The Mediating Role of Kynurenine Pathway Metabolites on the Relationship Between Inflammation and Muscle Mass in Oldest-Old Men.

Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Proinflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. Five hundred and five men (85.0 ± 4.2 years) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D3Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein [CRP], alpha-1-acid glycoprotein [AGP] and a subsample [n = 305] with interleukin [IL-6, IL-1β, IL-17A] and tumor necrosis factor-α [TNF-α]) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23%-92% of the inverse relationship between inflammatory markers and D3Cr muscle mass was mediated by KP metabolites (indirect effect p < .05). 3-hydroxyanthranilic acid (3-HAA), quinolinic acid (QA), TRP, xanthurenic acid (XA), KYN/TRP, 3-hydroxykynurenine (3-HK)/3-HAA, QA/3-HAA, and nicotinamide (NAM)/QA mediated the AGP relationship. 3-HAA, QA, KYN/TRP, 3-HK/XA, HKr ratio, 3-HK/3-HAA, QA/3-HAA, and NAM/QA mediated the CRP. KYN/TRP, 3-HK/XA, and NAM/QA explained the relationship for IL-6 and 3-HK/XA and QA/3-HAA for TNF-α. No mediation effect was observed for the other cytokines (indirect effect p > .05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA, and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D3Cr muscle mass may focus on KP metabolites rather than inflammation per se.

Hetherington-Rauth M ，Johnson E ，Migliavacca E ，Langsetmo L ，Hepple RT ，Ryan TE ，Ferrucci L ，Breuillé D ，Corthesy J ，Lane NE ，Feige JN ，Napoli N ，Tramontana F ，Orwoll ES ，Cawthon PM ... -  《-》

Capillary electrochromatography-mass spectrometry of kynurenine pathway metabolites.

Few articles are reported for the simultaneous separation and sensitive detection of the kynurenine pathway (KP) metabolites. This work describes a capillary electrochromatography-mass spectrometry (CEC-MS) method using acrylamido-2-methyl-1-propanesulfonic acid (AMPS) functionalized stationary phase. The AMPS column was prepared by first performing silanization of bare silica with gamma-maps, followed by polymerization with AMPS. The CEC-MS/MS methods were established for six upstream and three downstream KP metabolites. The simultaneous separation of all nine KP metabolites is achieved without derivatization for the first time in the open literature. Numerous parameters such as pH and the concentration of background electrolyte, the concentration of the polymerizable AMPS monomer, column length, field strength, and internal pressure were all tested to optimize the separation of multiple KP metabolites. A baseline separation of six upstream metabolites, namely tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (HKYN), kynurenic acid (KA), anthranilic acid (AA), and xanthurenic acid (XA), was possible at pH 9.25 within 26 min. Separation of six downstream and related metabolites, namely: tryptamine (TRPM), hydroxy‑tryptophan (HTRP), hydroxyindole-3 acetic acid (HIAA), 3-hydroxyanthranilic acid (3-HAA), picolinic acid (PA), and quinolinic acid (QA), was achieved at pH 9.75 in 30 min. However, the challenging simultaneous separation of all nine KP metabolites was only accomplished by increasing the column length and simultaneous application of internal pressure and voltage in 114 min. Quantitation of KP metabolites in commercial human plasma was carried out, and endogenous concentration of five KP metabolites was validated. The experimental limit of quantitation ranges from 100 to 10,000 nM (S/N = 8-832, respectively), whereas the experimental limit of detection ranges from 31 to 1000 nM (S/N = 2-16, respectively). Levels of five major KP metabolites, namely TRP, KYN, KA, AA, and QA, and their ratios in patient plasma samples previously screened for inflammatory biomarkers [C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α)] was measured. Pairs of the level of metabolites with significant positive correlation were statistically evaluated.

Chawdhury ASMMR ，Shamsi SA ，Miller A ，Liu A ... -  《-》

Tryptophan catabolism and vitamin B-6 status are affected by gender and lifestyle factors in healthy young adults.

