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Association between altered tryptophan metabolism, plasma aryl hydrocarbon receptor agonists, and inflammatory Chagas
Laura Fernanda Ambrosio1,2, Ximena Volpini1,2, Juan Nahuel Quiroz1,2
1Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Insights
Investigating the Aryl hydrocarbon receptor (AhR) and tryptophan metabolism in Chagas disease revealed impaired AhR activity and altered metabolite profiles in patients, suggesting potential biomarkers for disease severity and new therapeutic targets.
Area of Science:
- Immunology and Infectious Diseases
- Molecular Biology and Biochemistry
Background:
- Chagas disease leads to cardiac complications via immunoinflammatory reactions and myocardial remodeling.
- The Aryl hydrocarbon receptor (AhR) regulates inflammation, and its ligands include tryptophan (Trp) metabolites.
- Understanding the role of AhR and Trp metabolism is crucial for explaining varying disease progression in Chagas disease.
Purpose of the Study:
- To investigate AhR expression, activity, and Trp metabolite profiles in mouse models and human patients with Chagas disease.
- To assess the correlation between AhR function, Trp metabolism, and the development of Chronic Chagas Cardiomyopathy (CCC).
- To identify potential non-invasive biomarkers for predicting Chagas disease prognosis and severity.
Main Methods:
- Compared AhR-dependent responses (IDO activity, Treg induction, CYP1A1 expression) in two T. cruzi-infected mouse strains (B6 and Balb/c).
- Analyzed plasma Trp catabolites and AhR agonistic activity in Chronic Chagas Disease (CCD) patients and healthy donors (HD) using LC-MS and luciferase reporter assays.
- Assessed AhR expression and agonist response following activation in mouse models.
Main Results:
- T. cruzi-infected B6 mice exhibited impaired AhR-dependent responses and lower AhR agonist activity compared to Balb/c mice.
- CCD patients showed decreased plasma AhR agonistic activity and dysregulated Trp metabolic pathways compared to HD.
- Severe CCC patients had elevated N-acetylserotonin levels, indicating specific metabolic alterations.
Conclusions:
- Impaired AhR activity and altered Trp metabolism are associated with Chagas disease progression and cardiac complications.
- AhR agonistic activity and Trp metabolic profiles in plasma may serve as novel, non-invasive biomarkers for Chagas disease prognosis.
- These findings offer insights for developing targeted therapeutic strategies for Chagas disease.
Introduction:
Chagas disease causes a cardiac illness characterized by immunoinflammatory reactions leading to myocardial fibrosis and remodeling. The development of Chronic Chagas Cardiomyopathy (CCC) in some patients while others remain asymptomatic is not fully understood, but dysregulated inflammatory responses are implicated. The Aryl hydrocarbon receptor (AhR) plays a crucial role in regulating inflammation. Certain tryptophan (Trp) metabolites have been identified as AhR ligands with regulatory functions.
Methods Results And Discussion:
We investigated AhR expression, agonist response, ligand production, and AhR-dependent responses, such as IDO activation and regulatory T (Treg) cells induction, in two T. cruzi-infected mouse strains (B6 and Balb/c) showing different polymorphisms in AhR. Furthermore, we assessed the metabolic profile of Trp catabolites and AhR agonistic activity levels in plasma samples from patients with chronic Chagas disease (CCD) and healthy donors (HD) using a luciferase reporter assay and liquid chromatography-mass spectrophotometry (LC-MS) analysis. T. cruzi-infected B6 mice showed impaired AhR-dependent responses compared to Balb/c mice, including reduced IDO activity, kynurenine levels, Treg cell induction, CYP1A1 up-regulation, and AhR expression following agonist activation. Additionally, B6 mice exhibited no detectable AhR agonist activity in plasma and displayed lower CYP1A1 up-regulation and AhR expression upon agonist activation. Similarly, CCC patients had decreased AhR agonistic activity in plasma compared to HD patients and exhibited dysregulation in Trp metabolic pathways, resulting in altered plasma metabolite profiles. Notably, patients with severe CCC specifically showed increased N-acetylserotonin levels in their plasma. The methods and findings presented here contribute to a better understanding of CCC development mechanisms and may identify potential specific biomarkers for T. cruzi infection and the severity of associated heart disease. These insights could be valuable in designing new therapeutic strategies. Ultimately, this research aims to establish the AhR agonistic activity and Trp metabolic profile in plasma as an innovative, non-invasive predictor of prognosis for chronic Chagas disease.
