Background: Recent studies confirm the involvement of activated immune-inflammatory responses and increased oxidative and nitrosative stress in Long COVID (LC) disease. However, the influence of these pathways on the metabolism of tryptophan (TRP) through the TRP catabolite (TRYCAT) pathway and their mediating effects on LC pathophysiology, has not been fully explored. Objective: This meta-analysis investigates peripheral TRP and TRYCAT levels and the TRYCAT pathway in patients with LC disease. Method: This review utilized systematic searches of PubMed, Google Scholar, and SciFinder, including 14 full-text articles and 1,167 participants, consisting of 480 patients with LC and 687 normal controls. Results: The results indicated a significant increase in the kynurenine (KYN)/TRP ratio, with a large effect size (standardized mean difference, SMD = 0.755; confidence intervals, CI: 0.119;1.392), in LC patients compared to normal controls. Additionally, LC patients exhibited a significant decrease in TRP levels (SMD = -0.520, CI: -0.793; -0.246) and an increase in KYN levels after imputing missing studies (SMD = 1.176, CI: 0.474; 1.877), suggesting activation of the Indoleamine 2,3-dioxygenase (IDO) enzyme and upregulation of the TRYCAT pathway. No significant elevation in TRYCAT-related neurotoxicity, kynurenic acid (KA)/KYN and 3-hydroxykynurenine (3-HK)/KYN ratios were observed in LC patients compared to normal controls. Conclusion: The current findings indicate that an activated TRYCAT pathway, characterized by decreased TRP levels and maybe elevated KYN levels, plays a significant role in the pathophysiology of LC.

The authors have declared no competing interest.

The study was funded by FF66 grant and a Sompoch Endowment Fund (Faculty of Medicine), MDCU (RA66/016) to MM, and Grant № BGRRP2.0040007С01 Strategic Research and Innovation Program for the Development of MUPLOVDIV(SRIPDMUP), Creation of a network of research higher schools, National plan for recovery and sustainability, European Union NextGenerationEU.

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Upon request, and subject to all authors' full consent, the corresponding author, MM, will respond to valid requests for the dataset employed in this meta-analysis, which will be provided in Excel file format.