Correlation between immune-related Tryptophan-Kynurenine pathway and severity of severe pneumonia and inflammation-related polyunsaturated fatty acids

Abstract

Background: Immune dysfunction and oxidative stress caused by severe pneumonia can lead to multiple organ dysfunction and even death, causing a significant impact on health and the economy. Currently, great progress has been made in the diagnosis and treatment of this disease, but the mortality rate remains high (approximately 50%). Therefore, there is still potential for further exploration of the immune response mechanisms against severe pneumonia.

Objective: This study analyzed the difference in serum metabolic profiles between patients with severe pneumonia and health individuals through metabolomics, aiming to uncover the correlation between the Tryptophan-Kynurenine pathway and the severity of severe pneumonia, as well as N-3/N-6 polyunsaturated fatty acids (PUFAs).

Methods: In this study, 44 patients with severe pneumonia and 37 health controls were selected. According to the changes in the disease symptoms within the 7 days of admission, the patients were divided into aggravation (n = 22) and remission (n = 22) groups. Targeted metabolomics techniques were performed to quantify serum metabolites and analyze changes between groups.

Results: Metabolomics analysis showed that serum kynurenine and kynurenine/tryptophan (K/T) were significantly increased and tryptophan was significantly decreased in patients with severe pneumonia; HETE and HEPE in lipids increased significantly, while eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), α-linolenic acid (linolenic acid, α-LNA), arachidonic acid (ARA), Dihomo-γ-linolenic acid (DGLA), and 13(s)-hydroperoxylinoleic acid (HPODE) decreased significantly. Additionally, the longitudinal comparison revealed that Linolenic acid, DPA, and Tryptophan increased significantly in the remission group, while and kynurenine and K/T decreased significantly. In the aggravation group, Kynurenine and K/T increased significantly, while ARA, 8(S)-hydroxyeicosatetraenoic acid (HETE), 11(S)-HETE, and Tryptophan decreased significantly. The correlation analysis matrix demonstrated that Tryptophan was positively correlated with DGLA, 12(S)-hydroxyeicosapentaenoic acid (HEPE), ARA, EPA, α-LNA, DHA, and DPA. Kynurenine was positively correlated with 8(S)-HETE and negatively correlated with DHA. Additionally, K/T was negatively correlated with DGLA, ARA, EPA, α-LNA, DHA, and DPA.

Conclusion: This study revealed that during severe pneumonia, the Tryptophan-Kynurenine pathway was activated and was positively correlated with the disease progression. On the other hand, the activation of the Tryptophan-Kynurenine pathway was negatively correlated with N-3/N-6 PUFAs.

Keywords: N-3/N-6 polyunsaturated fatty acids; indoleamine 2,3 dioxygenase; kynurenine; severe pneumonia.

Figure 1

Metabolic analysis of patients with severe pneumonia. (A) Partial least squares discriminant analysis (PLS‐DA) analysis showed a significant separation of serum metabolic phenotypes between patients with severe pneumonia and health people. (B) Volcano plot of targeted metabolomics analysis showed top serum metabolites that increased (red) or decreased (blue) in severe pneumonia compared to controls. (C) Heatmap analysis emphasized the significant changes in N‐3/N‐6 polyunsaturated fatty acids and the kynurenine pathway in patients with severe pneumonia compared with health people.

Figure 2

Tryptophan‐Kynurenine metabolic pathway was significantly affected by severe pneumonia, and the asterisk indicated the significance. (*p <.05; **p < .01; ***p < .001).

Figure 3

(A) The N‐6 fatty acid metabolic pathway. (B) The N‐3 fatty acid metabolic pathway. The asterisk indicates the significance. (*p < .05; **p < .01; ***p < .001).

Figure 4

Longitudinal time‐point comparison of severe pneumonia patients at various disease stages.

Figure 5

Correlation analysis between the Tryptophan‐Kynurenine pathway indicators and N‐3/N‐6 fatty acid metabolites. The asterisk indicates the significance (*p < .05; **p < .01; ***p < .001).