Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression

Haroon, Ebrahim; Welle, James R; Woolwine, Bobbi J.; Goldsmith, David R.; Baer, Wendy; Patel, Trusharth; Felger, Jennifer C.; Miller, Andrew H.

doi:10.1038/s41386-020-0607-1

Cited by 118 publications

(93 citation statements)

References 66 publications

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“…Nevertheless, KYN and TRP are known to cross the BBB and there is some evidence that QA also has this capacity ( Heyes and Morrison, 1997 ). Accordingly, a recent paper reported significant correlations between KYN/TRP (r = 0.77) and QA (r = 0.55) concentrations in the plasma and CSF of depressed patients ( Haroon et al, 2020 ). However, even if it turns out that the serum concentrations of KP metabolites are not reflective of central nervous system (CNS) measurements, serum assays could be of great practical value if they predict therapeutic outcome.…”

Section: Discussionmentioning

confidence: 97%

Real-time fMRI neurofeedback amygdala training may influence kynurenine pathway metabolism in major depressive disorder

Tsuchiyagaito

Smith

El-Sabbagh

et al. 2021

NeuroImage: Clinical

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Highlights rtfMRI-nf LA emotional training reduces depressive symptoms. rtfMRI-nf LA training increases KynA/3-HK, a neuroprotective index. Baseline KynA/QA is associated with the ability to upregulate the LA. In partial responder group LA upregulation positively correlates with KynA/QA. In partial responder group LA upregulation inversely correlates with MADRS. Modulation of the KP may drive rtfMRI-nf-induced changes in neuroplasticity. Non-specific effects cannot be ruled out due to the lack of a sham control.

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Section: Discussionmentioning

confidence: 97%

Real-time fMRI neurofeedback amygdala training may influence kynurenine pathway metabolism in major depressive disorder

Tsuchiyagaito

Smith

El-Sabbagh

et al. 2021

NeuroImage: Clinical

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“…Inflammatory factors IFN-gamma, IL-1, LPS and TNF-alpha stimulate the expression of IDO, which is the rate-limiting enzyme of the Kyn pathway [ 53 , 54 , 55 ]. Kyn can cause inflammation in various organs and Kyn/Trp has been used as an indicator of the progression of inflammation [ 56 , 57 , 58 ].…”

Section: Gut Microbiota Metabolites In the Pathogenesis Of Nafldmentioning

confidence: 99%

Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications

Chen¹,

Vitetta

2020

IJMS

184

137

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Gut microbiota dysregulation plays a key role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through its metabolites. Therefore, the restoration of the gut microbiota and supplementation with commensal bacterial metabolites can be of therapeutic benefit against the disease. In this review, we summarize the roles of various bacterial metabolites in the pathogenesis of NAFLD and their therapeutic implications. The gut microbiota dysregulation is a feature of NAFLD, and the signatures of gut microbiota are associated with the severity of the disease through altered bacterial metabolites. Disturbance of bile acid metabolism leads to underactivation of bile acid receptors FXR and TGR5, causal for decreased energy expenditure, increased lipogenesis, increased bile acid synthesis and increased macrophage activity. Decreased production of butyrate results in increased intestinal inflammation, increased gut permeability, endotoxemia and systemic inflammation. Dysregulation of amino acids and choline also contributes to lipid accumulation and to a chronic inflammatory status. In some NAFLD patients, overproduction of ethanol produced by bacteria is responsible for hepatic inflammation. Many approaches including probiotics, prebiotics, synbiotics, faecal microbiome transplantation and a fasting-mimicking diet have been applied to restore the gut microbiota for the improvement of NAFLD.

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“…In contrast to the findings of Oxenkrug et al (55), AA was not elevated in SCZ vs. CON in our study (55). A heightened conversion of AA to 3-OHAA may be an indicator of increased neurotoxicity (56), and there is a strong correlation between plasma AA and cerebrospinal fluid (CSF) AA levels (57). The association of lower KYNA with slower latency was unexpected but highlights the complex role of this metabolite in schizophrenia pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma gondii Effects on the Relationship of Kynurenine Pathway Metabolites to Acoustic Startle Latency in Schizophrenia vs. Control Subjects

et al. 2020

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Background: Chronic infection with Toxoplasma gondii (TOXO) results in microcysts in the brain that are controlled by inflammatory activation and subsequent changes in the kynurenine pathway. TOXO seropositivity is associated with a heightened risk of schizophrenia (SCZ) and with cognitive impairments. Latency of the acoustic startle response, a putative index of neural processing speed, is slower in SCZ. SCZ subjects who are TOXO seropositive have slower latency than SCZ subjects who are TOXO seronegative. We assessed the relationship between kynurenine pathway metabolites and startle latency as a potential route by which chronic TOXO infection can lead to cognitive slowing in SCZ.Methods: Fourty-seven SCZ subjects and 30 controls (CON) were tested on a standard acoustic startle paradigm. Kynurenine pathway metabolites were measured using liquid chromatography-tandem mass spectrometry were kynurenine (KYN), tryptophan (TRYP), 3-hydroxyanthranilic acid (3-OHAA), anthranilic acid (AA), and kynurenic acid (KYNA). TOXO status was determined by IgG ELISA.Results: In univariate ANCOVAs on onset and peak latency with age and log transformed startle magnitude as covariates, both onset latency [F(1,61) = 5.76; p = 0.019] and peak latency [F(1,61) = 4.34; p = 0.041] were slower in SCZ than CON subjects. In stepwise backward linear regressions after stratification by Diagnosis, slower onset latency in SCZ subjects was predicted by higher TRYP (B = 0.42; p = 0.008) and 3-OHAA:AA (B = 3.68; p = 0.007), and lower KYN:TRYP (B = −185.42; p = 0.034). In regressions with peak latency as the dependent variable, slower peak latency was predicted by higher TRYP (B = 0.47; p = 0.013) and 3-OHAA:AA ratio (B = 4.35; p = 0.010), and by lower KYNA (B = −6.67; p = 0.036). In CON subjects neither onset nor peak latency was predicted by any KYN metabolites. In regressions stratified by TOXO status, in TOXO positive subjects, slower peak latency was predicted by lower concentrations of KYN (B = −8.08; p = 0.008), KYNA (B = −10.64; p = 0.003), and lower KYN:TRYP ratios (B = −347.01; p = 0.03). In TOXO negative subjects neither onset nor peak latency was predicted by any KYN metabolites.Conclusions: KYN pathway markers predict slowing of startle latency in SCZ subjects and in those with chronic TOXO infection, but this is not seen in CON subjects nor TOXO seronegative subjects. These findings coupled with prior work indicating a relationship of slower latency with SCZ and TOXO infection suggest that alterations in KYN pathway markers may be a mechanism by which neural processing speed, as indexed by startle latency, is affected in these subjects.

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Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression

Cited by 118 publications

References 66 publications

Real-time fMRI neurofeedback amygdala training may influence kynurenine pathway metabolism in major depressive disorder

Real-time fMRI neurofeedback amygdala training may influence kynurenine pathway metabolism in major depressive disorder

Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications

Toxoplasma gondii Effects on the Relationship of Kynurenine Pathway Metabolites to Acoustic Startle Latency in Schizophrenia vs. Control Subjects

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