Effect of Dysglycemia on Urinary Lipid Mediator Profiles in Persons With Pulmonary Tuberculosis

Abstract

Background: Oxidized lipid mediators such as eicosanoids play a central role in the inflammatory response associated with tuberculosis (TB) pathogenesis. Diabetes mellitus (DM) leads to marked changes in lipid mediators in persons with TB. However, the associations between diabetes-related changes in lipid mediators and clearance of M. tuberculosis (Mtb) among persons on anti-TB treatment (ATT) are unknown. Quantification of urinary eicosanoid metabolites can provide insights into the circulating lipid mediators involved in Mtb immune responses.

Methods: We conducted a multi-site prospective observational study among adults with drug-sensitive pulmonary TB and controls without active TB; both groups had sub-groups with or without dysglycemia at baseline. Participants were enrolled from RePORT-Brazil (Salvador site) and RePORT-South Africa (Durban site) and stratified according to TB status and baseline glycated hemoglobin levels: a) TB-dysglycemia (n=69); b) TB-normoglycemia (n=64); c) non-TB/dysglycemia (n=31); d) non-TB/non-dysglycemia (n=29). We evaluated the following urinary eicosanoid metabolites: 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (major urinary metabolite of prostaglandin E2, PGE-M), tetranor-PGE₁ (metabolite of PGE2, TN-E), 9α-hydroxy-11,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (metabolite of PGD2, PGD-M), 11-dehydro-thromboxane B2 (11dTxB2), 2,3-dinor-6-keto-PGF₁α (prostaglandin I metabolite, PGI-M), and leukotriene E4 (LTE₄). Comparisons between the study groups were performed at three time points: before ATT and 2 and 6 months after initiating therapy.

Results: PGE-M and LTE₄ values were consistently higher at all three time-points in the TB-dysglycemia group compared to the other groups (p<0.001). In addition, there was a significant decrease in PGI-M and LTE₄ levels from baseline to month 6 in the TB-dysglycemia and TB-normoglycemia groups. Finally, TB-dysglycemia was independently associated with increased concentrations of PGD-M, PGI-M, and LTE₄ at baseline in a multivariable model adjusting for age, sex, BMI, and study site. These associations were not affected by HIV status.

Conclusion: The urinary eicosanoid metabolite profile was associated with TB-dysglycemia before and during ATT. These observations can help identify the mechanisms involved in the pathogenesis of TB-dysglycemia, and potential biomarkers of TB treatment outcomes, including among persons with dysglycemia.

Keywords: Mycobacterium tuberculosis; anti-tuberculosis treatment; dysglycemia; lipid mediators; urinary eicosanoids.

Figure 1

Comparison of the distribution of urinary eicosanoids between the study groups. Box plot depicting the distribution of eicosanoids (median and interquartile range) among TB-dysglycemia, TB, dysglycemic patients and non-TB/non-dysglycemia individuals at each timepoint. Groups were compared using Kruskal Wallis (for four groups) and Mann Whitney tests (for two groups). Individuals without TB (Dysglycemia and non-TB/non-dysglycemia groups) had only two visits (baseline and month 6). TB, tuberculosis; PGE-M, major urinary PGE₂ metabolite; PGD-M, major urinary PGD₂ metabolite; PGI-M, 2,3-dinor-6-keto-PGF_1α (PGI₂ Metabolite); 11dTxB2, 11-dehydro-thromboxane B₂ (TxB₂ urinary metabolite); TN-E, tetranor-PGE₁ (urinary PGE₂ metabolite); LTE₄, Leukotriene E₄.

Figure 2

Urinary eicosanoids levels through of study timepoints. Distribution of eicosanoids (each point represents group medians) in TB-dysglycemia, TB, dysglycemia and non-TB/non-dysglycemia groups across study visits. Timepoints were compared using Friedman or Wilcoxon test (when corresponding). Individuals without TB (Dysglycemia and non-TB/non-dysglycemia groups) had only two visits (baseline and month 6). Details of central dispersion and tendency of the data are shown in the Table S2. TB, tuberculosis; PGE-M, major urinary PGE₂ metabolite; PGD-M, major urinary PGD₂ metabolite; PGI-M, 2,3-dinor-6-keto-PGF_1α (PGI₂ Metabolite); 11dTxB2, 11-dehydro-thromboxane B₂ (TxB₂ urinary metabolite); TN-E, tetranor-PGE₁ (urinary PGE₂ metabolite); LTE₄, Leukotriene E₄.

Figure 3

(A) Spearman correlation analysis plots between HbA1c (%) and TB-dysglycemia, TB, dysglycemic patients and non-TB/non-dysglycemia individuals at baseline. Significant correlations (p< 0.05) are represented in red bars. (B) Network analysis of eicosanoids in TB and TB-dysglycemic patients in the baseline, month 2 (M2) and month 6 (M6) among patient from Brazil and South Africa. Red solid lines: positive significant correlations (Spearman correlation). (C) Network densities of each bootstrap were calculated for each study group and timepoint as described in Methods. TB, tuberculosis; Dys, dysglycemia; PGE-M, major urinary PGE₂ metabolite; PGD-M, major urinary PGD₂ metabolite; PGIõ-M, 2,3-dinor-6-keto-PGF_1α (PGI₂ Metabolite); 11dTxB2, 11-dehydro-thromboxane B₂ (TxB₂ urinary metabolite); TN-E, tetranor-PGE₁ (urinary PGE₂ metabolite); LTE₄, Leukotriene E₄.

Figure 4

Urinary eicosanoid levels and tuberculosis severity. Scatter plot depicting the distribution of eicosanoids (median and interquartile range) among TB-Dysglycemia and TB cases with cavitation (CAV+) and without cavitation (CAV-) at baseline. Groups were compared using Kruskal Wallis test. Only statistically significant differences are shown. PGE-M, major urinary PGE₂ metabolite; PGD-M, major urinary PGD₂ metabolite; PGI-M, 2,3-dinor-6-keto-PGF_1α (PGI₂ Metabolite); 11dTxB2, 11-dehydro-thromboxane B₂ (TxB₂ urinary metabolite); TN-E, tetranor-PGE₁ (urinary PGE₂ metabolite); LTE₄, Leukotriene E₄.

Figure 5

Multinomial logistic regression, adjusted for age (years), sex (male), country, PGD, PGIM, TNE, 11dTxB2, LTE4 and BMI assessed at baseline with the TB-dysglycemia condition. OR, Odds ratio; 95% CI, 95% confidence intervals; PGE-M, major urinary PGE₂ metabolite; PGD-M, major urinary PGD₂ metabolite; PGI-M, 2,3-dinor-6-keto-PGF_1α (PGI₂ Metabolite); 11dTxB2, 11-dehydro-thromboxane B₂ (TxB₂ urinary metabolite); TN-E, tetranor-PGE₁ (urinary PGE₂ metabolite); LTE₄, Leukotriene E₄.