Kynurenine pathway activation and deviation to anthranilic and kynurenic acid in fibrosing chronic graft-versus-host disease.

Fibrosing chronic graft-versus-host disease (cGVHD) is a debilitating complication of allogeneic stem cell transplantation (alloSCT). A driver of fibrosis is the kynurenine (Kyn) pathway, and Kyn metabolism patterns and cytokines may influence cGVHD severity and manifestation (fibrosing versus gastrointestinal [GI] cGVHD). Using a liquid chromatography-tandem mass spectrometry approach on sera obtained from 425 patients with allografts, we identified high CXCL9, high indoleamine-2,3-dioxygenase (IDO) activity, and an activated Kyn pathway as common characteristics in all cGVHD subtypes. Specific Kyn metabolism patterns could be identified for non-severe cGVHD, severe GI cGVHD, and fibrosing cGVHD, respectively. Specifically, fibrosing cGVHD was associated with a distinct pathway shift toward anthranilic and kynurenic acid, correlating with reduced activity of the vitamin-B2-dependent kynurenine monooxygenase, low vitamin B6, and increased interleukin-18. The Kyn metabolite signature is a candidate biomarker for severe fibrosing cGVHD and provides a rationale for translational trials on prophylactic vitamin B2/B6 supplementation for cGVHD prevention.

Serum Kynurenines Correlate With Depressive Symptoms and Disability in Poststroke Patients: A Cross-sectional Study.

BACKGROUND: Poststroke depression (PSD) is related to adverse functional and cognitive prognosis in stroke patients. The participation of kynurenine pathway metabolites in depression has been previously proposed; however, there are few studies on its role in PSD and disability in stroke. OBJECTIVE: To investigate if there is a correlation between serum kynurenines levels with poststroke anxiety and depression symptoms and disability scales. METHODS: A cross-sectional case-control study was conducted in patients with first stroke, of >1 month and <1 year of evolution, with no history of previous psychiatric or neurological disorders; the Hospital Anxiety and Depression Scale (HADS), Montreal Cognitive Assessment (MoCA), functional evaluations (Barthel index, Functional Independence Measure [FIM]) were applied and serum kynurenines (Kyns) were determined. RESULTS: Sixty patients were included; significant depressive symptoms were found in 63% of the cases; a significant and positive correlation was obtained between levels of 3-hydroxykynurenine (3-HK) with HADS-T (r = 0.30, P = .025) and HADS-D (r = 0.28, P = .039). Depressed patients showed significantly higher levels of 3HK (P = .048) and KYNA (P = .0271) than nondepressed patients; the 3HK levels were inversely correlated with functional scales: Barthel index (r = -0.31, P = .02), FIM (r = -0.40, P = .01); in addition, serum 3HK levels were significantly higher in patients with poor sleep quality (P = .0190). CONCLUSIONS: Serum Kyns show correlation with the presence and severity of depressive symptoms and with the disability and sleep quality. Kyns may be a potential marker of depression risk and disability in stroke in future.

The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation.

OBJECTIVE: This study characterized the kynurenine pathway (KP) in human obesity by evaluating circulating levels of kynurenines and the expression of KP enzymes in adipose tissue. METHODS: Tryptophan and KP metabolite levels were measured in serum of individuals from the D.E.S.I.R. cohort (case-cohort study: 212 diabetic, 836 randomly sampled) and in women with obesity, diabetic or normoglycemic, from the ABOS cohort (n = 100). KP enzyme gene expressions were analyzed in omental and subcutaneous adipose tissue of women from the ABOS cohort, in human primary adipocytes and in monocyte-derived macrophages. RESULTS: In the D.E.S.I.R. cohort, kynurenine levels were positively associated with body mass index (BMI) (P = 4.68 × 10(-19) ) and with a higher HOMA2-IR insulin resistance index (P = 6.23 × 10(-4) ). The levels of kynurenine, kynurenic acid, and quinolinic acid were associated with higher BMI (P < 0.05). The expression of several KP enzyme genes (indoleamine 2,3-dioxygenase 1 [IDO1], kynureninase [KYNU], kynurenine 3-monooxygenase [KMO], and kynurenine aminotransferase III [CCBL2]) was increased in the omental adipose tissue of women with obesity compared to lean (P < 0.05), and their expression was induced by proinflammatory cytokines in human primary adipocytes (P < 0.05), except for KMO that is not expressed in these cells. The expressions of IDO1, KYNU, KMO, and CCBL2 were higher in proinflammatory than in anti-inflammatory macrophages (P < 0.05). CONCLUSIONS: In the context of obesity, the presence of macrophages in adipose tissue may contribute to diverting KP toward KMO activation.

[Tryptophan and its metabolites in renal allograft recipients]. / Tryptofan i jego metabolity u pacjentów po transplantacji nerki.

AIM: Disturbances in amino acids metabolism are common in chronic renal failure and subside partially after renal tranplantation. Tryptophan (TRP) is one of the most important exogenous amino acids. Its main derivative is L-kynurenine (KYN). Disorders in the TRP metabolism via kynurenine pathway may lead to neurologic disturbances, hypertension and anaemia. The aim of this study was to assess peripheral kynurenine pathway in 28 renal allograft recipients (RAR) (12 women and 16 men) in comparison to 10 hemodialysed patients with chronic renal failure (CRF) and 10 healthy subjects. METHODS: TRP, KYN, 3-hydroxykynurenine (3-HKYN), kyn-urenic acid (KYNA) and quinolinic acid (QA) were determined in plasma using high performance liquid chromatography technique. RESULTS: The plasma concentration of tryptophan in RAR was not significantly different from the control group, but it was almost twice higher than in CRF. There was an increase in most of kynurenine metabolites in RAR as compared to healthy subjects, although not as high as in CRF. We found a significant negative correlation between TRP and serum concentration of urea and creatinine as well as a positive correlation with GFR. CONCLUSIONS: Kidney transplantation tends to normalize TRP level and markedly lowers blood concentration of kynurenine and its main derivatives. A significant negative correlation was found between TRP level and the concentration of urea and creatinine. Lowering of the KYN metabolites level may play a role in lessening uremic neurological symptomes as well as hypertension and anemia in kidney graft recipients.