Serum Metabolic Profiles of the Tryptophan-Kynurenine Pathway in the high risk subjects of major depressive disorder

Abstract

Previous reports have shown that during chronic inflammation, the tryptophan (TRP)-kynurenine (KYN) pathway plays a pivotal role in the onset of depression. The aim of this study was to investigate the characteristics of the serum TRP-KYN pathway metabolite profile in high-risk subjects of major depressive disorder (HRMDD) defined by depression scores. The concentrations of TRP-KYN pathway metabolites {TRP, KYN, 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), kynurenic acid (KYNA) and anthranilic acid (AA)} were assessed in serum from HRMDD, chronic pain disorder patients and healthy controls. In serum from HRMDD, elevated levels of AA and decreased levels of TRP were observed, but the levels of other metabolites were not changed. Furthermore, the change in the AA 2nd / AA 1st ratio in subjects who progressed from a healthy state to a depressive state was correlated with an increase in the CES-D score. The level of IL-1 receptor antagonist (IL-1RA) was negatively correlated with that of AA. Interestingly, we confirmed AA as a possible biomarker for depression-related symptoms, since the metabolite profiles in the chronic pain disorder group and chronic unpredictable mild stress model mice were similar to those in the HRMDD. These results suggest that AA may be an effective marker for HRMDD. More than 300 million people suffered from major depressive disorder (MDD) in 2017, and the number is increasing year by year 1. Several theories of MDD onset have been proposed 2. The monoamine hypothesis, the chronic inflammation hypothesis, and the abnormalities in the hypothalamus-pituitary-adrenal (HPA) system hypothesis are the predominant hypotheses regarding the pathogenesis of MDD 3. Among these hypotheses, the chronic inflammation hypothesis is closely associated with the kynurenine (KYN) pathway 4. The KYN pathway is one of several tryptophan (TRP) metabolism pathways, and it is the main pathway involved in TRP metabolism 5,6. Inflammatory cytokines such as IFN-γ induce the expression of indoleamine 2,3-dioxygenase (IDO1), which is a

Indoleamine 2,3-Dioxygenase Activity Is Increased in Myelodysplastic Syndrome Patients

“…In a recent study, Dong et al reported an increase in serum KYN in AML patients compared to healthy controls [10]; this is in good agreement with the increase in serum KYN that we observed in all hematological categories. In accordance with previous reports [9], the levels of serum TRP in patients with hematological malignant tumors were lower in females than in males. However, IDO activity showed no differences between men and women.…”

“…Activation of AHR by KYN on dendritic cells inhibits dendritic cell maturation and immune surveillance, thereby promoting tumor survival [11]. Our results show that KYN and AA concentrations increased, while 3-HAA concentration decreased, in hematological malignant tumors compared to our previous data on healthy volunteers [9]. Moreover, 3-HAA inhibits nitric oxide synthase in macrophages and shows antioxidant activity in response to the local oxidative environment, thus regulating the tissue oxidative status [7].…”

“…Darlington et al reported that AA plasma concentrations are higher in depressive patients than in healthy controls [7]. High levels of AA and low levels of TRP were also observed in the serum of depressive patients [9]. Despite recent extensive efforts, the role of KYN metabolic products and their enzymatic activities has not been clarified in patients with hematological malignant tumors.…”

Crosstalk of multi-omics reveals specific characteristics in active ulcerative colitis patients with depression and anxiety

“…Though tryptophan metabolism was not suggested in our analysis, one metabolite in its pathway, anthranilic acid, was signi cantly associated with anxiety levels in UC patients. Anthranilic acid is a secondary metabolite of kynurenine, and is reported to be a biochemical "warning sign" of early-stage depression [37] and a marker for in ammation assessment in the brain [38].…”

Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress

“…Classical conceptualizations of stress and depression have attributed such changes to the associated decrease in brain serotonin as well as to the neuroregulatory effects of kynurenine pathway products, such kynurenic acid and quinolinic acid [ 38 ]. However, there is a growing appreciation that even classical psychiatric disorders—such as depression [ 39 , 40 ], anxiety [ 41 ], and schizophrenia [ 42 ]—are powerfully determined by alterations in the kynurenine pathway and the AhR regulation of the immune system. The role of neuronal activity in mediating stress/depression has now shifted to viewing neuronal activity more as a form of ‘immune-to-immune’ communication [ 43 ].…”