Abnormalities of tryptophan (Trp) metabolism through the kynurenine (Kyn) pathway have been reported in various diseases; however, nutritional and lifestyle factors that affect this pathway in healthy individuals are not well documented. Our aim was to examine the effect of vitamin B-6 status and lifestyle factors including the use of vitamin B-6 supplements, alcohol, smoking, and oral contraceptives on Trp and its Kyn metabolites in a cohort of 2436 healthy young adults aged 18-28 y. Anthropometric and lifestyle data were collected by questionnaire. Participants provided blood samples for analysis of Trp, Kyn, anthranilic acid, kynurenic acid (KA), 3-hydroxykynurenine (HK), 3-hydroxyanthranilic acid (HAA), and xanthurenic acid (XA). Vitamin B-6 species were also measured. Serum Trp metabolites were 10-15% higher among men (n = 993) compared with women (n = 1443; P < 0.0001), except for HK and XA. In all participants, serum Trp was positively associated with plasma pyridoxal 5'-phosphate (PLP; r = 0.28, P < 0.0001), reaching a plateau at PLP concentrations of ∼83 nmol/L. HK was inversely associated with PLP (r = -0.14, P < 0.01). Users of vitamin B-6 supplements (n = 671) had 6% lower concentrations of HK than nonusers (n = 1765; P = 0.0006). Oral contraceptive users (n = 385) had lower concentrations of KA (20.7%) but higher XA (24.1%) and HAA (9.0%) than did nonusers (n = 1058; P < 0.0001). After adjustment for gender and other lifestyle variables, XA concentrations were 16% higher in heavy drinkers (n = 713) than in never or occasional drinkers (n = 975; P = 0.0007). Concentrations of 2 other essential amino acids, methionine and arginine, also were positively associated with serum Trp (r = 0.65 and 0.33, respectively; P < 0.0001). In this population of healthy young adults, gender has the largest influence on serum Kyn metabolite concentrations. The significant covariance of Trp with unrelated amino acids suggests that protein intake may be an important consideration in evaluating Kyn metabolism.

Deac OM ，Mills JL ，Shane B ，Midttun Ø ，Ueland PM ，Brosnan JT ，Brosnan ME ，Laird E ，Gibney ER ，Fan R ，Wang Y ，Brody LC ，Molloy AM ... -  《-》

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases.

Song P ，Ramprasath T ，Wang H ，Zou MH ... -  《-》

Influence of periodontal inflammation on tryptophan-kynurenine metabolism: a cross-sectional study.

Kynurenine pathway (KP) is the primary way of degrading tryptophan (TRP) and generates several bioactive metabolites (such as kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3OHKYN)) to regulate biological processes that include host-microbiome signaling and immune cell response. This study is aimed to determine the relationship between periodontal inflammation and tryptophan-kynurenine metabolism and identify their association with periodontal clinical parameters. Saliva and serum samples were collected from 20 stage III, grade B generalized periodontitis patients, and 20 periodontally healthy control individuals. Samples were analyzed for IL-6, KYN, TRP, KYN/TRP ratio, KYNA, 3OHKYN, picolinic acid (PA), and quinolinic acid (QA) by liquid chromatography-mass spectrometry. Clinical periodontal parameters (plaque index (PI), probing pocket depth (PPD), gingival recession (GR), clinical attachment loss (CAL), and bleeding on probing (BOP)) were recorded. Clinical parameters were significantly higher in the periodontitis group (p < 0.001). Salivary IL-6, TRP, KYN, KYNA, PA, and QA levels were significantly higher and KYN/TRP ratio was significantly lower in periodontitis group than control group (p < 0.05). Serum KYN, KYN/TRP ratio and PA levels were significantly higher in periodontitis group than control group (p < 0.05). PPD, BOP, PI, and CAL had significantly positive correlations with salivary IL-6, TRP, PA, QA, and serum KYN and significantly negative correlations with salivary KYN/TRP ratio. Our results suggest that periodontal inflammation plays a role in local and systemic tryptophan-kynurenine metabolism. Due to their effects on the immune and inflammatory systems, kynurenines may be potential agents for diagnosis and treatment of periodontal diseases.

Kurgan Ş ，Önder C ，Balcı N ，Akdoğan N ，Altıngöz SM ，Serdar MA ，Günhan M ... -  《-》