Inflammation-driven reprogramming of tryptophan-kynurenine metabolism defines an integrative metabolomic phenotype of cardio-renal dysfunction
R B Alieva, K H G Fozilov, Y U N Belenkov, M V Kozhevnikova, M F Petrukhova, E O Korobkova, S A Appolonova, V Y Zektser, N V Khabarova, K M ShestakovaAbstract
Background
Immunometabolic reprogramming is increasingly recognised as a fundamental mechanism linking chronic inflammation to progressive cardiac and renal dysfunction. The tryptophan-kynurenine pathway represents a central metabolic hub integrating inflammatory signalling, oxidative stress and neurohumoral regulation. Whether coordinated alterations within this pathway define a metabolomic phenotype of cardio-renal disease progression remains insufficiently explored.
Purpose
To characterize inflammation-driven reprogramming of the tryptophan–kynurenine–serotonin axis using targeted metabolomics and to determine its value as a metabolic phenotype across stages of cardio-reno-metabolic syndrome (CRMS).
Methods
Targeted metabolomic profiling was performed in 498 individuals, including 404 patients with CRMS stages 1-4 and 94 healthy controls (stage 0). Circulating levels of tryptophan (Trp), kynurenine (Kyn), kynurenic,anthranilic, quinolinic, 3-hydroxyanthranilic and xanthurenic acids, serotonin (Ser) and 5-methoxytryptamine, were quantified using HPLC-MS/MS. Metabolic flux indices (Kyn/Trp and Trp/(Kyn+QA)) were calculated. Metabolomic data were integrated with markers of systemic inflammation, cardiac function and renal impairment.
Results
CRMS progression was characterized by a shift toward enhanced Kyn pathway (KP) activation accompanied by depletion of Ser-related metabolites. The protective Trp/(Kyn+QA) ratio, reflecting a balance favoring protective metabolic pathways, was significantly lower already at stages associated with obesity (5.64 mmol/L vs 8.99 mmol/L in controls, р=0.005) and continued to decrease in hyperuricemia (4.44 mmol/L, p=0.012) and proteinuria (4.55 mmol/L, p=0.030), characteristic of later CRMS stages. Ser levels were significantly reduced starting from stages complicated by post-infarction cardiosclerosis (−0.22 mmol/L vs −0.12 in controls, p<0.001), coronary artery atherosclerosis (−0.21 mmol/L, p<0.001), as well as in concomitant type 2 diabetes mellitus (−0.20 mmol/L, p<0.001). Its reduction correlated inversely with C-reactive protein (r=−0.339, p<0.001), MBLF index (r=−0.383, p<0.001), and CKD stage (r=−0.362, p<0.001), and positively with EF (r=0.417, p<0.001). The Kyn/Trp ratio, a marker of pro-inflammatory KP activation, was elevated in post-infarction cardiosclerosis (0.95 mmol/L vs 0.27 mmol/L in controls, p<0.001) and hyperuricemia (1.25 mmol/L, p<0.001), corresponding to advanced CRMS stages (3-4). Kyn levels were higher in proteinuria (1.18 vs 0.62 mmol/L, p=0.007) and correlated with renal dysfunction markers: creatinine (r=0.318) and eGFR (r=−0.312).
Conclusion
Targeted metabolomics identifies a reproducible tryptophan-kynurenine-serotonin phenotype reflecting inflammation-driven metabolic reprogramming in CRMS. This metabolomics signature provides mechanistic insight into heart failure progression and represents a promising biomarker framework for phenotyping and risk stratification in CRMS.