Activation of tryptophan metabolism in cardiometabolic disorders: Prognostic role of IDO and TDO enzymes

Abstract

Background: Cardiometabolic disorders, including cardiovascular disease and type 2 diabetes mellitus (T2DM), represent a major global health burden and are closely associated with metabolic abnormalities such as obesity, dyslipidemia, and impaired glucose regulation. Disease progression is strongly influenced by chronic low-grade inflammation and dysregulated immune responses. Tryptophan, an essential amino acid, plays an important role in immune regulation and maintenance of inflammatory homeostasis. Overactivation of the kynurenine pathway leads to the accumulation of toxic metabolites, which promote inflammation and increase the risk of atherosclerosis, pulmonary arterial hypertension (PAH), and non-alcoholic fatty liver disease (NAFLD).

Methods: This study was conducted between October 2024 and February 2025 and included total 150 participants. Ninety patients with cardiometabolic disorders were enrolled, including 30 patients with coronary artery disease (CAD) combined with T2DM, 30 patients with CAD combined with PAH, and 30 patients with CAD combined with NAFLD. 

Sixty apparently healthy individuals served as a control group. Venous blood samples were collected from all participants. Hematological parameters were evaluated using an automated complete blood count analyzer. Serum levels of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) were determined using enzyme-linked immunosorbent assay techniques. CD8+ T cell expression was determined using flow cytometry. All patients had angiographically confirmed coronary artery disease.

Results: Serum IDO levels were significantly elevated in patients with CAD combined with T2DM (4.85 ± 1.21 ng/mL), CAD combined with PAH (4.32 ± 1.08 ng/mL), and CAD combined with NAFLD (5.01 ± 1.34 ng/mL) compared to the control group (2.13 ± 0.74 ng/mL; P < 0.01). Similarly, serum TDO levels were significantly higher in CAD + T2DM (3.76 ± 0.98 ng/mL), CAD + PAH (3.54 ± 0.87 ng/mL), and CAD + NAFLD (3.92 ± 1.05 ng/mL) than in controls (1.89 ± 0.63 ng/mL; P < 0.01). CD8⁺ T-cell proportions were also significantly increased in CAD + T2DM (32.4 ± 5.8%), CAD + PAH (30.7 ± 5.1%), and CAD + NAFLD (31.9 ± 6.0%) compared to healthy controls (21.3 ± 4.2%; P < 0.01).

Novelty of the Study: This study is among the first to simultaneously evaluate CD8⁺ T cell expression and IDO and TDO enzyme activity in several cardiometabolic disorders, highlighting their combined prognostic significance in inflammation-driven metabolic pathology.

Conclusions: These findings suggest that inflammation-related activation of tryptophan metabolism through the kynurenine pathway plays an important role in immune disturbances and disease progression in cardiometabolic disorders. IDO and TDO enzymes may serve as valuable diagnostic biomarkers and potential therapeutic targets in inflammation-induced metabolic diseases.

Keywords: Chronic inflammation; Tryptophan metabolism; IDO and TDO enzymes; Kynurenine pathway; Cardiometabolic disorders; Functional food biomarkers