Tryptophan catabolism reflects disease activity in human tuberculosis
Jeffrey M. Collins, Amnah Siddiqa, Dean P. Jones, Ken Liu, Russell R. Kempker, Azhar Nizam, N. Sarita Shah, Nazir Ismail, Samuel G. Ouma, Nestani Tukvadze, Shuzhao Li, Cheryl L. Day, Jyothi Rengarajan, James C.M. Brust, Neel R. Gandhi, Joel D. Ernst, Henry M. Blumberg, Thomas R. Ziegler
Jeffrey M. Collins, Amnah Siddiqa, Dean P. Jones, Ken Liu, Russell R. Kempker, Azhar Nizam, N. Sarita Shah, Nazir Ismail, Samuel G. Ouma, Nestani Tukvadze, Shuzhao Li, Cheryl L. Day, Jyothi Rengarajan, James C.M. Brust, Neel R. Gandhi, Joel D. Ernst, Henry M. Blumberg, Thomas R. Ziegler
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Research Article Infectious disease Metabolism

Tryptophan catabolism reflects disease activity in human tuberculosis

Abstract

There is limited understanding of the role of host metabolism in the pathophysiology of human tuberculosis (TB). Using high-resolution metabolomics with an unbiased approach to metabolic pathway analysis, we discovered that the tryptophan pathway is highly regulated throughout the spectrum of TB infection and disease. This regulation is characterized by increased catabolism of tryptophan to kynurenine, which was evident not only in active TB disease but also in latent TB infection (LTBI). Further, we found that tryptophan catabolism is reversed with effective treatment of both active TB disease and LTBI in a manner commensurate with bacterial clearance. Persons with active TB and LTBI also exhibited increased expression of indoleamine 2,3-dioxygenase-1 (IDO-1), suggesting IDO-1 mediates observed increases in tryptophan catabolism. Together, these data indicate IDO-1–mediated tryptophan catabolism is highly preserved in the human response to Mycobacterium tuberculosis and could be a target for biomarker development as well as host-directed therapies.

Authors

Jeffrey M. Collins, Amnah Siddiqa, Dean P. Jones, Ken Liu, Russell R. Kempker, Azhar Nizam, N. Sarita Shah, Nazir Ismail, Samuel G. Ouma, Nestani Tukvadze, Shuzhao Li, Cheryl L. Day, Jyothi Rengarajan, James C.M. Brust, Neel R. Gandhi, Joel D. Ernst, Henry M. Blumberg, Thomas R. Ziegler

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Figure 2

Tryptophan catabolism in persons with DS pulmonary TB disease in Georgia.

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Tryptophan catabolism in persons with DS pulmonary TB disease in Georgia...
(A) Plasma tryptophan concentrations were significantly lower in persons with DS pulmonary TB disease from Georgia (light blue; n = 89) versus controls without active TB disease (red; n = 57) and (B) significantly increased after 1, 2, and 4 months of DOT compared with baseline. The red line indicates the trend of the mean over time. (C) Plasma kynurenine concentrations were significantly higher in Georgian patients with DS-TB versus controls and (D) significantly declined after 1, 2, and 4 months of active TB treatment. (E) The plasma kynurenine/tryptophan (K/T) ratio was also significantly higher in patients with active TB versus controls and (F) declined with antibiotic therapy in a stepwise fashion. (G) The receiver operator characteristic curve (ROC) for the plasma K/T ratio demonstrated excellent classification accuracy for identification of pulmonary TB. Active TB cases from Georgia were compared with controls using a Wilcoxon rank-sum test. Changes in tryptophan, kynurenine, and the K/T ratio relative to baseline were compared using a Wilcoxon signed-rank test (*P ≤ 0.05, **P < 0.01, and ***P < 0.001). The AUC for the ROC curve was calculated using logistic regression with 2-fold crossvalidation. The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range.