99%

Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model

Chen

et al. 2022

BMC Neurosci

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Inflammation and glutamate (GLU) are widely thought to participate in the pathogenesis of depression, and current evidence suggests that the development of depression is associated with the activation of the kynurenine pathway (KP). However, the exact mechanism of KP among the inflammation, GLU and depression remain poorly understood. In this study, we examined the involvement of KP, inflammation and GLU in depressive phenotype induced by chronic unpredictable mild stress (CUMS) in C57B/6 J mice. Our results showed that CUMS caused depressive like-behavior in the sucrose preference test, tail suspension test and forced swimming test. From a molecular perspective, CUMS upregulated the peripheral and central inflammatory response and activated indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of KP, which converts tryptophan (TRP) into kynurenine (KYN). KYN is a precursor for QA in microglia, which could activate the N-methyl-D-aspartate receptor (NMDAR), increasing the GLU release, mirrored by increased IDO activity, quinolinic acid and GLU levels in the hippocampus, prefrontal cortex and serum. However, intervention with IDO inhibitor 1-methyl-DL-tryptophan (50 mg/kg/s.c.) and 1-methyl-L-tryptophan (15 mg/kg/i.p.) reversed the depressive-like behaviors and adjusted central and peripheral KP’s metabolisms levels as well as GLU content, but the inflammation levels were not completely affected. These results provide certain evidence that KP may be a vital pathway mediated by IDO linking inflammation and glutamate, contributing to depression.

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“…Tryptophan is needed to make serotonin, and its conversion into kynurenine may deplete the availability of serotonin in the brain [ 73 ]. Increases in kynurenine and decreases in tryptophan have been observed in patients with MDD episodes [ 74 , 75 ]. The kynurenine to tryptophan ratio was higher in COVID-19 patients than in healthy controls ( n = 394, mean = 0.05, CI = 0.03–0.10 vs. n = 239, mean = 0.03, CI = 0.02–0.03; p < 0.0001), and correlated positively with disease severity [ 76 ], but its role has not yet been investigated in the pathogenesis of post-COVID-19 depression.…”

Section: Neurobiology Of Post-covid-19 Depressive Symptomsmentioning

confidence: 99%

Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment

et al. 2022

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The Coronavirus Disease 2019 (COVID-19) pandemic is still spreading worldwide over 2 years since its outbreak. The psychopathological implications in COVID-19 survivors such as depression, anxiety, and cognitive impairments are now recognized as primary symptoms of the “post-acute COVID-19 syndrome.” Depressive psychopathology was reported in around 35% of patients at short, medium, and long-term follow-up after the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. Post-COVID-19 depressive symptoms are known to increase fatigue and affect neurocognitive functioning, sleep, quality of life, and global functioning in COVID-19 survivors. The psychopathological mechanisms underlying post-COVID-19 depressive symptoms are mainly related to the inflammation triggered by the peripheral immune-inflammatory response to the viral infection and to the persistent psychological burden during and after infection. The large number of SARS-CoV-2-infected patients and the high prevalence of post-COVID-19 depressive symptoms may significantly increase the pool of people suffering from depressive disorders. Therefore, it is essential to screen, diagnose, treat, and monitor COVID-19 survivors’ psychopathology to counteract the depression disease burden and related years of life lived with disability. This paper reviews the current literature in order to synthesize the available evidence regarding epidemiology, clinical features, neurobiological underpinning, and pharmacological treatment of post-COVID-19 depressive symptoms.

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Peripheral and central kynurenine pathway abnormalities in major depression

Cited by 67 publications

References 66 publications

Microbiome-Related Indole and Serotonin Metabolites are Linked to Inflammation and Psychiatric Symptoms in People Living with HIV

Microbiome-Related Indole and Serotonin Metabolites are Linked to Inflammation and Psychiatric Symptoms in People Living with HIV

Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model

Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment

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