Tryptophan Metabolism in Cardiometabolic Diseases: Focus on the Kynurenine Pathway

Figure 1. Overview of tryptophan (TRP) metabolism pathways. Dietary TRP is absorbed in the intestine and enters the systemic circulation, contributing to the circulating TRP pool available for cellular uptake. TRP is metabolized through three major pathways. The kynurenine pathway, accounting for approximately 90–95% of TRP degradation, is initiated by indoleamine 2,3-dioxygenase 1 (IDO1) or tryptophan-2,3-dioxygenase (TDO), leading to the formation of kynurenine (KYN) and downstream metabolites that ultimately contribute to nicotinamide adenine dinucleotide (NAD+) synthesis. The serotonin pathway, mediated by tryptophan hydroxylase (TPH), converts TRP into serotonin, which can be further metabolized into melatonin. In parallel, TRP is metabolized by the gut microbiota into indole-derived compounds, including indole-3-propionic acid (IPA), indole-3-acetic acid (IAA), and indole-3-aldehyde (IAld), which act as ligands for the aryl hydrocarbon receptor (AHR) and modulate host signaling pathways.

Figure 2. Overview of the tryptophan (TRP)–kynurenine pathway and its major metabolic branches. This figure illustrates the principal metabolic pathways of TRP. TRP can be converted into serotonin and subsequently melatonin. Alternatively, TRP is metabolized by indoleamine 2,3-dioxygenase (IDO1) to form kynurenine (KYN), initiating the kynurenine pathway. KYN is further metabolized through two main branches. Via kynurenine aminotransferase (KAT), KYN is converted to kynurenic acid (KA). Through kynurenine 3-monooxygenase (KMO), KYN is converted to 3-hydroxykynurenine (3-HK), which is subsequently metabolized by kynureninase to 3-hydroxyanthranilic acid (3-HAA). 3-HAA is further converted by 3-hydroxyanthranilate 3,4-dioxygenase (3-HAO) to quinolinic acid (QA). Quinolinic acid is then metabolized by quinolinate phosphoribosyltransferase (QPRT) to form nicotinamide.

Figure 3. Tryptophan (TRP) metabolism in cardiometabolic diseases. Chronic inflammation induces indoleamine 2,3-dioxygenase 1 (IDO1), leading to activation of the kynurenine pathway and accumulation of altered TRP metabolites. In obesity and type 2 diabetes (T2D), kynurenine (KYN) pathway activation is associated with insulin resistance, adipose inflammation, and increased circulating KYN, kynurenine-to-tryptophan ratio (KTR), 3-hydroxykynurenine (3-HK), and kynurenic acid (KA). In atherosclerosis, elevated KYN metabolites are linked to plaque inflammation and lipid dysregulation. In myocardial infarction (MI), increased KYN pathway activity is associated with adverse remodeling, cardiomyocyte apoptosis, and prognostic elevation of circulating metabolites. In heart failure with preserved ejection fraction (HFpEF), kynurenine pathway activation and reduced microbiome-derived metabolites, such as indole-3-propionic acid (IPA), are associated with impaired energetics, reduced nicotinamide adenine dinucleotide (NAD+) availability, and decreased exercise capacity. ↑ and ↓ indicate increased and decreased levels, ratios, expression/activity, or disease related features, respectively.

Figure 4. Branch and cell-specific mechanisms downstream of tryptophan metabolism in cardiometabolic diseases. Inflammatory and metabolic stimuli, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), lipopolysaccharide (LPS), reactive oxygen species (ROS), and angiotensin II (Ang II), induce indoleamine 2,3-dioxygenase 1 (IDO1) and/or tryptophan-2,3-dioxygenase (TDO), promoting tryptophan (TRP) conversion into kynurenine (KYN). The biological consequences of this activation depend on the downstream branch engaged, the cell or tissue compartment involved, and the signaling node activated. IDO1-mediated local TRP depletion can limit activated T-cell proliferation and support regulatory T-cell/dendritic-cell (Treg/DC)-mediated immune tolerance. KYN can activate aryl hydrocarbon receptor (AHR)-dependent signaling in adipocytes, macrophages, endothelial cells, and cardiomyocytes, linking TRP metabolism to impaired insulin signaling, tissue factor expression, oxidative stress, apoptosis, and remodeling. In contrast, conversion of KYN through kynurenine aminotransferases (KATs) to kynurenic acid (KA) may support regulatory or cytoprotective signaling through G protein-coupled receptor…